AN ANTICANCER MOLECULE WITH A1AR AND PDE10A INHIBITORY POTENTIAL.

Abstract

The invention relates to a novel tryptamine-thiazolidine-4-one derivative molecule for use in the treatment of cancer and neurological diseases.

Description

1 TARIFF AN ANTICANCER WITH A1AR AND PDE10A INHIBITORY POTENTIAL. MOLECULE Technical Field to Which the Invention Relates 5 The invention develops a new tryptamine for use in the treatment of cancer and neurological diseases. It is related to a thiazolidine-4-one derivative molecule. This molecule is A1AR (A1 potential for inhibition of Adenosine Receptor) and PDE10A (Phosphodiesterase 10A) It has this property and is synthesized via a three-component condensation reaction in a single vessel. State of the Art Indole scaffolding is a pharmacophore widely used in drug discovery, and is very common. basic structure of numerous synthetic and naturally occurring biologically active molecules In the literature, compounds containing indole nuclei are used as antidepressants. 15 with various pharmacological effects such as anticancer, antipsychotic and anti-inflammatory. It is known that tryptamine (indol-3-yl-ethylamine) derivatives, in particular, affect serotonin (5- in neurotransmitter and hormone structures such as hydroxytryptamine (5-HT) and melatonin It occurs naturally and affects many physiological functions such as pain, sleep, appetite, mood, and memory. It plays a role in this process. Therefore, tryptamine derivatives are antidepressants. 20 various therapeutic agents such as antipsychotics and serotonergic hallucinogens They are used as fundamental building blocks in its development. The structural properties of tryptamine. Through modifications, receptor selectivity and metabolic stability were improved, thus By optimizing pharmacokinetic and pharmacodynamic profiles, it becomes safer and more effective. Drug candidates have been obtained. The effects of psychoactive tryptamine compounds are particularly evident in 5- It occurs via the HT2A receptor, but other serotonin receptors, 25 via alternative targets such as monoamine transporters and trace amine-related receptors It has also been reported that the effects can be modulated by Arp 2 / 3 inhibitor [1]. In the literature, it has also been reported that Arp 2 / 3 inhibitor Some clinically important compounds such as CK-666 and the antileukemic agent panobinostat It has been reported that it contains indol-3-yl ethylamine unit [2]. Compounds containing a thiazolidinone skeleton exhibit structural diversity and versatile biological properties. It attracts attention with its activities. Antibacterial, antiviral (especially anti-HIV), Anticancer, anticonvulsant, antihistaminic, anti-inflammatory and cardiovascular effects. Thiazolidinone derivatives are among the pharmaceutically valuable application areas. 2 It is also used as an ARP 2 / 3 inhibitor of CK-869, and etozolin is a... ralitolin has been successfully used as an antihypertensive agent and as a potent anticonvulsant. Its development reveals the therapeutic potential of the thiazolidinone core. These findings indicate that both tryptamine and thiazolidinone scaffolds are part of a single structure. By combining molecules, 5 new multi-target and clinically significant drug candidates can be created. This provides a strong basis for the design of these strong pharmacophore structures [3]. Hybrid molecules obtained by combining (tryptamine and thiazolidinone), especially effects on target proteins involved in neurological and oncological diseases It is being researched with increasing interest in recent years. In this context, A1 adenosine receptor (A1AR) and phosphodiesterase 10A (PDE10A) enzymes, drug development 10 A1AR is considered one of the two key biological targets that stand out in these processes. a G protein-coupled protein that regulates synaptic transmission and is characterized by its neuroprotective effects. receptors are involved in pain, epilepsy, neurodegeneration, cardiovascular disorders, and It plays a role in the pathogenesis of many diseases, such as cancer. On the other hand, The PDE10A enzyme is particularly heavily expressed in the striatum region, and 15 It plays a critical role in the regulation of dopamine and cAMP signaling pathways. PDE10A inhibitors are used in schizophrenia, Huntington's disease, and some types of tumors. It shows therapeutic potential. Tryptamine-thiazolidinone hybrids, both A1AR Significant biological effects in terms of both antagonism and PDE10A inhibition. This demonstrates the pharmacological profiles of such combined structures targeting multiple objectives. This supports the structures in question, which were identified as A1AR through both in silico and in vitro analyses. They bind with high affinity to binding sites and PDE10A enzymatic Multi-target therapy strategies by demonstrating that they inhibit its activity. In this respect, they represent promising new classes of compounds. Thus, indole and Strategic combination of thiazolidinone scaffolds, neurological and oncological 25 reliable, selective and effective targeting the molecular mechanisms of disorders It offers a rational approach to the development of therapeutic candidates. A1 adenosine receptor (A1AR) is involved in immunosuppression and cell activity in the tumor microenvironment. It is a purinergic target that affects the proliferation of tumor cells, 30 It regulates signals that facilitate its survival. A1AR's extreme expression, cell proliferation in glioblastoma and various solid tumors, It has been associated with angiogenesis and chemotherapy resistance. Therefore, A1AR antagonists interrupt growth signals on tumor cells, immune 3 potential for strengthening the response and increasing sensitivity to treatment They are considered as anticancer agents. Similarly, phosphodiesterase 10A The enzyme (PDE10A) controls intracellular cAMP and cGMP levels, thereby affecting cellular processes. It regulates the processes of proliferation, differentiation, and apoptosis. Finally... Studies have shown that PDE10A expression is associated with colorectal cancer, lung cancer, and glioma 5. It has been shown to increase in cell lines with various malignancies such as [4]. PDE10A inhibitors stop the growth of tumor cells by blocking these signaling pathways. It suppresses, halts the cell cycle, and induces apoptosis. Additionally, PDE10A inhibition affects Wnt / β-catenin and ERK / MAPK in tumor cells. It has been associated with downregulation of oncogenic pathways [5]. In this context, 10 Compounds obtained by combining tryptamine and thiazolidinone backbones are both A1AR And because it targets PDE10A, it inhibits not only tumor cell proliferation. not only in terms of suppression; but also in terms of reactivating the immune system. the manipulation, reshaping of the tumor microenvironment and multiple signaling pathways 15 in terms of multifaceted anticancer mechanisms such as simultaneous control They are also extremely valuable. Thus, these hybrid structures are both directly cytotoxic and... By offering suppressive effects on the tumor-promoting microenvironment, it provides innovative and effective oncological solutions. It contributes to the development of treatment strategies. Although indole and thiazolidinone scaffolds have extensive separate applications in the pharmaceutical field... They are described in the literature as building blocks with biological activity profiles and various Although many molecules have been developed targeting biological targets, the current technique is limited to these two. The combination of the scaffold allows it to act on multiple biological targets simultaneously, especially A1AR. and can simultaneously inhibit oncology-critical targets such as PDE10A This remains limited in the development of new hybrid molecules. In the literature, A1AR 25 Although various compounds associated with antagonism or inhibition of PDE10A have been reported. However, it combines these effects within the same molecule, and also provides these effects both in silico. and systematically validated at the in vitro level, clinically significant multi-targeted And the number of structures based on rational design at the molecular level is quite small. Furthermore, current studies show that inhibitors of these two targets affect the cancer microenvironment by 30 Their effects are generally considered separately; A1AR-related immune modulation and The effect of PDE10A on oncogenic signaling pathways (Wnt / β-catenin, (ERK / MAPK, for example) are not evaluated in an integrated manner. This situation, in particular... Targeting multiple signaling mechanisms in aggressive and treatment-resistant tumor types 4 This makes the need for next-generation small molecule inhibitors even more apparent. Therefore, the current technique will both enhance the therapeutic effect and... structurally designed to offer a multi-targeted strategy to reduce systemic toxicity. fully developing optimized, biologically validated new hybrid structures It cannot meet this requirement. 5 Brief Description and Objectives of the Invention The invention develops new technologies for use in the treatment of cancer and neurological diseases. A tryptamine-thiazolidine-4-one derivative molecule is described. This molecule, A1AR (A1 Adenosine Receptor) and PDE10A (Phosphodiesterase 10A) inhibition 10 It has the potential to undergo a three-component condensation reaction in a single vessel. It is being synthesized. The anticancer molecule that is the subject of the invention is represented by Formula 1. (4R)-N-(2-(1H-indol-3-yl)ethyl)-4-(4-bromophenyl)-1,3-thiazolidine- represented by formula 1 The compound that is the subject of the invention, called 2-one, is used in colorectal cancer and lung cancer. (especially non-small cell lung cancer), prostate cancer, glioblastoma, and brain cancer 15 in the treatment of tumors and hepatocellular carcinoma (liver cancer) It is used. Formula 1 The aim of the invention is to achieve multi-target therapeutic potential in cancer treatment. This is the presentation of a new class of tryptamine-thiazolidine-4-one hybrids. 25 Structural design of tryptamine-thiazolidin-4-one hybrids enhances chemical stability. It reduces degradation under physiological conditions and is suitable for long-term use. It provides reliability. Tryptamine and thiazolidinone pharmacophores By combining them, the compound represented by Formula 1, which is the subject of the invention, produces multiple biological compounds. They exert a synergistic effect on the pathway; this leads to diseases such as cancer and neurological disorders. It increases effectiveness in treating complex diseases. One aim of the invention is to have high receptor selectivity and strong metabolic stability. The goal is to develop a molecule that both increases efficacy and improves the safety profile. is being improved. High receptor selectivity makes the compound the primary target biological agent. its dominant binding to the receptor, unlike other receptors with similar structural features This ensures that it exhibits minimal affinity to receptor subtypes. These 10 This situation minimizes the risk of unwanted physiological effects by reducing off-target interactions. It reduces and increases therapeutic sensitivity. Furthermore, increased metabolic stability, This allows the molecule to remain active in the body for a longer period; this makes it therapeutic. maintaining concentration and potentially increasing dosing frequency It allows for a reduction. By optimizing selectivity, permanent metabolic 15 By combining robustness, the invention maximizes the intended interaction. a more effective and safer therapeutic approach that minimizes negative consequences while removing it The candidate is presenting. One aim of the invention is to synthesize 20 through a reaction mechanism carried out in a single vessel. to simplify the process, facilitate large-scale production, reduce costs and The goal is to align processes with the principles of sustainable green chemistry. Explanation of Figures 25 Figure 1. A1AR protein of the compound indicated by Formula 1 (PDB ID: 5N2S), which is the subject of the invention. Interactions with critical residues (reference molecule 92469631) (a) Reference molecule on A1AR protein, presented comparatively), (b) Surface representation of 92469631, (b) critical remnants of 92469631 on A1AR. Ligand interaction diagram, (c) 30 during 50 ns molecular dynamics (MD) simulation. protein-92469631 contact panel; the upper panel shows total contacts, and the lower panel shows established and... (d) shows the disrupted interactions with 92469631 throughout the MD simulation. Interaction rates between residues in the binding pocket of the A1AR protein and Characterization of interactions, (e) surface of YS4 compound on A1AR protein 6 (f) Ligand interaction diagram of YS4 with critical residues on A1AR, (g) Protein-YS4 contact panel during 50 ns MD simulation; upper panel total contacts, the lower panel shows the interactions that are established and broken, (h) MD during simulation, residues in the binding pocket of YS4 and A1AR protein Interaction rates and characterization of interactions. 5 Detailed Description of the Invention The invention develops a new tryptamine for use in the treatment of cancer and neurological diseases. It is related to a thiazolidine-4-one derivative molecule. This molecule is A1AR (A1 10 potential for inhibition of Adenosine Receptor) and PDE10A (Phosphodiesterase 10A) It has this property and is synthesized via a three-component condensation reaction in a single vessel. The anticancer molecule that is the subject of this invention is represented by Formula 1. Formula 1 shown as (4R)-N-(2-(1H-indol-3-yl)ethyl)-4-(4-bromophenyl)-1,3-thiazolidin-2-one 15 The compound that is the subject of the invention named above is used to treat colorectal cancer, lung cancer (especially small lung cancer). noncellular lung cancer), prostate cancer, glioblastoma, and brain tumors and It is used in the treatment of hepatocellular carcinoma (liver cancer). Formula 1 The molecule synthesized within the scope of this invention, denoted by Formula 1, contains tryptamine and 25 A novel hybrid formed by the combination of thiazolidine-4-one scaffolds in a single structure. It is a derivative. This compound is formed by a three-component condensation reaction carried out in a single pot. synthesized with 4-bromophenyl aldehyde, mercaptoacetic acid and tryptamine derivative. 7 The starting materials were heated in benzene for 18 hours using a Dean-Stark setup. It was obtained with approximately 44% efficiency by reacting it in the reflux process. Structural Confirmation was performed using FT-IR, 1H NMR, 13C NMR, and HR-MS analyses; these data... The study revealed that the molecule possesses the expected structural properties. In particular... Carbonyl absorption above 1665 cm⁻¹ observed in the FT-IR spectrum and 5 In NMR spectra, characteristic methylene and thiazolidinone signals indicate synthesis. This shows that it has been successful. The compound described in this invention has high biological activity potential in in silico analyses. It has been exhibited. 10 projects carried out by SwissTargetPrediction and MetaDrug platforms. According to target predictions, the compound shown with Formula 1 is the A1 adenosine receptor. (A1AR, PDB ID: 5N2S) and phosphodiesterase 10A (PDE10A, PDB ID: 8DI4) proteins It has been shown to be among the candidates that can establish high-affinity interactions with molecular substances. In docking analyses, the compound subject to the invention has a presence on A1AR. The binding energy was calculated as -7.45 kcal / mol, based on the MM / GBSA method. The binding free energy was found to be –64.07 ± 4.07 kcal / mol. The values ​​are competitive compared to the reference molecule 92460631 (–83.29 kcal / mol). This indicates the binding profile. Furthermore, it refers to molecular dynamics over 50 nanoseconds. During the simulations, Phe171, Ile175, and Trp247 were found in the A1AR binding pocket of the compound. and forms stable and continuous interactions with critical amino acid residues such as His278. This was observed during the simulation, both in terms of the total number of contacts and... The time-dependent changes in the interactions that occur / disrupt have been analyzed, and the aforementioned It has been confirmed that the molecule exhibits a binding dynamic compatible with the receptor. Within the scope of in vitro biological evaluations of the compound, the compound subject to the invention, 25 It exhibited significant antiproliferative activity on the YKG-1 glioblastoma cell line. It has been shown that the compound subject to this invention, with an IC₅₀ value measured as 20 nanomolar, In terms of its application, traditional chemotherapeutic agents include 5-fluorouracil (5-FU, IC₅₀ ≈ 152 µM) and more than 1000 times more when compared with temozolomide (TMZ, IC₅₀ ≈ 17 µM). It has shown high efficacy. In the SH-SY5Y neuroblastoma cell line, sufficient efficacy was observed. Since no correlation could be established, the IC₅₀ value was not calculated. The subject of the invention... This high antiproliferative effect shown by the compound is due to A1AR antagonism and possible With multiple targeted mechanisms of action based on PDE10A inhibition. They are related. 8 In light of the above findings, the compound subject to the invention can be synthesized using both a robust synthesis method. a new tryptamine that stands out with its high biological activity profile It is a thiazolidinone derivative. It exhibits binding to A1AR and PDE10A proteins. Its potential makes this molecule promising for both neurological and oncological diseases. This makes it a promising candidate. Furthermore, its low IC₅₀ value indicates long-term durability. Thanks to its molecular interaction stability and structural flexibility, it can be used in different therapeutic applications. It also allows for the development of derivatives aimed at specific goals. This With these properties, the compound in question is used in next-generation multitarget drug designs. It offers a valuable and innovative chemical platform that can be used. 10 Industrial Applicability of the Invention The invention develops a new tryptamine for use in the treatment of cancer and neurological diseases. It relates to a thiazolidine-4-one derivative molecule and has industrial applicability. The invention is not limited to the above descriptions, and a person skilled in the field can easily make further discoveries. It can demonstrate different applications of the invention. These are the claims and demands of the invention. It should be evaluated within the scope of the protection granted. 25 9 REFERENCES [1] Rickli, A.; Moning, O.D.; Hoener, M.C.; Liechti, ME Receptor Interaction Profiles of Novel Psychoactive Tryptamines Compared with Classic Hallucinogens. Euro. Neuropsychopharmacol. 2016, 26 (8), 1327– 1337, DOI: 10.1016 / j.euroneuro.2016.05.001 5 [2] Baggett, A. W.; Cournia, Z.; Han, M. S.; Patargias, G.; Glass, A. C.; Liu, S.-Y.; Nolen, B. J. Structural Characterization and Computer-Aided Optimization of a Small Molecule Inhibitor of Arp2 / 3 Complex, a Key Regulator of the Actin Cytoskeleton. [3] Patel, R. V.; Patel, P. K.; Kumari, P.; Rajani, D. P.; Chikhalia, K. H. Synthesis of 10 Benzimidazolyl-1,3,4-Oxadiazol-2ylthio-N-Phenyl (Benzothiazolyl) Acetamides as Antibacterial, Antifungal and Antituberculosis Agents. Eur. J. Med. Chem. 2012, 53, 41– 51, DOI: 10.1016 / j.ejmech.2012.03.033 [4] Zhu, B., Lindsey, A., Li, N., Lee, K., Ramirez-Alcantara, V., Canzoneri, J. C., Fajardo, A., Madeira da Silva, L., Thomas, M., Piazza, J. T., Yet, L., Eberhardt, B. 15 T., Gurpinar, E., Otali, D., Grizzle, W., Valiyaveettil, J., Chen, X., Keeton, A. B., & Piazza, G. A. (2017b, August 27). Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling. [5] Lee, K., Lindsey, A. S., Li, N., Gary, B., Andrews, J., Keeton, A. B., & Piazza, 20 G. A. (2016, February 2). Β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cgmp elevation, and activation of pkg. 30

Claims

REQUESTS 1. The compound represented by formula 1: Formula 1 2. (4R)-N-(2-(1H-indol-3-yl)ethyl)-4-(4-bromophenyl)-1,3-thiazolidine-2-one formula It is a compound property according to Claim 1.

3. (4R)-N-(2-(1H-indol-3-yl)ethyl)-4-(4-bromophenyl)-1,3- shown with formula 1 Use of thiazolidine-2-one compound as an ERCC1 / XPF inhibitor. 10 4. 2-[4-fluoro(phenylsulfonyl)anilino]-N-{4- [(phenylsulfanyl)methyl]phenyl}acetamide compound A1AR (A1 Adenosine Receptor) and its use as a PDE10A (Phosphodiesterase 10A) inhibitor.

5. It is a compound represented by formula 1, and its characteristic feature is that its IC₅₀ value is 20 nM.

6. A1AR (A1 Adenosine Receptor) and PDE10A (Phosphodiesterase 10A) inhibitor 15 A compound according to either claim 1 or 2, to be used as such.

7. Inhibitor of A1AR (A1 Adenosine Receptor) and PDE10A (Phosphodiesterase 10A). a compound according to any of claim 1, 2 or 6 for use as pharmaceutical composition containing.

8. A1AR (A1 Adenosine Receptor) and PDE10A (Phosphodiesterase 10A) inhibitor 20 a compound according to any of claim 1, 2 or 6 for use as medicine containing 9. Determined by in silico simulation, chemotherapy agent or neurological Request 1- for use as an active ingredient in the treatment of diseases. A compound according to either of the two. 25 10. Determined by in silico simulation, chemotherapy agent or neurological Request 1, 2 for use as an active ingredient in the treatment of diseases. or a pharmaceutical composition containing a compound according to any of the 9. 11 11. Determined by in silico simulation, chemotherapy agent or neurological intended to be used as an active ingredient in the treatment of diseases 1, 2 or A medicine containing a compound according to any of the 9.

12. According to claims 1, 2 or 8, a compound may be used to treat colorectal cancer, lung cancer (especially non-small cell lung cancer), prostate cancer, 5 glioblastoma and brain tumors and hepatocellular carcinoma (liver (cancer) treatment. 15 25

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