Cobalt-polypyridyl complex for treatment of cancer, a pharmaceutical composition and a kit comprising it

a technology of cobalt polypyridyl complex and cancer, which is applied in the direction of heavy metal compound active ingredients, medical preparations, antineoplastic agents, etc., can solve the problems of dna damage, cancer cell apoptosis, and cancer is still a life-threatening disease affecting an increasing number of people in the world, so as to effectively target cancer and achieve high cytotoxic activity , the effect of reducing the dos

Active Publication Date: 2018-02-22
MACAU UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]The present invention also provides a kit comprising an effective dose of the cobalt-polypyridyl complex as described above and an effective dose of at least a further chemotherapeutic compound commonly used for treating cancer, namely selected from the group consisting of a topoisomerase-II inhibitor, an anthracycline, a coordination complex of platinum, a taxane, a protein kinase inhibitor, a vinca alkaloid or derivative thereof, a topoisomerase-I inhibitor and a nucleotide analog or precursor analog. The kit may further comprise excipients, in particular pharmaceutically acceptable excipients, such as a carrier, salt, buffer, water, or a combination thereof. Accordingly, the present invention provides a novel and highly advantageous treatment option for treating cancer from various origins. It has been found that the cobalt-polypyridyl complex as described above, in particular a cobalt-polypyridyl complex comprising a structure of Formula (III), (IV) or (VII) is especially suitable for treating cancer and especially multidrug-resistant cancer as it possesses a high cytotoxic activity against cancer cells and specifically towards multidrug-resistant cancer cells such as of human origin. Said cobalt-polypyridyl complex described above, thus, allows for effectively targeting cancer and especially multidrug-resistant cancer, either alone or in combination with conventional chemotherapeutic compounds. It provides an advantageous treatment approach for cancer exceptionally suitable to specifically address multidrug-resistant cancer.
[0018]In particular, the cobalt-polypyridyl complex comprising structures of Formulas (III), (IV) or (VII) and in particular essentially consisting of structures of Formulas (III), (IV) or (VII) and optionally a counterion proved to specifically and advantageously target P-glycoprotein-dependent multidrug-resistant and / or p53-deficient multidrug-resistant cancer cells through collateral sensitivity, i.e. it is especially suitable to selectively kill these multidrug-resistant cancer cells. Namely, a significantly lower dose is required for treating said multidrug-resistant cancer cells compared to cancer cells of the same cell type without a multidrug-resistant phenotype, usually the IC50 of the cobalt-polypyridyl complex towards multidrug-resistant cancer cells is significantly reduced.
[0019]Summing up, the herewith provided class of cobalt-polypyridyl complexes shows highly promising anti-cancer effects and more importantly collateral sensitivity towards multidrug-resistant cancers.

Problems solved by technology

Cancer is still a life-threatening disease affecting an increasing number of people in the world.
However, a significant number of patients have acquired or develop resistance to these chemotherapeutic compounds after initial therapeutic treatments.
Such drug-resistance in cancer is the major impediment to a successful treatment.
For example, cisplatin (cis-[PtII(NH3)2Cl2]) can bind to the purine bases of the DNA, thereby led to DNA damage resulting in apoptosis in cancer cells.
However, due to severe side effects such as dose-dependent toxicity, allergy, effects on the kidneys and immunity, gastrointestinal disorders, hemorrhage and loss of hearing, the clinical use of cisplatin is limited.

Method used

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  • Cobalt-polypyridyl complex for treatment of cancer, a pharmaceutical composition and a kit comprising it
  • Cobalt-polypyridyl complex for treatment of cancer, a pharmaceutical composition and a kit comprising it
  • Cobalt-polypyridyl complex for treatment of cancer, a pharmaceutical composition and a kit comprising it

Examples

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example 1

Preparation of Cobalt-Polypyridyl Complexes of the Present Invention

[0148]Cobalt-polypyridyl complexes of Formula (V) and (VI) with a counterion were synthesized according to the method below. Other cobalt-polypyridyl complexes were prepared by the modification of the reported procedure.

Preparation of [CoII(N̂N)3](PF6)2 (Cobalt-Polypyridyl Complex of Formula (V) with PF6− as Counterion)

[0149]A mixture of CoC12.6H2O (4 mmol) and 2,2′-bipyridine (13.2 mmol) in methanol (100 mL) was heated to reflux under N2 for 2 h. After cooling down to room temperature, NH4PF6 (20 mmol) was added to the reaction mixture and the reaction mixture was stirred for another 1 h. The precipitate was filtrated and washed with methanol and then diethyl ether.

Preparation of [CoIII(N̂N)3](PF6)3 (Cobalt-Polypyridyl Complex of Formula (VI) with PF6− as Counterion)

[0150]Oxidation of [CoII(N̂N)3](PF6)2 (2 mmol) was carried out by the treatment of NOBF4 (2 mmol) in acetonitrile (40 mL) at room temperature for 1 h. ...

example 2

Cytotoxicity Assays

[0155]All prepared cobalt-polypyridyl complexes were dissolved in DMSO at a final concentration of 50 mmol / L and stored at −20° C. before use. Cytotoxicity was assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (5.0 mg / ml) assay as previously described (Wong, V. K. et al., Cell Death Dis, 2013, 4, e720). Briefly, 4×103 cells per well were seeded in 96-well plates before drug treatments. After overnight culture, the cells were then exposed to different concentrations of selected compounds (0.039-100 μmol / L) for 72 h. Cells without drug treatment were used as control. Subsequently, MTT (10 μL) solution was added to each well and incubated at 37° C. for 4 h followed by the addition of 100 μL solubilization buffer (10% SDS in 0.01 mol / L HCl) and overnight incubation. A570 nm was then determined in each well on the next day. The percentage of cell viability was calculated using the following formula: Cell viability (%)=Atreated / Aco...

example 3

Collateral Sensitivity in Taxol-Resistant and p53-Deficient Cancer Cells

[0157]All prepared cobalt-polypyridyl complexes were dissolved in DMSO at a final concentration of 50 mmol / L and stored at −20° C. before use. Cytotoxicity was assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (5.0 mg / ml) assay as previously described (Wong, V. K. et al., Cell Death Dis, 2013, 4, e720). Briefly, 4×103 cells per well were seeded in 96-well plates before drug treatments. After overnight culture, the cells were then exposed to different concentrations of selected compounds (0.039-100 μmol / L) for 72 h. Cells without drug treatment were used as control. Subsequently, MTT (10 μL) solution was added to each well and incubated at 37° C. for 4 h followed by the addition of 100 μL solubilization buffer (10% SDS in 0.01 mol / L HCl) and overnight incubation. A570 nm was then determined in each well on the next day. The percentage of cell viability was calculated using t...

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PUM

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Abstract

A method for treating a subject suffering from a cancer, in particular a multidrug-resistant cancer includes administrating a cobalt-polypyridyl complex to the subject. A method for suppressing the growth of cancer cells, in particular inducing autophagy of the cancer cells, inducing cell cycle arrest of the cancer cells and / or inhibiting cell invasion of the cancer cells and for specifically targeting cancer cells with multidrug-resistance includes contacting said cancer cells with the cobalt-polypyridyl complex. A pharmaceutical composition and a kit are provided and include the cobalt-polypyridyl complex. Unexpectedly, the cobalt-polypyridyl complex is especially suitable to treat cancer, in particular multidrug-resistant cancer with an exceptionally increased cytotoxic activity towards multidrug-resistant cancer cells.

Description

TECHNICAL FIELD[0001]The present invention relates in a first aspect to a method for treating a subject suffering from a cancer, in particular a multidrug-resistant cancer, i.e. a cancer with multidrug-resistant phenotype and, thus, a specific subgroup of subjects with cancer. The method comprises administrating a cobalt-polypyridyl complex to said subject. In another aspect of the present invention, a method for suppressing the growth of cancer cells, in particular inducing autophagy of the cancer cells, inducing cell cycle arrest of the cancer cells and / or inhibiting cell invasion of the cancer cells and for specifically targeting cancer cells with multidrug-resistance is provided comprising contacting said cancer cells with the cobalt-polypyridyl complex. In a further aspect, the present invention provides a pharmaceutical composition and a kit comprising the cobalt-polypyridyl complex.BACKGROUND OF THE INVENTION[0002]Cancer is still a life-threatening disease affecting an increa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/555A61K45/06
CPCA61K31/555A61K45/06A61P35/00A61K2300/00A61K31/28
Inventor WONG, KAM WAIWONG, MAN CHUNG
Owner MACAU UNIV OF SCI & TECH
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