Method for producing atomic quantum cluster derivatives - Patents.com

Abstract

The present invention relates to compounds of formula (I): (2y / z) [M x (GO3) y ](I)(wherein, [M x (GO3) y ] is an anion, and M x is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, G is Si or Ti, and y is an integer selected from 1, 2, 3, 4, 5, and 6, and the compound of formula (I) has no net charge. Additionally, the present invention is directed to compositions comprising the compound of formula (I), methods for making the compound of formula (I), uses of the compound of formula (I), and the compound of formula (I) for use as a pharmaceutical, second medical uses thereof, pharmaceutical compositions, kits of parts, and apoptotic agents comprising said compound of formula (I).

Description

[Technical Field]

[0001] The present invention relates to a method for producing atomic quantum cluster (AQC) derivatives. [Background technology]

[0002] The high catalytic activity of atomic quantum clusters (AQCs) compared to isolated atoms or nanoparticles is well known in the prior art [A. Corma et al., Nature Chemistry, Vol. 5, pp. 775-781, 2013]. Due to their potential applications in biosensors, electrocatalysis, magnetism, photoluminescence, and catalysis, there has been great interest in developing synthetic methods for producing AQCs. There are several methods for synthesizing stable AQCs and AQC derivatives: i) a top-down approach by etching small nanoparticles with excess strongly binding ligands; and ii) a bottom-up approach, which typically involves the use of strong reducing agents, in which strongly binding ligands are used to inhibit AQC growth. The use of organic ligands is usually required in both approaches. However, organic ligands can interfere with some important properties of AQCs, such as their catalytic properties. In addition, AQCs can catalyze the oxidation of the organic groups of the ligands, preventing their attachment. Additionally, AQCs containing organic ligands can easily decompose at temperatures above 100-200°C, resulting in cluster aggregation.

[0003] Therefore, despite reported synthetic methods, there remains a need in the art for new, simple, and scalable methods for producing different AQC derivatives in high concentrations and yields. Summary of the Invention

[0004] The present authors have synthesized compounds of formula (I) containing AQC and inorganic ligands, such as titanate or silicate, that overcome the drawbacks of AQCs containing organic ligands. In particular, compounds of formula (I) containing AQC and inorganic ligands are much more resistant to aggregation and agglomeration than bare AQC or AQCs bearing organic ligands, making it possible to create solutions with high concentrations of AQC derivatives. In addition, the use of inorganic ligands, such as titanate or silicate groups, does not interfere with the catalytic properties of the AQC. Furthermore, compounds of formula (I) containing AQC and inorganic ligands are stable at temperatures up to 700°C or even higher without losing their physicochemical and biological properties. As a result, the range of potential catalytic and therapeutic applications of the compounds is significantly enhanced / increased.

[0005] In addition, the authors of the present invention have developed a new method for the synthesis of compounds of formula (I) containing AQC and inorganic ligands, which shows higher product yields than synthetic methods without the presence of these ligands.

[0006] A first aspect of the present invention is a compound of formula (I) N (2y / z) [M x (GO3) y ] (I) (In the formula: N is at least a cation having one or two positive charges; z is 1 or 2; [M x (GO3) y ] is an anion, M x is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, optionally where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; G is Si, Ti, or a combination thereof; y is an integer selected from 1, 2, 3, 4, 5 and 6); The compounds of formula (I) have no net charge. The target is.

[0007] In a second aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: Atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10 zerovalent metal atoms, wherein the metal atoms are selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof; and "y" number formula (GO3 2- ), where G is Si or Ti, preferably metasilicate (SiO 2- ) or metatitanate (TiO3 2- ) wherein y is an integer selected from 1, 2, 3, 4, 5 and 6. represents an anion consisting of

[0008] Furthermore, in a third aspect, the present invention provides a method for producing a compound of formula (I), comprising the steps of: i.-·polar solvents, and Atomic quantum clusters (AQCs) of formula (II) M x (II) (In the formula, M x is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, optionally where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. a first solution comprising: a precursor compound, the precursor compound comprising at least one of Si or Ti preparing a ii. adding a precursor to the solution of step (i) to obtain a second solution; iii. Optionally, repeating steps (i) and / or (ii). Includes; The molar ratio between the precursor added in each step and the AQC in the solution of the previous step is in the range of 0.1 to 10 equivalents; Here's how.

[0009] In a further aspect, the present invention is directed to the use of a compound of formula (I) as a catalyst.

[0010] In an additional aspect, the present invention is directed to a compound of formula (I) for use as a pharmaceutical.

[0011] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and, together with the description, serve to explain the principles of the invention. [Brief explanation of the drawings]

[0012] [Figure 1] Calculation of the stability of the compounds [Cu5SiO3]2- and [Cu5(SiO3)2]4-. [Figure 2] Schematic representation of the structures of the compounds [Cu5SiO3]2- and [Cu5(SiO3)2]4-. [Figure 3] (i) Ag5-silicate atomic quantum cluster compounds, e.g., Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], (ii) Ag+ as a control, and (iii) % viability versus dose response curves for A549 cell results for cisplatin. [Figure 4] Figure 1 shows the % viability response data for A549 cell results to Ag+ used as a control, different concentrations of selumetinib, sotorasib, and different concentrations of Ag5-silicate atomic quantum cluster compound. [Figure 5] The percentage of inhibition test results for NCI-H358 cells is shown. [Figure 6] The percentage of inhibition test results against NCI-H23 cells is shown. [Figure 7]Figure 1 shows survival percentage results versus radiation dose for a five-atom Ag5-silicate atomic quantum cluster compound in combination with external radiation. [Figure 8] Shown are the results of % survival versus days after injection of the cell line for control samples (no treatment), historical controls, and samples treated with Ag5-silicate atomic quantum cluster compound. [Figure 9] Shown are the RLU (μg protein) results for A549-luc cells for control (untreated) samples and samples treated with cisplatin (4 mg / kg) and Ag5-silicate atomic quantum cluster compound (0.25 mg / kg). [Figure 10] Figure 1 shows the % inhibition results for (a) NCI-H358 cells and (b) NCI-H23 cells treated with untreated cells, treated with Ag+ as a control, treated with 10 μM of BI-3406 (Sos1 inhibitor) for 24 hours, different concentrations (2.6 μM and 4 μM) of 5-atom Ag5-silicate atomic quantum clusters for 1 hour, different concentrations of BI-3406 and 5-atom Ag5-silicate atomic quantum clusters, and a combination of BI-3406 and sotorasib. [Figure 11] Figure 1 shows the % viability versus micromolar (μM) Ag5-silicate atomic quantum cluster compound concentration for the A549 cell line compared to the % viability results of 2 μM selumetinib, AZ, and the combination of 2 μM selumetinib and Ag5-silicate atomic quantum cluster compound. [Figure 12] Figure 1 shows the % viability versus micromolar (μM) Ag5-silicate atomic quantum cluster compound concentration for the H359 cell line compared to the % viability results of 100 nM sotorasib and the combination of 100 nM sotorasib and Ag5-silicate atomic quantum cluster compound. [Figure 13] 1 shows the results for tumor size (%) over in vivo monitoring of tumor growth for control samples and samples treated with Ag5-silicate atomic quantum cluster compounds in a U87 orthotopic in vivo model. [Figure 14]Figure 1 shows the results of in vitro treatment of patient-derived glioblastoma multiforme (GBM) cell lines (20+ lines tested here) as a function of % viable cells vs. log10 μM of Ag5-silicate atomic quantum cluster compound. [Figure 15] Figure 1 shows the % cell viability versus micromolar concentration (μM) of Ag5-silicate atomic quantum cluster compounds in a patient-derived esophageal cancer cell line (KYSE350). [Figure 16] 4 shows the % cell viability by Dunnett's assay versus micromolar concentration of Ag5-silicate atomic quantum cluster compound for 72 hours of treatment. DETAILED DESCRIPTION OF THE INVENTION

[0013] With respect to the terms used in this disclosure, unless otherwise defined, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those skilled in the art. The meaning and scope of the terms should be clear; however, in the event of potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions.

[0014] As used herein, the term "about" or "approximately" refers to a slight variation of the specified value, preferably within 10% of the specified value. Nevertheless, the term "about" or "approximately" may mean a higher tolerance for variation, for example, depending on the experimental techniques used. Such variation of the specified value is understood by those skilled in the art and is within the context of the present invention. Furthermore, to explain more simply, some of the quantitative expressions described herein are not qualified by the term "about." Regardless of whether the term "about" is explicitly used, any quantity described herein is intended to indicate an actual given value, and also to indicate an approximation to such a given value that would be reasonably estimated based on ordinary skill in the art, including equivalents and approximations resulting from experimental and / or measurement conditions for such a given value.

[0015] Throughout this specification, unless the context requires otherwise, the term "consisting essentially of," and variations such as "consist essentially of," are intended to encompass the stated integer, step, group of integers, or group of steps to the exclusion of any other integer, step, group of integers, or group of steps that significantly affects the essential characteristics of the stated integer, step, group of integers, or group of steps.

[0016] The term "substantially free of" may be used to indicate a composition that is largely or completely free of the entity specifically named thereafter, or that at least does not contain the entity in such an amount that the entity affects the effectiveness, storage, usefulness with respect to necessary safety concerns, and / or stability of the composition.

[0017] A first aspect of the present invention is a compound of formula (I) N (2y / z) [M x (GO3) y ] (I) (In the formula: N is at least a cation having one or two positive charges; z is 1 or 2; [M x (GO3) y ] is an anion (In the formula, M x is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, optionally where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; G is Si, Ti, or a combination thereof; y is an integer selected from 1, 2, 3, 4, 5 and 6); The compounds of formula (I) have no net charge. The target is.

[0018] In one embodiment, N in the compound of formula (I) is a cation having one or two positive charges, preferably a metal cation, more preferably an alkali metal cation, an alkaline earth metal cation, or a combination thereof, even more preferably Li + , Na + , K. + , Ca 2+ , Mg 2+ and combinations thereof, preferably Na + or K + is.

[0019] In one embodiment, z in the compound of formula (I) is an integer selected from 1 or 2.

[0020] In one embodiment, the [M x (GO3) y ] is an anion, i.e., contains or is negatively charged.

[0021] In a more particular embodiment, the [M x (GO3) y ] is comprised of an atomic quantum cluster (AQC) consisting of 2, 3, 4, 5, 6, 7, 8, 9, or 10 zerovalent metal atoms containing anionic ligands (GO3), G is Si, Ti, or a combination thereof, and y is an integer selected from 1, 2, 3, 4, 5, and 6, and preferably (GO3) is SiO3 2- or TiO3 2- is.

[0022] In one embodiment, the [M x (GO3) y ]teeth, - atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 or 10 zerovalent metal atoms selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or their bimetallic and polymetallic combinations; and - at least inorganic ligands, e.g., SiO3 2- or TiO3 2- , preferably 1 to 6 inorganic ligands is an anion containing

[0023] In certain embodiments, the compounds of formula (I) have no net charge (are uncharged), preferably the net or total charge of said compounds is zero.

[0024] In one embodiment, the compound of formula (I) [M x (GO3) y ] anion M x is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms. In the context of the present invention, the term "cluster" refers to nanometer and / or subnanometer species consisting of well-defined structures of metal atoms with sizes below approximately 1-2 nm. Due to quantum effects, clusters exhibit distinct energy levels and band gaps that increase as the size of the AQC decreases.

[0025] In the context of the present invention, the term "atomic quantum cluster" or "AQC" refers to a group of two or more zerovalent metal atoms, preferably zerovalent transition metal atoms, according to the present invention. Atomic quantum clusters are also known in the art as "metal quantum clusters." In one embodiment, the AQC consists of identical (mononuclear clusters) or different (heteronuclear clusters) zerovalent transition metals. The term "metal" in the context of the present invention refers to elements of the periodic table known as "metals," particularly "transition metals," but does not refer to the electrical behavior of said elements. The limitations of electrodes in AQCs stem from the quantum separation of energy levels, which results in significant changes in the properties of these materials. Therefore, metal atoms in AQCs have semiconductor-like, or even insulating, behavior.

[0026] The AQC of the compound of formula (I) of the present invention is "M x ", where "M" represents a zero-valent metal element, and "x" represents the number of atoms of the zero-valent metal element in the AQC.

[0027] In one embodiment, M x The number of atoms x is less than 100 atoms, preferably less than 50, more preferably less than 40, even more preferably less than 30, and even more preferably less than 20 or less than 10.

[0028] In one embodiment, M x The number of atoms x is 2 or more and 40 or less, preferably 2 or more and 30 or less, and more preferably 2 or more and 15 or less.

[0029] In a more particular embodiment, M x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9 and 10, more preferably an integer selected from 3, 4, 5, 6, 7, 8, 9 and 10, preferably an integer selected from 3, 4, 5, 6, 7 and 8, more preferably the integers 4, 5, 6 and 7, even more preferably the integers 4, 5 and 6.

[0030] In one embodiment, the atomic quantum cluster (AQC) of the present invention, M x The average size of the AQCs is less than 2 nm, preferably less than 1.5 nm, more preferably less than 1 nm. In the context of the present invention, the average size of the AQCs may be calculated from measurements of a significant number of methods known in the art, such as microscopy, spectroscopy and mass spectrometry.

[0031] In one embodiment, the compound of formula M xis selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, preferably M is selected from Ag, Cu, Au and Pt, or bimetallic and polymetallic combinations thereof, more preferably M is Ag, Cu, or bimetallic combinations thereof, even more preferably Ag or Cu.

[0032] In one embodiment, (GO3) of the compound of formula (I) y is an inorganic ligand, in particular, (GO3) y is M x and preferably M x is covalently attached to

[0033] In one embodiment, (GO3) of the compound of formula (I) y is an ionic compound, preferably a silicate or titanate compound, more preferably a metasilicate (SiO 2- ) or metatitanate (TiO3 2- ) compounds, more preferably y is an integer selected from 1, 2, 3, 4, 5 and 6, preferably representing the number of metasilicate or metatitanate ions in the compound of formula (I).

[0034] In certain embodiments, the group (GO3) of the compound of formula (I) y is a ligand of Mx, which is an AQC, and is preferably an inorganic ligand, more preferably an anionic inorganic ligand.

[0035] In certain embodiments, the present invention provides a compound of formula (I) N (2y / z) [M x (GO3) y ] (I) (In the formula: N is Li + , Na + , K. + , Ca 2+ , Mg2+ or a combination thereof; z is 1 or 2; [M x (GO3) y ] is an anion (In the formula, M x is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; (GO3) is (SiO3 2- ) or (TiO3 2- an anionic compound selected from: y is an integer selected from 1, 2, 3, 4, 5 and 6); The compounds of formula (I) have no net charge. The target is.

[0036] In one embodiment, the compound of formula (I) is - atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 or 10 zerovalent metal atoms selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or their bimetallic and polymetallic combinations; At least anionic inorganic ligands, preferably 1 to 6 anionic inorganic ligands, more preferably the anionic inorganic ligands are titanates, silicates, or mixtures thereof, e.g., SiO 2- , TiO3 2- or a mixture thereof; and at least a counterion, preferably a cation, more preferably Li + , Na + , K. + , Ca 2+ , Mg 2+ or a combination thereof. Including, The compounds of formula (I) have no net charge.

[0037] In the context of the present invention, the compounds of formula (I) may be referred to as atomic quantum cluster (AQC) derivatives.

[0038] In one embodiment, the compound of formula (I) is - atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 or 10 zerovalent metal atoms selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or their bimetallic and polymetallic combinations; -1 to 6 SiO3 2- and / or TiO3 2- Ligand; and - at least a counterion, preferably Li + , Na + , K. + , Ca 2+ , Mg 2+ or a combination thereof It consists of The compounds of formula (I) have no net charge.

[0039] anions One aspect of the present invention is Atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10 zerovalent metal atoms, wherein the metal atoms are selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof; and "y" number formula (GO3 2- ), where G is Si or Ti, preferably metasilicate (SiO 2- ) or metatitanate (TiO3 2- ) wherein y is an integer selected from 1, 2, 3, 4, 5 and 6. The anion of interest is

[0040] In one embodiment, the anion is - atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 or 10 zerovalent metal atoms selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or their bimetallic and polymetallic combinations; and - at least inorganic ligands, e.g., SiO3 2- , TiO3 2- or mixtures thereof, preferably 1 to 6 inorganic ligands Includes.

[0041] In one embodiment, the anion is - atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 or 10 zerovalent metal atoms selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or their bimetallic and polymetallic combinations; and - at least inorganic ligands, e.g., SiO3 2- , TiO3 2- or mixtures thereof, preferably 1 to 6 inorganic ligands It consists of:

[0042] method One aspect of the present invention is a method for producing a compound of formula (I), comprising the steps of: i.-·polar solvents, and Atomic quantum clusters (AQCs) of formula (II) M x (II) (In the formula, M x is an atomic quantum cluster (AQC) consisting of "x" number of zerovalent metal atoms "M", optionally where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. a first solution comprising: a precursor compound, the precursor compound comprising at least one of Si or Ti preparing a ii. adding a precursor to the solution of step (i) to obtain a second solution; iii. Optionally, repeating steps (i) and / or (ii). Including, The molar ratio between the precursor added in each step and the AQC in the solution of the previous step is in the range of 0.1 to 10 equivalents; Target methods.

[0043] In certain embodiments, the polar solvent in step (i) is selected from water, methanol, ethanol, acetonitrile, chloroform, dichloromethane, acetic acid, toluene and mixtures thereof, preferably water, more preferably milli Q water.

[0044] Suitable atomic quantum clusters (AQCs) of formula (II) in step (i) include any commercially available AQCs or those obtained in laboratories by methods known in the art.In addition, some commercially available metal salts may already contain a small amount of AQCs, which can act as starting AQCs (Peyser, LA; Vinson, AE; Bartko, AP; Dickson, RM Science 2001, 291, 103-106).However, strict control of the amount of clusters present in metal salts is recommended to obtain reproducible results.

[0045] In certain embodiments, the atomic quantum cluster (AQC) of step (i) comprises "x" number of zerovalent metal atoms "M", where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0046] In certain embodiments, the atomic quantum cluster (AQC) of formula (II) in step (i) consists of "x" number of zerovalent metal atoms "M", where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0047] The atomic quantum clusters (AQCs) of formula (II) in step (i) of the process of the present invention are of formula M as defined above for the compounds of formula (I) of the present invention, including all specific embodiments thereof. x It has the same advantages and features as the AQC's.

[0048] In certain embodiments, the precursor compound of step (i) comprises at least one element selected from Si, Ti, or a combination thereof; preferably, the precursor compound comprises O and at least one of Si or T; more preferably, it is a silicate and / or titanate; even more preferably, it is a monosilicate and / or monotitanate; much more preferably, it is an alkali and / or alkaline earth monosilicate or monotitanate; and even much more preferably, it is a sodium monosilicate and / or monotitanate.

[0049] In certain embodiments, the first solution of step (i) is prepared by the following steps: a.-metal electrodes, optionally in which the metal is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and multimetallic combinations thereof; and -Solutions containing polar solvents providing a the electrode is in contact with the solution; b. applying an electric current to the electrodes of step (a) for at least 50 seconds to obtain a first solution comprising a polar solvent and an atomic quantum cluster of formula (II). The compound is obtained by a method comprising:

[0050] In certain embodiments, the metal of the electrode in step (a) is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and multimetallic combinations thereof, preferably Ag, Cu, Au and Pt, or bimetallic and multimetallic combinations thereof, more preferably Ag, Cu, or bimetallic combinations thereof, and even more preferably Ag or Cu.

[0051] In certain embodiments, the metal of the electrode in step (a) is oxide-free.

[0052] In certain embodiments, the metal electrode in step (a) is a polished metal electrode, preferably a polished metal electrode under wet conditions.

[0053] In certain embodiments, the metal electrode in step (a) is part of a cell further comprising a working electrode and a reference electrode, and the current in step (b) is obtained by applying a potential difference between the working electrode and the reference electrode. The working electrode and the reference electrode in step (b) can be any electrodes known in the art.

[0054] In certain embodiments, the reference electrode is a normal hydrogen electrode (NHE).

[0055] In a more specific embodiment, the potential difference between the working electrode and the reference electrode is 0.1 to 15 V, preferably 0.2 to 10 V, more preferably 0.5 to 8 V, even more preferably 1 to 3 V, even more preferably 1.1 to 2.5 V, and more preferably about 1.5 V.

[0056] In more particular embodiments, the potential difference between the working electrode and the reference electrode is applied for more than 50 seconds, preferably more than 100 seconds, more preferably more than 200 seconds, and even more preferably more than 300 seconds.

[0057] In a more specific embodiment, the potential difference between the working electrode and the reference electrode is applied for a period of 50 to 2000 seconds, preferably 100 to 1500 seconds, more preferably 200 to 1000 seconds, even more preferably 300 to 800 seconds, and even more preferably 400 to 600 seconds.

[0058] In a more particular embodiment, the current in step (b) is 20 A / cm 2 Less than, preferably 19 A / cm 2 less than, more preferably, 18 A / cm 2 is less than.

[0059] In a more specific embodiment, the current in step (b) is between 0.01 and 20 A / cm 2 , preferably 0.05 to 19 A / cm 2 , more preferably 0.08 to 18 A / cm 2 is.

[0060] In certain embodiments, step (b) is carried out at room temperature, preferably 15-35°C, more preferably 20-30°C, even more preferably about 25°C.

[0061] In certain embodiments, step (b) is carried out at atmospheric pressure (ie, 1 atm).

[0062] In a particular embodiment, step (b) is carried out under stirring, preferably at 200 rpm.

[0063] Process (ii) In certain embodiments, in step (ii), a precursor compound is added to the solution of step (i) to obtain a second solution.

[0064] In certain embodiments, step (ii) is carried out at room temperature, preferably 15-35°C, more preferably 20-30°C, even more preferably about 25°C.

[0065] In certain embodiments, step (ii) is carried out at atmospheric pressure (ie, 1 atm).

[0066] In a particular embodiment, step (ii) is carried out under stirring, preferably at 200 rpm.

[0067] In certain embodiments, the precursor compound is added to the solution of step (i) under stirring to obtain a second solution.

[0068] In certain embodiments, the molar ratio between the precursor compound added in a step and the AQC of the solution of the previous step is in the range of between 0.1 and 10 equivalents, preferably 0.2 to 9 equivalents, more preferably 0.5 to 8, even more preferably 0.8 to 7, even more preferably 0.9 to 6, more preferably about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 equivalents.

[0069] In certain embodiments, the molar ratio between the precursor compound added in step (n) and the AQC in the solution in step (n-1) is in the range of between 0.1 and 10, preferably 0.2 and 9, more preferably 0.5 and 8, even more preferably 0.8 and 7, even more preferably 0.9 and 6, more preferably about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6, where "n" is an integer.

[0070] In a more particular embodiment, the molar ratio between the precursor compound added in a step and the AQC of the solution of the previous step is in the range of 0.5 to 2, preferably about 1 equivalent.

[0071] Process (iii) In certain embodiments, step (iii) comprises repeating step (i) and step (ii) at least once, preferably at least twice, more preferably at least three times, more preferably at least five times.

[0072] In certain embodiments, step (iii), which consists of repeating step (i) and step (ii), is repeated at least once, preferably at least twice, more preferably at least three times.

[0073] In certain embodiments, the applied current is increased by at least 0.5%, preferably at least 1%, and more preferably at least 5% in each repetition of step (i).

[0074] In certain embodiments, step (iii) consists of repeating step (ii) at least once, preferably at least twice, more preferably at least three times, and even more preferably at least five times.

[0075] In another particular embodiment, step (iii) comprises repeating step (i) and step (ii) 2 to 100 times, preferably 3 to 50 times, more preferably 4 to 10 times.

[0076] In one embodiment, the molar ratio between the precursor added in each step and the AQC of the solution of the previous step is in the range of between 0.1 and 10 equivalents, preferably 0.2 to 9, more preferably 0.5 to 8, even more preferably 0.8 to 7, even more preferably 0.9 to 6, more preferably about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6.

[0077] In certain embodiments, the method comprises the steps of: i.-metallic electrodes, the electrodes of which are selected from Ag, Cu, Co, Au, Pt, Fe, Pd and Ni, or their bimetallic and multimetallic combinations, and which are part of a cell further comprising a working electrode and a reference electrode; and -Polar solvent solution wherein a metal electrode is in contact with the solution; ii. applying an electric current to the metal electrode of step (i) for 100 to 1000 seconds, A current is obtained by applying a potential difference between the working electrode and the reference electrode of 0.1 to 15 V, and the atomic quantum cluster (AQC) of formula (II) M x (II) wherein M is at least an element selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. obtaining a solution containing a polar solvent containing the compound; iii. adding a precursor compound to a solution of water, wherein the precursor compound comprises at least one of Si or Ti, preferably O and at least one of Si or Ti; iv. Repeating the sequence of steps (ii) and (iii) at least twice, more preferably at least three times. Including, The molar ratio between the precursor compound added in each step and the AQC in the solution of the previous step is between 0.1 and 10 equivalents, preferably in the range of 0.5 to 8 equivalents.

[0078] In certain embodiments, the molar ratio between the precursor compound added in each step and the AQC of the solution of the previous step is constant and preferably kept constant in each repetition.

[0079] In certain embodiments, the applied current is increased by at least 0.5%, preferably at least 1%, and more preferably at least 5% in each repetition of step (i).

[0080] According to the authors, the method for producing the compound of formula (I) of the present invention is a simple and inexpensive procedure, which can therefore be applied for large-scale production of the compound of formula (I).

[0081] One aspect of the present invention is directed to a composition comprising a compound of formula (I) as defined in any one of claims 1 to 6, or an anion of claim 7, and an additional agent or compound, preferably an additional therapeutic agent or compound.

[0082] First medical use In a further aspect, the present invention relates to a compound or anion of formula (I) as defined in any of the above embodiments for use as a medicament.

[0083] The above aspect may be formulated as the use of a compound or anion of formula (I) as defined in any of the above embodiments in the manufacture of a medicament.

[0084] The above aspects may be formulated as methods for treating or preventing a disease, the method comprising administering a compound of formula (I) or an anion as defined in any of the above embodiments to a patient in need of such prevention or treatment, preferably administering a therapeutically effective amount of said compound of formula (I) or said anion.

[0085] Additionally, a further aspect is directed to a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments, for use as a pharmaceutical.

[0086] The above aspect may be formulated as the use of a composition comprising a compound of formula (I) or an anion as defined in any of the above embodiments in the manufacture of a medicament.

[0087] The above aspects may be formulated as methods for treating or preventing a disease, the method comprising administering to a patient in need of such prevention or treatment a composition comprising a compound of formula (I) or an anion as defined in any of the above embodiments, preferably administering a therapeutically effective amount of said compound of formula (I) or said anion.

[0088] Secondary medical use In one aspect, the present invention relates to a compound or anion of formula (I) as defined in any of the above embodiments for use in the treatment or prevention of a cell proliferative disorder.

[0089] The above aspect may be formulated as the use of a compound or anion of formula (I) as defined in any of the above embodiments in the manufacture of a medicament for the prevention or treatment of a cell proliferative disorder, such as a tumor and / or cancer.

[0090] The above aspect may be formulated as the use of a compound or anion of formula (I) as defined in any of the above embodiments as a medicament for the prevention or treatment of a cell proliferative disorder, such as a tumor and / or cancer.

[0091] The above aspects may be formulated as methods for treating or preventing a cell proliferative disorder, such as a tumor and / or cancer, the method comprising administering to a patient in need of such prevention or treatment a compound or anion of formula (I) as defined in any of the above embodiments.

[0092] In another aspect, the invention relates to a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments for use in the treatment or prevention of a cell proliferative disorder, such as a tumor and / or cancer.

[0093] The above aspect may be formulated as the use of a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments in the manufacture of a medicament for the prevention or treatment of a cell proliferative disorder, such as a tumor and / or cancer.

[0094] The above aspect may be formulated as the use of a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments as a medicament for the prevention or treatment of a cell proliferative disorder, such as a tumor and / or cancer.

[0095] The above aspects may be formulated as methods for treating or preventing a cell proliferative disorder, such as a tumor and / or cancer, the method comprising administering to a patient in need of such prevention or treatment a compound of formula (I) or a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments.

[0096] Reference to a "cell proliferative disorder" refers to a disorder that results in new, abnormal growth of cells, or abnormal cell growth without physiological control. This can result in an unstructured mass, i.e., a tumor.

[0097] In one embodiment, the cell proliferative disorder is a tumor and / or cancer.

[0098] The compounds of formula (I) as defined in any of the above embodiments, anions, or compositions comprising said compounds or anions may be used to treat cell proliferative disorders, including but not limited to primary tumors, metastases, precancerous conditions (precancerous stages), endometriosis, and polycystic ovary syndrome.

[0099] Excessive cell proliferation and cell-matrix turnover contribute significantly to the pathogenesis of several diseases, including cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, and liver cirrhosis, among others.

[0100] Cancer may include, but is not limited to, spleen cancer, colorectal cancer and / or colon cancer, colon cancer, ovarian cancer, ovarian cancer, endometrial cancer, breast cancer, uterine carcinoma, lung cancer, stomach cancer, esophageal cancer, liver cancer, pancreatic carcinoma, kidney cancer, bladder cancer, prostate cancer, testicular cancer, bone cancer, thyroid cancer, skin cancer such as melanoma, sarcoma, Kaposi's sarcoma, brain cancer such as glioma, medulloblastoma or neuroblastoma, blood cancer such as lymphoma and leukemia, myosinoma, and head and neck cancer.In one embodiment, cancer is selected from lung cancer, breast cancer, colon cancer or brain cancer (particularly glioblastoma).In another embodiment, cancer is brain cancer, particularly brain cancer selected from glioma (such as glioblastoma multiforme, oligodendroglioma, ependymoma, brainstem glioma), craniopharyngioma, hemangioblastoma, malignant meningioma, pineal gland tumor and vestibular schwannoma. In still further embodiments, the brain cancer is a glioma, particularly a glioblastoma.

[0101] In another embodiment, the cell proliferative disorder is selected from the group consisting of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0102] In certain embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, blood cancers such as lymphoma and leukemia, lung cancer, skin cancer, endometrial cancer, thyroid cancer, gastric cancer, bladder cancer, head and neck cancer, colon cancer, brain cancer or breast cancer, preferably lung cancer, gastric cancer or brain cancer, in particular glioblastoma.

[0103] The present invention has particular use in treating cancers / tumors with RAS mutations, such as KRAS, NRAS, or HRAS mutations, particularly KRAS mutations. Such mutations have been shown to cause oxidative stress in tumor cells resulting in high levels of ROS; see, e.g., Shaw et al. (2011) PNAS 108(21):8773-8778.

[0104] Therefore, in one embodiment, cell proliferation disorder (for example, cancer and / or tumor) comprises RAS mutation.In a further embodiment, RAS mutation is selected from KRAS, NRAS or HRAS mutation, particularly KRAS mutation.It will be understood that such cancer / tumor can also be referred to as RAS mutant cancer, for example, KRAS, HRAS or NRAS mutant cancer or tumor.In yet a further embodiment, RAS mutation is activating mutation, that is, mutation causes increased activity or constitutive activity of RAS protein.

[0105] The RAS family of proteins are GTPases that hydrolyze GTP to GOP, enabling the activation of several downstream signaling pathways. For example, KRAS has been shown to be involved in the mitogen-activated kinase pathway. Common mutations in KRAS reduce its intrinsic GTPase function, preventing the hydrolysis of GTP to GOP, thus locking KRAS in its activated state. This results in the constitutive activation of downstream signaling pathways that can drive oncogenesis.

[0106] Many RAS mutations are known in the art, and KRAS mutation is the most frequent oncogenic mutation in human cancer.Cancer contains RAS mutation when one or more cells in cancer contain RAS mutation.The subject with RAS mutation can be identified by methods known in the art, such as PCR, nucleic acid sequencing, allele-specific PCR, single-strand conformation polymorphism analysis, melting curve analysis, probe hybridization, pyrosequencing (i.e., nucleotide extension sequencing), genotyping and other sequencing methods (see, for example, Anderson (2011) Expert Rev Mol Diagn.11(6):635-642 and Ogino et al. (2005) J.Mol.Diagn.7:413-421).

[0107] As shown herein, compounds of formula (I) containing AQC and an inorganic ligand have a toxic effect on A549 cell lines, which contain KRAS mutations (such as KRAS G12S, in which the glycine residue at position 12 is mutated). Furthermore, cells containing HRAS mutations (HRasV12, in which the valine residue at position 12 is mutated) were more sensitive to the toxic effects of compounds of formula (I) containing AQC and an inorganic ligand compared to control cells.

[0108] An estimated 30% of all human cancers harbor RAS mutations, including 88% of pancreatic ductal adenocarcinomas, 52% of colorectal cancers, 43% of multiple myelomas, 32% of lung adenocarcinomas, 28% of melanomas, 25% of endometrial cancers, 13% of thyroid cancers, 12% of gastric cancers, 11% of acute myeloid leukemias, 11% of bladder cancers, 6% of head and neck squamous cell carcinomas, and 2% of breast cancers (data pooled from the Cancer Cell Line Encyclopedia (CCLE); International Cancer Genome Consortium (ICGC); and The Cancer Genome Atlas Data Portal (TCGA)).

[0109] Thus, in one embodiment, the cell proliferative disorder (particularly, a cell proliferative disorder with a RAS mutation) is selected from pancreatic cancer, colorectal cancer, blood cancer, lung cancer, skin cancer, endometrial cancer, thyroid cancer, gastric cancer, bladder cancer, head and neck cancer, or breast cancer. In a further embodiment, the cell proliferative disorder (particularly, a cell proliferative disorder with a RAS mutation) is selected from pancreatic cancer, colorectal cancer, blood cancer, lung cancer, skin cancer, endometrial cancer, thyroid cancer, gastric cancer, bladder cancer, or head and neck cancer, preferably lung cancer.

[0110] In one embodiment, cell proliferation disorder is pancreatic cancer, for example, pancreatic ductal adenocarcinoma, particularly RAS mutant pancreatic cancer, for example, RAS mutant pancreatic ductal adenocarcinoma.In another embodiment, cell proliferation disorder is colorectal cancer, particularly RAS mutant colorectal cancer.In another embodiment, cell proliferation disorder is blood cancer, for example, multiple myeloma or acute myeloid leukemia, particularly RAS mutant blood cancer, for example, RAS mutant multiple myeloma or RAS mutant acute myeloid leukemia.In another embodiment, cell proliferation disorder is lung cancer, for example, non-small cell lung cancer, for example, lung adenocarcinoma, particularly RAS mutant lung cancer, for example, RAS mutant non-small cell lung cancer, for example, RAS mutant lung adenocarcinoma.In another embodiment, cell proliferation disorder is skin cancer, for example, melanoma, particularly RAS mutant skin cancer, for example, RAS mutant melanoma.

[0111] In alternative embodiments, the cell proliferative disorder is endometrial cancer, particularly RAS mutant endometrial cancer.In alternative embodiments, the cell proliferative disorder is thyroid cancer, particularly RAS mutant thyroid cancer.In alternative embodiments, the cell proliferative disorder is gastric cancer, particularly RAS mutant gastric cancer.In alternative embodiments, the cell proliferative disorder is bladder cancer, particularly RAS mutant bladder cancer.In alternative embodiments, the cell proliferative disorder is head and neck cancer, for example, head and neck squamous cell carcinoma, particularly RAS mutant head and neck cancer, for example, RAS mutant head and neck squamous cell carcinoma.

[0112] The present invention has particular use in the treatment of cancers with low drug accessibility, such as large tumors with low levels of vascularity or brain tumors that are separated from the circulatory system by the blood-brain barrier. This is due to the neutral charge and small size of the therapeutic compounds of formula (I) containing AQC and inorganic ligands, allowing them to access areas of tumors or cancers that are not easily accessible to traditional anti-neoplastic drugs.

[0113] Evidence is provided herein demonstrating the ability of compounds of formula (I) to penetrate the central hypoxic region of multicellular tumor spheroids.

[0114] Preventing and treating cancer metastasis is an important part of cancer treatment to prevent secondary cancer and recurrence.Surprisingly, it has been found that the compound of formula (I) has additional beneficial effects of treating cancer metastasis and primary tumor.

[0115] Thus, according to one aspect of the present invention, there is provided a compound of formula (I) as described herein, or a composition comprising a compound of formula (I), for use in the prevention and / or treatment of metastasis, e.g., lymph node metastasis, particularly for treating and / or preventing lung cancer metastasis. According to another aspect of the present invention, there is provided a composition as described herein for use in the prevention and / or treatment of cancer lymph node metastasis.

[0116] In a further embodiment, the lymph nodes are mediastinal lymph nodes, which are a group of lymph nodes located in the thoracic cavity of the body.

[0117] Combination therapy One aspect of the present invention is directed to a composition comprising a compound of formula (I) of the present invention as described in any of its specific embodiments, an anion, and an additional agent, preferably an additional therapeutic agent.

[0118] The compositions described herein can be used in combination with the compounds or anions of formula (I) of the present invention described in any of its specific embodiments.It has been found that compounds of formula (I) can intercalate into DNA and cause chromatin decompression.This can therefore be used to increase the sensitivity of treated cells to radiation and improve the effectiveness of radiation therapy.

[0119] In one embodiment, a compound or anion of formula (I) of the present invention (referred to as a first agent) is administered simultaneously with an additional agent. In this embodiment, the two agents are administered at the same time or substantially the same time. They may also be administered by the same route, optionally in the same composition. Alternatively, they may be administered at the same time or substantially the same time, but by different routes, i.e., separately.

[0120] In alternative embodiments, the composition of the present invention and the compound of formula (I) or anion are administered sequentially.In this embodiment, the two agents are administered at different times, so that one agent is administered before the second agent.For example, the composition can be administered before or after the compound of formula (I) or anion of the present invention.They can be administered by the same or different routes.

[0121] According to another aspect of the present invention, there is provided either a compound of formula (I) of the present invention, an anion, or a composition comprising a compound of formula (I) or an anion of the present invention, in combination with radiation therapy, for use in the treatment of a cell proliferative disorder.

[0122] The present inventors have surprisingly found that the compounds or anions of formula (I) of the present invention have a catalytic effect on thiol oxidation, which leads to cell destruction. Thus, the compounds or anions of formula (I) of the present invention may themselves be used as cancer therapies, and therefore, in one embodiment, the compositions described herein do not contain an additional anti-neoplastic agent.

[0123] In one embodiment, the composition of the present invention comprising the compound or anion of formula (I) of the present invention may contain an additional therapeutic agent or may be used in combination with an additional therapeutic agent. Such an agent may be an active agent used in conjunction with cancer therapy, for example, a drug used as a palliative treatment to improve unwanted side effects. Thus, in one embodiment, the additional therapeutic agent is a drug used as a palliative treatment. In a further embodiment, the palliative treatment is selected from the group consisting of antiemetics, drugs intended to improve pain such as opioids, drugs used to reduce high blood uric acid levels such as allopurinol or rasburicase, antidepressants, sedatives, anticonvulsants, laxatives, antidiarrheals, and / or antacids.

[0124] In one embodiment, the additional therapeutic agent is not an anti-neoplastic agent. In an alternative embodiment, the additional therapeutic agent is an anti-neoplastic agent. In one embodiment, the anti-neoplastic agent is selected from the group consisting of alkylating agents (e.g., nitrogen mustard analogs, nitrosoureas, alkylsulfonates, platinum-containing compounds, ethylemines, and imidazotetrazines), cytotoxic antibiotics (e.g., anthracyclines, actinomycin), plant alkaloids and other natural products (e.g., camptothecin derivatives, epipodophyllotoxins, taxanes, and vinca alkaloids), antimetabolites (e.g., cytidine analogs, folic acid analogs, purine analogs, pyrimidine analogs, urea derivatives), and drugs for targeted therapy (e.g., kinase inhibitors and monoclonal antibodies).

[0125] In one embodiment, the compound, anion, or composition of formula (I) of the present invention (as a first agent) and an additional therapeutic agent are administered simultaneously. In this embodiment, the two agents are administered at the same time or substantially the same time. They may also be administered by the same route, optionally in the same composition. Alternatively, they may be administered at the same time or substantially the same time, but by different routes, i.e., separately.

[0126] In an alternative embodiment, the composition and the additional therapeutic agent are administered sequentially. In this embodiment, the two agents are administered at different times, such that one agent is administered before the second agent. They can be administered by the same or different routes.

[0127] In one embodiment, the composition is administered before the additional therapeutic agent, hi an alternative embodiment, the composition is administered after the additional therapeutic agent.

[0128] In a further aspect, the invention relates to a compound or anion of formula (I) as defined in any of the above embodiments for use in the treatment or prevention of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0129] In a further aspect, the invention relates to a composition comprising a compound of formula (I) or an anion as defined in any of the above embodiments for use in the treatment or prevention of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0130] The above aspects may be formulated as the use of a compound of formula (I) or anion as defined in any of the above embodiments as a medicament for the prevention or treatment of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0131] The above aspects may be formulated as the use of a composition comprising a compound of formula (I) or anion as defined in any of the above embodiments as a medicament for the prevention or treatment of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0132] The above aspect may be formulated as the use of a compound or anion of formula (I) as defined in any of the above embodiments in the manufacture of a medicament for the prevention or treatment of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0133] The above aspect may be formulated as the use of a composition comprising a compound of formula (I) or an anion as defined in any of the above embodiments in the manufacture of a medicament for the prevention or treatment of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver.

[0134] The above aspects may be formulated as methods for treating or preventing atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and liver cirrhosis, the method comprising administration of a compound or anion of formula (I) as defined in any of the above embodiments to a patient in need of such prevention or treatment.

[0135] The above aspects may be formulated as methods for treating or preventing atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome and cirrhosis of the liver, preferably atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and cirrhosis of the liver, the method comprising administering to a patient in need of such prevention or treatment a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments.

[0136] In a further aspect, the invention relates to a compound or anion of formula (I) as defined in any of the above embodiments for use in the treatment or prevention of infections, such as yeast infections and / or fungal infections, including topical and systemic fungal infections.

[0137] In a further aspect, the invention relates to a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments for use in the treatment or prevention of infections, such as yeast infections and / or fungal infections, including topical and systemic fungal infections.

[0138] The above aspects may be formulated as the use of a compound or anion of formula (I) as defined in any of the above embodiments in the manufacture of a medicament for the prevention or treatment of infections, such as yeast infections and / or fungal infections, including local and systemic fungal infections.

[0139] The above aspects may be formulated as the use of a composition comprising a compound of formula (I) or anion as defined in any of the above embodiments in the manufacture of a medicament for the prevention or treatment of infections, such as yeast infections and / or fungal infections, including local and systemic fungal infections.

[0140] The above aspects may be formulated as the use of a compound or anion of formula (I) as defined in any of the above embodiments as a medicament for the prevention or treatment of infections, such as yeast infections and / or fungal infections, including local and systemic fungal infections.

[0141] The above aspects may be formulated as the use of a composition comprising a compound of formula (I) or anion as defined in any of the above embodiments as a medicament for the prevention or treatment of infections, such as yeast infections and / or fungal infections, including local and systemic fungal infections.

[0142] The above aspects may be formulated as methods for treating or preventing infections, such as yeast infections and / or systemic and localized fungal infections, the method comprising administering to a patient in need of such prevention or treatment a compound or anion of formula (I) as defined in any of the above embodiments.

[0143] The above aspects may be formulated as methods for treating or preventing infections, such as yeast infections and / or systemic and localized fungal infections, the method comprising administering to a patient in need of such prevention or treatment a composition comprising a compound or anion of formula (I) as defined in any of the above embodiments.

[0144] In one embodiment, the infection is caused by yeast overgrowth, in which case the compounds or anions of formula (I) according to the invention are used for "yeast infection".

[0145] In another embodiment, the fungal infection can be a localized or systemic infection.

[0146] In certain embodiments, the topical fungal infection is a fungal infection of the skin and mucous membranes.

[0147] In another embodiment, the fungal infection is an Aspergillus fungal infection.

[0148] The term "treatment" or "to treat" in the context of this specification means the administration of a compound of formula (I) or anion as defined in any of the above embodiments to ameliorate or eliminate a disease or disorder, or one or more symptoms associated with said disease or disorder. "Treatment" also encompasses ameliorating or eliminating the physiological sequelae of a disease or disorder.

[0149] In the context of this specification, the term "prevention" or "to prevent" means reducing the risk of acquiring or developing a disease or disorder, or one or more symptoms associated with said disease or disorder.

[0150] The terms "effective amount," "therapeutically effective amount," or "effective dose" refer to an amount sufficient to induce the desired pharmacological or therapeutic effect, thus resulting in effective prevention or treatment of a disorder. Prevention of a disorder is manifested by delaying the onset of symptoms of the disorder to a medically significant extent. Treatment of a disorder is manifested by a decrease in symptoms associated with the disorder or an amelioration of the recurrence of symptoms of the disorder.

[0151] The authors observed that compounds of formula (I) containing AQC and inorganic ligands such as titanates or silicates exhibit a similar mechanism of action for the treatment and prevention of diseases than bare AQC or AQC containing organic ligands. The activity of compounds of formula (I) was confirmed by the results obtained in the examples included in this patent application. Interestingly, compounds of formula (I) containing AQC and inorganic ligands are much more stable in solution and more resistant to aggregation and agglomeration than naked or bare AQC or AQC with organic ligands. In addition, the production method results in compounds of formula (I) containing AQC and inorganic ligands with fewer contaminants than similar bare AQC or AQC with organic ligands.

[0152] Radiation therapy Radiation therapy (also called radiation therapy) uses high doses of radiation to damage cell DNA, thus killing cancer cells and shrinking tumors.This therapy can be in the form of external radiation or internal radiation therapy.The choice of radiation therapy can depend not only on the type of cancer, tumor size, tumor location, but also on other factors, such as the patient's age, overall health and medical history, and the type of other cancer treatments used.

[0153] Radiation therapy is administered for over 50% of all cancers worldwide and is particularly important in emerging and middle-income countries. However, the effectiveness of radiation therapy is limited by a variety of factors, including damage to healthy surrounding tissue, proximity to nearby organs, and tumors that develop radiation resistance. Therefore, there is a significant unmet need for agents to improve the effectiveness of radiation therapy.

[0154] The application of radiotherapy to cancer cells leads to an increase in the production of ROS.As shown by the evidence provided herein, the effect of the compound or anion of formula (I) defined in any of the above embodiments is enhanced in the presence of ROS.Therefore, the compound or anion of formula (I) defined in any of the above embodiments is particularly suitable as a therapeutic agent for enhancing the effectiveness of radiotherapy.

[0155] According to one aspect of the present invention, there is provided a compound of formula (I), an anion, or a composition comprising a compound or anion of formula (I), as defined in any of the above embodiments, as described herein, in combination with radiation therapy for use in the treatment of a cell proliferative disorder, such as cancer.

[0156] Radiation therapy (also called radiation therapy) uses high doses of radiation to damage cell DNA, thus killing cancer cells and shrinking tumors.This therapy can be in the form of external radiation or internal radiation therapy.The choice of radiation therapy can depend on the type of cancer, tumor size, tumor location, and also other factors, such as patient's age, overall health and medical history, and the type of other cancer treatments used.

[0157] According to one aspect of the present invention, there is provided the use of a compound of formula (I), an anion, or a composition comprising a compound of formula (I), as defined in any of the above embodiments, as a radiotherapy sensitizer.

[0158] According to another aspect of the present invention, there is provided the use of a compound of formula (I), an anion, or a composition comprising a compound or anion of formula (I), as defined in any of the above embodiments, as a radiotherapy sensitizer for proliferating cells. It will be understood that the term "radiotherapy sensitizer," also referred to as "radiosensitizer," refers to a drug used to enhance / increase the cytotoxic effect of radiotherapy. Cancers or tumors that are affected by radiotherapy are referred to as "radiosensitive."

[0159] According to another aspect, the present invention provides a compound of formula (I), an anion, or a composition comprising a compound of formula (I) or an anion, as defined in any of the above embodiments, for use as a radiotherapy desensitizing agent for non-proliferating cells.

[0160] The compound of formula (I), an anion, or composition comprising a compound of formula (I) or anion as defined in any of the above embodiments may be used to protect non-proliferating (such as non-dividing) cells from radiation therapy. It will be understood that the term "radiation therapy desensitizing agent," also referred to as "radiation desensitizer," refers to an agent used to reduce / reduce the cytotoxic effects of radiation therapy.

[0161] The compounds of formula (I), anions, or compositions comprising compounds or anions of formula (I) as defined in any of the above embodiments are therefore particularly advantageous when used in combination with radiation therapy, as they have the dual effect of enhancing the effects of radiation therapy on proliferating cells (i.e., cancer cells), while protecting non-proliferating cells (i.e., non-diseased cells) from harmful radiation.

[0162] References to "proliferation" will be understood by those skilled in the art. As used herein, "proliferating cells" refer to cells undergoing cell proliferation, e.g., cell growth and division. In particular, the present invention is used to target cancer cells with rapid, abnormal, and / or uncontrolled cell proliferation. In one embodiment, proliferating cells are cancer cells, progenitor cells, or other abnormal, rapidly dividing cells in a subject. Also, as used herein, "non-proliferating cells" refer to cells not undergoing cell proliferation. These cells may also be described as "quiescent," "arrested," "quiescent," "non-dividing," "non-cycling," or "Go cells." In one embodiment, non-proliferating cells are non-cancerous cells.

[0163] Radiation therapy can be in the form of external radiation or internal radiation therapy. In one embodiment, radiation therapy involves external radiation therapy. External radiation therapy uses a radiation source external to the patient, typically either a radioisotope, such as cobalt-60 (Co), cesium-137 (Cs), or a high-energy x-ray source, such as a linear accelerator (LINAC). The external source generates a collimated beam directed at the tumor site in the patient. The adverse effects of irradiating healthy tissue can be reduced by projecting the external radiation beam onto the patient at various "gantry" angles and focusing the beam at the tumor site, while maintaining a given radiation dose in the tumorous tissue.

[0164] Examples of external radiation therapy treatments include, but are not limited to, conformal radiation therapy, intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), four-dimensional radiation therapy (40-RT), stereotactic radiation therapy and radiosurgery, proton therapy, electron beam radiation therapy, and matched radiation therapy.

[0165] In an alternative embodiment, radiation therapy comprises internal radiation therapy. In this embodiment, a radiopharmaceutical agent is administered to the patient and placed in the area to be treated. In one embodiment, the radiopharmaceutical agent comprises a radiation-emitting radioisotope. Radioisotopes are well known to those skilled in the art and can include metallic or non-metallic radioisotopes.Suitable metallic radioisotopes include, but are not limited to, actinium-225, antimony-124, antimony-125, arsenic-14, barium-103, barium-140, beryllium-1, bismuth-206, bismuth-207, bismuth-212, bismuth-213, cadmium-109, cadmium-115m, calcium-45, cerium-139, cerium-141, cerium-144, cesium-137, chromium-51, cobalt-55, cobalt-56, cobalt-57, cobalt-58, cobalt-60, cobalt-64, copper- 60, Copper-62, Copper-64, Copper-67, Erbium-169, Europium-152, Gallium-64, Gallium-67, Gallium-68, Gadolinium-153, Gadolinium-157, Gold-195, Gold-199, Hafnium-175, Hafnium-175-181, Holmium-166, Indium-110, Indium-111, Iridium-192, Iron-55, Iron-59, Krypton-85, Lead-203, Lead-210, Lutetium-177, Manganese-54, Mercury-197, Mercury-203, Molybdenum-99, Neodymium-147, Neptunium-237, Nickel Kel-63, Niobium-95, Osmium-185+191, Palladium-103, Palladium-109, Platinum-195m, Praseodymium-143, Promethium-147, Promethium-149, Protactinium-233, Radium-226, Rhenium-186, Rhenium-188, Rubidium-86, Ruthenium-97, Ruthenium-103, Ruthenium-105, Ruthenium-106, Samarium-153, Scandium-44, Scandium-46, Scandium-47, Selenium-75, Silver-10m, Silver-111, Sodium-22, Strontium Examples of suitable metals include tungsten-185, vanadium-85, strontium-89, strontium-90, sulfur-35, tantalum-182, technetium-99m, tellurium-125, tellurium-132, thallium-204, thorium-228, thorium-232, thallium-170, tin-113, tin-114, tin-117m, titanium-44, tungsten-185, vanadium-48, vanadium-49, ytterbium-169, yttrium-86, yttrium-88, yttrium-90, yttrium-91, zinc-65, zirconium-89, and zirconium-95.

[0166] Suitable non-metallic radioisotopes include, but are not limited to, iodine-131, iodine-125, iodine-123, phosphorus-32, astatine-211, fluorine-18, carbon-11, oxygen-15, bromine-76, and nitrogen-13.

[0167] The type of radiation suitable for use in the present invention can vary. In one embodiment, radiation therapy includes electromagnetic radiation or particle radiation. Electromagnetic radiation includes, but is not limited to, x-rays and gamma rays. Particle radiation includes, but is not limited to, electron beams (beta particles), alpha particles, proton beams, neutron beams, and negative pion beams.

[0168] In one embodiment, radiation therapy includes brachytherapy. In brachytherapy, a radiation source is placed directly at the site of the cancer or tumor. This has the advantage that the radiation only affects a very localized area, thereby minimizing exposure of healthy tissue to radiation. Furthermore, this allows tumors to be treated with very high doses of localized radiation while reducing the possibility of unnecessary damage to surrounding healthy tissue.

[0169] In one embodiment, brachytherapy includes intracavitary or interstitial therapy. Intracavitary therapy involves placing a container holding a radioactive source in a body cavity where the tumor is located or near where the tumor is located. Interstitial therapy involves placing a container holding a radioactive source directly into the tumor or body tissue. These radioactive sources can remain in the patient permanently. In most cases, the radioactive source is removed from the patient after a few days. The container may include a needle, seed, wire, or catheter.

[0170] In one embodiment, radiotherapy comprises systemic radioisotope therapy. In systemic radioisotope therapy, a radiopharmaceutical agent containing a radioisotope is delivered by injection or ingestion. The administered radioisotope can be targeted due to the chemical properties of the isotope, for example, radioactive iodine, which is preferentially absorbed by the thyroid gland. Targeting can also be achieved by conjugating the radioisotope to a targeting moiety, for example, a molecule or antibody that binds to the target tissue. In one embodiment, the radiopharmaceutical agent comprises a radioconjugate. In a further embodiment, the radioconjugate is a radiolabeled antibody.

[0171] In one embodiment, the radiopharmaceutical agent is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, bucally, intranasally, via inhalation, vaginally, intraocularly, topically, subcutaneously, intraadiposely, intraarticularly or intrathecally. In one embodiment, the radiopharmaceutical agent is in a delayed release dosage form.

[0172] The choice of radiation therapy may depend on the type of cancer, the size of the tumor, the location of the tumor, and other factors, such as the patient's age, overall health and medical history, and the types of other cancer treatments being used.

[0173] In one embodiment, the composition and radiation therapy are applied simultaneously.In an alternative embodiment, the composition and radiation therapy are applied sequentially, preferably the composition is applied before radiation therapy.When the agents are administered separately, radiation therapy can be administered while the composition is still effective, that is, the composition and radiation therapy are administered within a time frame that shows synergistic effect or at least combined effect when administered to patients.In one embodiment, the composition is administered 6 hours or less before radiation therapy, for example, 1 to 6 hours before radiation therapy.

[0174] In further embodiments, the composition is administered about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour before radiation therapy.

[0175] In one embodiment, the therapeutic effects of the composition and radiation therapy are synergistic, hi one embodiment, the composition sensitizes cancer cells in the patient to radiation therapy.

[0176] In one embodiment, the compositions of the invention can improve the effectiveness of radiation therapy by at least two-fold, e.g., three-fold, four-fold, five-fold, or more, compared to the effectiveness of radiation therapy for the treatment of the disorder alone.

[0177] Pharmaceutical Composition According to one aspect of the present invention, there is provided a pharmaceutical composition comprising the composition described herein.

[0178] Compositions and combinations may, where appropriate, be formulated as pharmaceutical compositions, optionally containing a pharmaceutically acceptable excipient, diluent, or carrier. The carrier, diluent, and / or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0179] Examples of pharmaceutically acceptable carriers may include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc., and combinations thereof. Suitable pharmaceutical carriers, excipients, or diluents are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Pharmaceutically acceptable carriers may further contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compositions of the present invention. Pharmaceutical compositions may also include anti-adherents, binders, coatings, disintegrants, flavors, colorants, lubricants, adsorbents, preservatives, sweeteners, lyophilization excipients (including lyophilization protectants), or compression aids.

[0180] The pharmaceutical compositions of the present invention can be administered in a number of dosage pharmaceutical forms, for example, as a solid (e.g., tablet, pill, granule, etc.) or liquid (e.g., solution, suspension, syrup, ointment, cream, gel, or emulsion).

[0181] The pharmaceutical composition of the present invention can comprise a therapeutically effective amount.The therapeutically effective amount (i.e., the amount that can help or produce the effect of curing the disorder being treated) that can be administered to a subject depends on several factors, such as the disease state, age, sex, and weight of the individual, and the ability of the pharmaceutical composition to induce a desired response in the individual.The therapeutically effective amount is also one in which any toxic or harmful effects of the pharmaceutical composition of the present invention are outweighed by the therapeutically beneficial effects.

[0182] In one embodiment, the compound of formula (I) as defined in any of the above embodiments is present in an aqueous solution. In a further embodiment, the aqueous solution contains dissolved oxygen, for example, at least two times, or at least three times the concentration of the compound of formula (I) present in the mixture.

[0183] In one embodiment, the composition is administered (or formulated for administration) by any suitable mode of delivery, for example, intravenously, intraarterially, intracardially, intradermally, subcutaneously, transdermally, intraperitoneally, intramuscularly, orally, lingually, sublingually, bucally, rectally, or by enema.

[0184] The compositions of the present invention can be administered directly to the target site (i.e., tumor site) or systemically (i.e., into the circulatory system). Targeted administration has the advantage of concentrating the therapeutic effect of the composition on the cancer or tumor being treated. Such administration also minimizes side effects. However, the compositions of the present invention are also suitable for systemic administration because their mechanism of action ensures that cell apoptosis occurs only in cells with high levels of ROS. ROS levels are high in proliferating cells, such as cancerous cells. However, in normal non-proliferating cells, ROS levels are relatively low, and therefore the compounds of formula (I) have a lower effect on normal cells, which helps minimize harmful side effects.

[0185] In one embodiment, the composition is administered orally, intravenously, or subcutaneously. In a further embodiment, the composition is administered orally. The advantage of the compositions of the present invention is that they can be depleted relatively quickly, and therefore, any side effects can be minimized because the compound of formula (I) does not persist in the body for a long period of time.

[0186] Local application is also possible (for example, for the treatment of melanoma).A particular form of local application is that the composition is introduced into a carrier system, particularly a drug delivery system, and the carrier system is embedded in cancerous tissue, and the carrier system then specifically releases the composition at the site of cancerous tissue.In this way, it is possible to avoid the side effects that may occur in the case of systemic administration, that is, to reduce the overall burden on the body.

[0187] use According to one aspect of the present invention, there is provided the use of a compound or anion of formula (I) or a composition comprising a compound or anion of formula (I) described herein for the treatment of a cell proliferative disorder.

[0188] According to one aspect of the present invention, the use of the composition described herein is provided for treating and / or preventing metastasis of cancer.In one embodiment, the composition is used for treating and / or preventing lymph node metastasis of cancer.In another embodiment, the composition is used for treating and / or preventing metastasis of lung cancer.

[0189] According to one aspect of the present invention, there is provided the use of a compound or anion of formula (I) described herein, or a composition comprising a compound or anion of formula (I), as a radiotherapy sensitizer for proliferative cells. The agent may be used for the treatment of cell proliferative disorders.

[0190] According to an aspect of the present invention, there is provided the use of a compound or anion of formula (I) or a composition comprising a compound or anion of formula (I) as described herein in combination with radiation therapy for the treatment of a cell proliferative disorder.

[0191] According to one aspect of the present invention, there is provided the use of a compound or anion of formula (I) described herein, or a composition comprising a compound or anion of formula (I), in the manufacture / preparation of a radiotherapy sensitizer for proliferative cells.

[0192] According to one aspect of the present invention, there is provided the use of a compound or anion of formula (I) described herein, or a composition comprising a compound or anion of formula (I), as a radiotherapy desensitizing agent for non-proliferating cells.

[0193] According to one aspect of the present invention, there is provided a compound or anion of formula (I) as described herein, or a composition comprising the compound or anion of formula (I), for the preparation of a pharmaceutical composition for the treatment of a cell proliferative disorder.

[0194] According to one aspect of the present invention, there is provided the use of a compound or anion of formula (I) or a composition comprising a compound or anion of formula (I) described herein in the manufacture of a medicament for the treatment of a cell proliferative disorder.

[0195] Treatment methods According to one aspect of the present invention, there is provided a method for preventing and / or treating a cell proliferative disorder, the method comprising administering to a patient in need thereof a compound or anion of formula (I) or a composition comprising a compound or anion of formula (I) as described herein.

[0196] In one embodiment, the method does not include treating the patient with an additional anti-neoplastic agent.

[0197] According to one aspect of the present invention, there is provided a method for preventing and / or treating a cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or anion of formula (I) described herein, or a composition comprising a compound or anion of formula (I).

[0198] According to one aspect of the present invention, there is provided a method of treating a patient having a cell proliferative disorder, comprising administering a compound or anion of formula (I) described herein, or a composition comprising a compound or anion of formula (I). The embodiments described previously herein for the compound or anion of formula (I) described herein, or a composition comprising a compound or anion of formula (I), can be applied to the method of treatment (e.g., timing and mode of administration, formulation of the composition, etc.).

[0199] According to one aspect of the present invention, there is provided a method for preventing and / or treating cancer metastasis, comprising administering a compound or anion of formula (I) described herein or a composition comprising a compound or anion of formula (I). In one embodiment, the method prevents and / or treats lymph node metastasis of cancer. In a further embodiment, the method prevents and / or treats lung cancer metastasis.

[0200] In one embodiment, the methods of treatment described herein additionally include treating the patient with radiation therapy, e.g., after administering the composition. As previously described herein, the compounds or anions of formula (I) described herein, or compositions comprising compounds or anions of formula (I), have particular use as radiation therapy sensitizers.

[0201] In one embodiment, the compounds or anions of Formula (I) described herein, or compositions comprising compounds of Formula (I), are administered orally, intravenously, or subcutaneously.

[0202] In one embodiment, a compound or anion of Formula (I) described herein, or a composition comprising a compound of Formula (I), is administered simultaneously with or prior to radiation therapy.

[0203] The patient can be any subject suffering from a disorder. In one embodiment, the patient is a mammal. In a further embodiment, the mammal is selected from a human or a mouse.

[0204] In one embodiment, the therapeutic effects of the composition and radiation therapy are synergistic. In one embodiment, the compound or anion of Formula (I) described herein, or a composition comprising a compound of Formula (I), sensitizes cancer cells in a patient to radiation therapy.

[0205] The method involves administering a therapeutically effective amount of radiation. The amount of radiation used in radiation therapy is measured in Gray (Gy) and varies depending on the type and stage of the cancer being treated. Furthermore, the total dose of radiation may be divided into multiple smaller doses known as "fractions" over a period of several days to minimize negative side effects. A typical fractionation schedule for adults is 1.8 to 2 Gy per day, 5 days per week. A typical fractionation schedule for children is 1.5 to 1.8 Gy per day, 5 days per week.

[0206] In one embodiment, a total dose of at least about 10 Gy, e.g., 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, 60 Gy, 65 Gy, 70 Gy, 75 Gy, 80 Gy, 85 Gy, 90 Gy, 95 Gy, or 100 Gy, is administered to a patient in need thereof. The patient may receive radiation three, four, or five times per week. The entire course of treatment may last from one to several weeks, depending on the type of cancer and the goals of treatment. In one embodiment, radiation therapy is administered for a period of at least 2, 3, or 4 weeks, e.g., 2 to 6 weeks, e.g., 2 to 4 weeks, or 5 to 8 weeks, particularly 5 to 7 weeks. For example, a patient may receive a dose of 2 Gy / day for about 30 days (i.e., 4 to 5 weeks).

[0207] In one embodiment, radiation is administered at least once a day for 5 consecutive days a week. For example, radiation is administered at least once a day in fractions of at least about 2 Gy. In one embodiment, radiation is administered every other day, 3 times a week. For example, radiation is administered in fractions of 10 Gy, 3 times a week, every other day.

[0208] In one embodiment, radiation therapy is hypofractionated. Hypofractionation is a treatment regimen in which higher doses of radiation are delivered in fewer visits. In an alternative embodiment, radiation therapy is hyperfractionated.

[0209] Hyperfractionation is a treatment regimen in which the total dose is divided into more deliveries. It will be appreciated that many other factors will be considered when selecting the dose, including whether the patient is receiving chemotherapy, the patient's comorbidities, whether radiation therapy is administered before or after surgery, and the success of the surgery.

[0210] According to another aspect, the present invention provides a method of preventing damage to non-proliferating cells in a patient undergoing radiation therapy, comprising administering to the patient prior to radiation therapy a therapeutically effective amount of a compound or anion of formula (I) as described herein, or a composition comprising a compound of formula (I).

[0211] According to an aspect of the present invention, there is provided a method of treating metastasis, e.g., lymph node metastasis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or anion of formula (I) described herein, or a composition comprising a compound of formula (I), in combination with radiation therapy.

[0212] kit According to one aspect of the invention, there is provided a kit of parts comprising a compound or anion of formula (I) as described herein, or a composition comprising a compound of formula (I), optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The kit according to this aspect of the invention may be used in the treatment of a cell proliferative disorder.

[0213] In one embodiment, the kit can be used in combination with radiation therapy for the treatment of cell proliferative disorders.

[0214] Additional Aspects According to one aspect of the present invention, there is provided an apoptotic agent comprising a compound or anion of formula (I) described herein, or a composition comprising a compound of formula (I). The apoptotic agent can comprise a composition described herein.

[0215] According to another aspect of the present invention, there is provided a method of inducing thiol oxidation comprising administering a compound or anion of formula (I) as described herein, or a composition comprising a compound of formula (I), optionally in combination with reactive oxygen species (ROS).

[0216] Other uses In a further aspect, the present invention is directed to the use of a compound or anion of formula (I) as described herein, or a composition comprising a compound or anion of formula (I), as a catalyst, preferably as a redox catalyst or photocatalyst.

[0217] The above aspects may be formulated as a method of catalysis for a chemical reaction comprising contacting at least one of the reactants of the chemical reaction catalyzed by a compound or anion of formula (I) as defined in any of the above embodiments, or a composition comprising the compound or anion.

[0218] Throughout this disclosure and claims, the word "comprises" and variations of that word are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprises" encompasses instances of "consisting of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the present invention.

[0219] The present invention will now be described in further detail with reference to the following examples, which are for illustrative purposes only and are not intended to limit the scope of the invention. [Example]

[0220] The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

[0221] Example 1: Cu in water 5 -Electrochemical synthesis of silicate atomic quantum clusters Cu5-silicate atomic quantum clusters were synthesized in water as follows.

[0222] Two copper electrodes (copper foil, 99.9% Cu, 50 × 50 × 50 mm, glued with Araldite on glass slides) were polished with cling film under wet conditions until a smooth and completely oxide-free surface was obtained.

[0223] The electrodes were then placed in a beaker with milli-Q water and sonicated for 5 minutes in an ultrasonic bath at a temperature not exceeding 30° C. to prevent oxidation of the copper foil, and then thoroughly washed with milli-Q water.

[0224] Two copper electrodes (at least one of which served as the working electrode WE) and a standard hydrogen electrode (NHE) reference electrode were placed in their corresponding positions in a glass beaker with a PTFE cap and filled with 250 mL of milli-Q water (while stirring) to form a cell. The beaker was then closed with a cap and placed in a constant temperature water bath at 25°C. Potentiostat wires were then connected to their corresponding electrodes, and a starting speed of 200 rpm was set.

[0225] The following steps were then carried out. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 0.100–0.500 mA). -31.25 μL of a sodium monosilicate solution in water ([Si]=4 g / L) was added to the beaker to obtain a concentration of [Si]=0.5 mg / L. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 0.500–1 mA). - 62.5 μL of a sodium monosilicate solution in water ([Si] = 4 g / L) was added to the beaker to obtain a concentration of [Si] = 1.5 mg / L. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 1–6 mA). - 93.75 μL of a sodium monosilicate solution in water ([Si] = 4 g / L) was added to the beaker to obtain a concentration of [Si] = 3 mg / L. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 3.5–11 mA). - 125 μL of sodium monosilicate solution in water ([Si] = 4 g / L) was added to the beaker to obtain a concentration of [Si] = 5 mg / L. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 4–15 mA). - 187.5 μL of a sodium monosilicate solution in water ([Si] = 4 g / L) was added to the beaker to obtain a concentration of [Si] = 8 mg / L. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 8–17 mA). - 125 μL of a sodium monosilicate solution in water ([Si] = 4 g / L) was added to the beaker to obtain a final concentration of [Si] = 10 mg / L. A voltage of −1.5 V (WE vs. NHE) was applied for 500 seconds (intensity range: 10–20 mA).

[0226] The wires were then cut from the caps and the electrodes were removed from the beakers. The resulting compounds were then transferred to glass bottles for characterization and stored at room temperature, preferably in the absence of light.

[0227] According to previous synthesis methods, Cu5-silicate atomic quantum cluster compounds, such as Na2[Cu5SiO3] or Na4[Cu5(SiO3)2], were synthesized in water.

[0228] Example 2 Using a method similar to that described in Example 1, five-atom Ag5-silicate atomic quantum cluster compounds, e.g., [Ag5SiO3], in water were prepared. 2- or [Ag5(SiO3)2] 4- and at least a counter ion (e.g., a cation such as sodium). Instead of a copper electrode, a silver electrode was used.

[0229] The authors of the present invention have reported that SiO3 2- or TiO3 2- It was observed that AQC derivatives containing a ligand and at least a counterion (e.g., a cation such as sodium) were more stable in solution than bare AQC or AQC stabilized with organic ligands, and showed reduced or no agglomeration. 2- or TiO3 2-AQC derivatives, which include a ligand and at least a counterion, are not adsorbed onto glass or other glassy surfaces, thus facilitating their study, purification, and manipulation.

[0230] Example 3: Efficacy of Ag5-silicate atomic quantum cluster compounds as anticancer agents against A549 lung cancer cells (KRAS mutant cell line) The efficacy as anticancer agents of five-atom Ag5-silicate atomic quantum cluster compounds with at least a counterion (e.g., a cation such as sodium), e.g., Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], prepared as described in Example 2, was tested. Note that these compounds are more succinctly named Ag5-silicate atomic quantum cluster compounds.

[0231] A549 cells were treated with Ag5-silicate atomic quantum cluster compounds for 1 hour or cisplatin for 48 hours. Ag+ was also used as a control. Cell viability was measured 48 hours after the start of treatment in all cases. Figure 3 shows the resulting curves of % viability versus dose response (expressed as micromolar concentration) for A549 cells in response to (i) Ag5-silicate atomic quantum cluster compounds, (ii) Ag+ as a control, and (iii) cisplatin. The results demonstrate high cell killing at low concentrations of Ag5-silicate atomic quantum cluster compounds. A549 cells are adenocarcinoma human alveolar basal epithelial cells, i.e., lung cancer cells.

[0232] Additionally, Figure 4 shows the viability % response data for the results of A549 cells to Ag+ used as a control, different concentrations of selumetinib, sotorasib, and different concentrations of Ag5-silicate atomic quantum cluster compound.

[0233] Selumetinib is known in the art as a small molecule inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1 / 2). Sotorasib is known in the art as being indicated for the treatment of KRAS G12C mutation-positive non-small cell lung cancer.

[0234] As shown herein, Ag5-silicate atomic quantum cluster compounds have been shown to have toxic effects on A549 cell lines, which contain KRAS mutations (such as KRAS G12S, in which the glycine residue at position 12 is mutated).

[0235] Example 4: Combined efficacy of Ag5-silicate atomic quantum cluster compounds and multi-targeted therapy in several cancer cell lines The combined efficacy of five-atom Ag5-silicate atomic quantum cluster compounds, e.g., Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], prepared as described in Example 2, with multi-targeted therapy in several cancer cell lines was tested.

[0236] Figure 5 shows (a) the % inhibition results for NCI-H358 cells (lung cancer) that were untreated, treated with Ag+ as a control, sotorasib (a G12C Kras inhibitor) at 100 nM for 24 hours, different concentrations (2.6 μM and 4 μM) of five-atom Ag5-silicate atomic quantum clusters for 1 hour, and a combination of sotorasib and five-atom Ag5-silicate atomic quantum clusters at different concentrations; and (b) the % inhibition results for NCI-H358 cells (lung cancer) that were treated with Ag+ as a control, RMC-4630 (a Shp2 inhibitor) at 10 μM for 24 hours, different concentrations (2.6 μM and 4 μM) of five-atom Ag5-silicate atomic quantum clusters for 1 hour, a combination of RMC-4630 and five-atom Ag5-silicate atomic quantum clusters at different concentrations, and a combination of sotorasib and RMC-4630. Cell viability was measured 48 hours after the start of treatment.

[0237] Figure 6 shows (a) the % inhibition results for NCI-H23 cells (lung cancer) that were untreated, treated with Ag+ as a control, sotorasib (a G12C Kras inhibitor) at 100 nM for 24 hours, different concentrations (1.0 μM and 1.5 μM) of five-atom Ag5-silicate atomic quantum clusters for 1 hour, and a combination of sotorasib and five-atom Ag5-silicate atomic quantum clusters at different concentrations; and (b) the % inhibition results for NCI-H23 cells (lung cancer) that were treated with Ag+ as a control, RMC-4630 (a Shp2 inhibitor) at 10 μM for 24 hours, different concentrations (1.5 μM and 2 μM) of five-atom Ag5-silicate atomic quantum clusters for 1 hour, a combination of RMC-4630 and five-atom Ag5-silicate atomic quantum clusters at different concentrations, and a combination of sotorasib and RMC-4630. Cell viability was measured 48 hours after the start of treatment.

[0238] Results show that the combined efficacy of five-atom Ag5-silicate atomic quantum cluster compounds, such as Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], with multiple targeted therapies in several cancer cell lines confers additive or greater-than-additive treatment benefits, which are clearly not predictable. This effect is seen in multiple cell lines with multiple agents, such as the mek inhibitor selumetinib, the SOS1 inhibitor BI-3406, cisplatin, and doxorubicin.

[0239] Example 5: Ag5-Silicate Atomic Quantum Cluster Compound Amplifies the Therapeutic Effect of Multiple Modalities of External Beam Radiation in Several Cell Types The therapeutic effects of five-atom Ag5-silicate atomic quantum cluster compounds, e.g., Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], and external irradiation were tested in several cell lines using a clonogenic assay of cell viability.

[0240] Figure 7 shows the survival rate versus radiation dose results for combining a five-atom Ag5-silicate atomic quantum cluster compound with external beam radiation. The results in Figure 6 demonstrate that the Ag5-silicate atomic quantum cluster compound amplifies the cell killing effect of photon beam radiation therapy in (a) the human glioblastoma U251 GBM cell line, (b) the human A549 cancer cell line, and (c) the U251 cell line. In addition, the Ag5-silicate atomic quantum cluster compound has the same amplifying effect when co-administered with proton beam radiation.

[0241] Example 6: In vivo efficacy of Ag5-silicate atomic quantum cluster compounds in an orthotopic lung cancer model (A549 KRASmut G12S, Keap1mut) at primary tumor and metastatic sites The in vivo efficacy of Ag5-silicate atomic quantum cluster compounds, e.g., Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], was tested in an orthotopic lung cancer model (A549 cells are KRASmut, SMARCA4mut, Keap1mut) of primary tumors and metastatic sites.

[0242] FIG. 8 shows the results of % survival versus days after injection of the cell line for control samples (no treatment), historical controls, and samples treated with Ag5-silicate atomic quantum cluster compounds.

[0243] FIG. 9 shows the RLU (μg protein) results for A549-luc cells for control (untreated) samples and samples treated with cisplatin (4 mg / kg) and Ag5-silicate atomic quantum cluster compound (0.25 mg / kg).

[0244] Results demonstrated high efficacy of treatment with Ag5-silicate atomic quantum cluster compounds in a difficult-to-treat orthotopic model, with evidence of enhanced efficacy in metastatic deposits. Additionally, the MTD was not reached.

[0245] Example 7: Combined efficacy of Ag5-silicate atomic quantum cluster compounds and multi-targeted therapy in several cancer cell lines The combined efficacy of five-atom Ag5-silicate atomic quantum cluster compounds, e.g., Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], prepared as described in Example 2, with multi-targeted therapy in several cancer cell lines was tested.

[0246] Figure 10 shows (a) % inhibition results for NCI-H358 cells (lung cancer) untreated, treated with Ag+ as a control, treated with 10 μM amount of BI-3406 (Sos1 inhibitor) for 24 hours, different concentrations (2.6 μM and 4 μM) of 5-atom Ag5-silicate atomic quantum clusters for 1 hour, different concentrations of BI-3406 and 5-atom Ag5-silicate atomic quantum clusters in combination, and a combination of BI-3406 and sotorasib; and (b) Percent inhibition results for NCI-H23 cells (lung cancer) untreated, treated with Ag+ as a control, treated with 10 μM of BI-3406 (Sos1 inhibitor) for 24 hours, different concentrations (2.6 μM and 4 μM) of 5-atom Ag5-silicate atomic quantum clusters for 1 hour, different concentrations of BI-3406 and 5-atom Ag5-silicate atomic quantum clusters in combination, and a combination of BI-3406 and sotorasib. Cell viability was measured 48 hours after the start of treatment.

[0247] Example 8: Orthogonal Combinations of Ag5-Silicate Atomic Quantum Cluster Compounds Across Treatment Modalities Orthogonal combinations of Ag5-silicate atomic quantum cluster compounds, such as Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], across treatment modalities were tested.

[0248] FIG. 11 shows the % viability versus micromolar (μM) Ag5-silicate atomic quantum cluster compound concentration for the A549 cell line compared to the % viability results of 2 μM selumetinib, AZ, and the combination of 2 μM selumetinib and Ag5-silicate atomic quantum cluster compound.

[0249] FIG. 12 shows the % viability versus micromolar (μM) Ag5-silicate atomic quantum cluster compound concentration for the H359 cell line compared to the % viability results for 100 nM sotorasib and the combination of 100 nM sotorasib and Ag5-silicate atomic quantum cluster compound.

[0250] Example 8: Ag5-silicate atomic quantum cluster compounds are tested for the treatment of glioblastoma multiforme Ag5-silicate atomic quantum cluster compounds, such as Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], were tested for the treatment of glioblastoma multiforme.

[0251] FIG. 13 shows the results for tumor size (%) over in vivo monitoring of tumor growth for control samples and samples treated with Ag5-silicate atomic quantum cluster compounds in a U87 orthotopic in vivo model.

[0252] FIG. 14 shows the results of % viable cells vs. log10 μM of Ag5-Silicate Atomic Quantum Cluster Compound in in vitro treatment of patient-derived glioblastoma multiforme (GBM) cell lines (20+ lines tested here).

[0253] Example 9: Ag5-silicate atomic quantum cluster compounds are tested for the treatment of gastric and gastroesophageal cancer Ag5-silicate atomic quantum cluster compounds, such as Na2[Ag5SiO3] or Na4[Ag5(SiO3)2], were tested for the treatment of gastric and gastroesophageal cancer.

[0254] FIG. 15 shows % cell viability versus micromolar concentration (μM) of Ag5-silicate atomic quantum cluster compounds in a patient-derived esophageal cancer cell line (KYSE350).

[0255] FIG. 16 shows the percent cell viability by Dunnett's assay versus micromolar concentration of Ag5-silicate atomic quantum cluster compound for 72 hours of treatment.

Claims

1. Compounds of formula (I): N （２ｙ／ｚ） [M ｘ (GO ３ ) ｙ ] (I) (In the formula: N is at least a cation having one or two positive charges; z is 1 or 2; [M ｘ (GO ３ ) ｙ ] is an anion (In the formula, M ｘ is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, optionally M is a zerovalent metal element selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; G is Si, Ti, or a combination thereof; y is an integer selected from 1, 2, 3, 4, 5 and 6; The compounds of formula (I) have no net charge.

2. 2. The compound of formula (I) according to claim 1, wherein M is selected from Ag, Cu, Au and Pt, or bimetallic and polymetallic combinations thereof, preferably M is Ag, Cu, or bimetallic combinations thereof.

3. 10. A compound of formula (I) according to any preceding claim, wherein x is an integer selected from 3, 4, 5, 6, 7 and 8, more preferably 4, 5 and 6.

4. 10. A compound of formula (I) according to the preceding claims, wherein y is 1 or 2.

5. 10. The compound of formula (I) according to the preceding claim, wherein N is an alkali metal cation, an alkaline earth metal cation, or a combination thereof, preferably N is selected from Li, Na, K, Ca, Mg, or a combination thereof.

6. N is an alkali metal cation or an alkaline earth metal cation; z is 1 or 2; M ｘ is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, M is selected from Ag, Pt, Cu and Au, and x is an integer selected from 3, 4, 5, 6, 7, 8, 9 and 10; G is Si or Ti; y is an integer selected from 1, 2, 3, 4, 5 and 6; A compound of formula (I) according to claim 1.

7. Atomic quantum clusters (AQCs) consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10 zerovalent metal atoms, wherein the metal atoms are selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof; and - "y" number formula (GO ３ ２－ ) anionic ligands, where G is Si or Ti, preferably metasilicate (SiO ３ ２- ) or metatitanate (TiO ３ ２- ) wherein y is an integer selected from 1, 2, 3, 4, 5 and 6; An anion consisting of

8. A process for producing a compound of formula (I) as defined in any one of claims 1 to 6, comprising the following steps: i. - a first solution, polar solvents, and Atomic quantum clusters (AQCs) of formula (II) M ｘ (II) (In the formula, M ｘ is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, optionally where M is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. a first solution comprising: a precursor compound, said precursor compound comprising at least one of Si or Ti; preparing a ii. adding the precursor compound to the solution of step (i) to obtain a second solution; iii. Optionally, repeating steps (i) and / or (ii). Including, The method, wherein the molar ratio between the precursor compound added in each step and the AQC of the solution of the previous step is in the range of 0.1 to 10 equivalents, preferably 0.5 to 8 equivalents.

9. The solution of step (i) is subjected to the following steps: a. - a metal electrode, optionally wherein the metal is selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and multimetallic combinations thereof; and - Solutions containing polar solvents preparing a the metal electrode is in contact with the solution; b. Applying a current to the electrodes of step (a) for at least 50 seconds to separate the polar solvent and the atomic quantum clusters (AQCs) of formula (II) M ｘ (II) (In the formula, M ｘ is an atomic quantum cluster (AQC) consisting of x number of zerovalent metal atoms, optionally where M is selected from Ag, Co, Cu, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. obtaining a solution comprising 9. The method of claim 8, obtained by a process comprising:

10. 10. The method of claim 9, wherein the metal electrode in step (a) is part of a cell further comprising a working electrode and a reference electrode, and the current in step (b) is obtained by applying a potential difference between the working electrode and the reference electrode.

11. The method according to claim 10, wherein the potential difference is between 0.1 and 15 V, preferably between 0.2 and 10 V.

12. 12. The process according to claims 8 to 11, wherein the polar solvent in step (i) or (a) is selected from water, acetonitrile, chloroform, dichloromethane, acetic acid, ethanol, methanol, isopropyl alcohol, and mixtures thereof, preferably water.

13. The following steps: i. - a metal electrode, wherein the metal of said metal electrode is selected from Ag, Cu, Co, Au, Pt, Fe, Pd and Ni, or bimetallic and multimetallic combinations thereof, and said metal electrode is part of a cell further comprising a working electrode and a reference electrode; and -Polar solvent solution preparing a the metal electrode being in contact with the polar solvent solution; ii. applying a current to the metal electrode of step (i) for 100 to 1000 seconds, wherein the current applies a potential difference between the working electrode and the reference electrode of 0.1 to 15 V to produce atomic quantum clusters (AQCs) of formula (II) M ｘ (II) wherein M is at least an element selected from Ag, Cu, Co, Au, Pt, Fe, Pd, Ni, or bimetallic and polymetallic combinations thereof, and x is an integer selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10. obtaining a solution containing a polar solvent containing iii. adding a precursor compound to a solution of water, wherein the precursor compound comprises at least one of Si or Ti, preferably a monotitanate or monosilicate precursor; iv. Repeating steps (ii) and / or (iii) at least twice. Including, 13. The method according to claims 8 to 12, wherein the molar ratio between the precursor compound added in each step and the AQC of the solution of the previous step is between 0.1 and 10 equivalents, preferably in the range of 0.5 to 8 equivalents.

14. A composition comprising a compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, and an additional compound or agent, preferably an additional therapeutic compound or agent.

15. Use of a compound of formula (I) as defined in any one of claims 1 to 6, or an anion of claim 7, or a composition of claim 14 as a catalyst, preferably as a redox reaction catalyst or as a photocatalyst.

16. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use as a pharmaceutical.

17. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use in the treatment or prevention of a cell proliferative disorder.

18. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use in the treatment or prevention of tumors.

19. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use in the treatment or prevention of cancer.

20. 15. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use in the treatment or prevention of spleen cancer, pancreatic cancer, colorectal and / or colon cancer, colon cancer, ovarian cancer, ovarian cancer, endometrial cancer, breast cancer, uterine carcinoma, lung cancer, stomach cancer, esophageal cancer, liver cancer, pancreatic carcinoma, kidney cancer, bladder cancer, prostate cancer, testicular cancer, bone cancer, thyroid cancer, skin cancer such as melanoma, brain cancer such as sarcoma, Kaposi's sarcoma, glioma, medulloblastoma or neuroblastoma, blood cancers such as lymphoma and leukemia, myosin, and head and neck cancer.

21. 21. The compound, anion or composition of formula (I) for use according to claim 20, wherein the cancer is selected from pancreatic cancer, colorectal and / or colon cancer, colon cancer, blood cancers such as lymphoma and leukemia, lung cancer, skin cancer, endometrial cancer, thyroid cancer, stomach cancer, bladder cancer, head and neck cancer, colon cancer, brain cancer such as glioma, medulloblastoma or neuroblastoma, or breast cancer.

22. 22. The compound, anion or composition of formula (I) for use according to claim 21, wherein the cancer is selected from lung cancer, gastric cancer or brain cancer such as glioma, medulloblastoma or neuroblastoma, in particular glioblastoma.

23. 15. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use in the treatment or prevention of atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, endometriosis, polycystic ovary syndrome, and liver cirrhosis.

24. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7 or a composition of claim 14 for use in the treatment or prevention of infections, preferably yeast infections and / or fungal infections.

25. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14 for use in the treatment or prevention of metastasis.

26. 16. A compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14, in combination with radiation therapy, for use in the treatment of a cell proliferative disorder such as cancer.

27. Use of a compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7 or a composition of claim 14 as a radiotherapy sensitizer, preferably for proliferating or non-proliferating cells.

28. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14.

29. 16. A kit of parts comprising a compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

30. An apoptotic agent comprising a compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14.

31. 16. A method of inducing thiol oxidation, comprising administering a compound of formula (I) as defined in any one of claims 1 to 6, an anion of claim 7, or a composition of claim 14, optionally in combination with reactive oxygen species (ROS).

Images