English version Ukrainian version
Last issue Archive Editorial board Instructions to authors Contact us




This site supported by
 


Ukr. Bioorg. Acta 2020, Vol. 15, N2, 32-39.

Synthesis and evaluation of new thiazole-containing rhodanine-3-alkanoic acids as inhibitors of protein tyrosine phosphatases and glutathione S-transferases

Oleksandr L. Kobzar, Vitaliy O. Sinenko, Yuriy V. Shulha, Vlasyslav M. Buldenko, Diana M. Hodyna, Stepan G. Pilyo, Volodymyr S. Brovarets and Andriy I. Vovk*

V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
tel.: +380-44-558-5388; e-mail: vovk@bpci.kiev.ua

ABSTRACT
Thiazole-containing derivativesof rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were discussed based on molecular docking calculations.

KEYWORDS
rhodanine; thiazole; protein tyrosine phosphatase, glutathione S-transferase; enzyme inhibition; molecular docking.

Full text: (PDF, in English)

REFERENCES
1. Sharma, P. C.; Bansal, K. K.; Sharma, A.; Sharma, D.; Deep, A. Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur. J. Med. Chem. 2020, 188, 112016.
2. Mishra, I.; Mishra, R.; Mujwar, S.; Chandra, P.; Sachan, N. A retrospect on antimicrobial potential of thiazole scaffold. J. Heterocycl. Chem. 2020, 57, 2304-2329.
3. Singh, I. P.; Gupta, S.; Kumar, S. Thiazole compounds as antiviral agents: An update. Med. Chem. 2020, 16, 4-23.
4. Kaminskyy, D.; Kryshchyshyn, A.; Lesk, R. Recent developments with rhodanine as a scaffold for drug discovery. Expert Opin. Drug Discov. 2017, 12, 1233-1252.
5. Nanjan, M. J.; Mohammed, M.; Kumar, B. R. P.; Chandrasekar M. J. N. Thiazolidinediones as antidiabetic agents: a critical review. Bioorg. Chem. 2018. 77. 548-567.
6. Bataille C. R.; Brennan M. B.; Byrne S.; Davies S. G.; Durbin M.; Fedorov O.; Huber K. V. M.; Jones A. M.; Knapp S.; Nadali A.; Quevedo C. E.; Russell A.; Walker R. G.; Westwood R.; Wynne G. M. Thiazolidine derivatives as potent and selective inhibitors of PIM kinase family. Bioorg. Mad. Chem. 2017. 25. 2657-2665.
7. Sawaguchi, Y.; Yamazaki, R.; Nishiyama, Y.; Sasai, T.; Mae, M.; Abe, A.; Yaegashi, T.; Nishiyama, H.; Matsuzaki, T. Rational design of a potent pan-Pim kinases inhibitor with a rhodanine-benzoimidazole structure. Anticancer Res. 2017. 37. 4051-4057.
8. Huang, M.-J.; Cheng, Y.-C.; Liu C.-R.; Lin S.; Liu H. E. A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia. Exp. Hematol. 2006. 34. 1480-1489.
9. Lin, C. P.; Liu, J.-D.; Chow, J.-M.; Liu, C.-R.; Liu, H.-E. Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulation human telomerase reverse transcriptase and enchances chemosensitivity in human hepatocellular carcinoma cell. Anticancer Drugs. 2007. 18. 161-170.
10. Vatolin, S.; Phillips, J. G.; Jha, B. K.; Govindgari, S.; Hu, J.; Grabowski, D.; Parker, Y.; Lindner D. J.; Zhong, F.; Distelhorst, C. W.; Smith, M. R.; Cotta, C.; Xu, Y.; Chilakala, S.; Kuang, R. R.; Tall, S.; Reu, F. J. Novel protein disulfide isomerase inhibitor with anticancer activity in multiple myeloma. Cancer. Res. 2016. 76. 3340-3350.
11. Furdas, S. D.; Shekfeh, S.; Knnan, S.; Sippl, W.; Jung, M. Rhodaninecarboxylic acids as novel inhibitors of histone acetyltransferases. Med. Chem. Commun. 2012. 3. 305-311.
12. Li, P.; Zhang, W.; Jiang, H.; Li, Y.; Dong, C.; Chen, H.; Zhang, K.; Du, Z. Design, synthesis and biological evaluation of benzimidazole-rhodanine conjugates as potent topoisomerase II inhibitors. Med. Chem. Comm. 2018. 9. 1194-1205.
13. Bernardo, P. H.; Sivaraman, T.; Wan, K.-F.; Xu, J.; Krishnamoorthy, J.; Song, C. M.; Tian, L.; Chin, J. S. F.; Lim, D. S. W.; Mok, H. Y. K.; Yu, V. C.; Tong, J. C.; Chai, C. L. L.Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1. Pure Appl. Chem. 2011. 83. 723-731.
14. Zervosen, A.; Lu, W.-P.; Chen, Z.; White, R. E.; Demuth, T. P., Jr.; Frere, J. M. Interactions between penicillin-binding proteins (PBPs) and two novel classes of PBP inhibitors, arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones. Antimicrob. Agents Chemother. 2004. 48. 961969.
15. Grant, E. B.; Guiadeen, D.; Baum, E. Z.; Foleno, B. D.; Jin, H.; Montenegro, D. A.; Nelson, E. A.; Bush, K.; Hlasta, D. J. The synthesis and SAR of rhodanines as novel class C ?-lactamase inhibitors. Bioorg. Med. Chem. Lett. 2000. 10. 2179-2182.
16. Xiang, Y.; Chen, C.; Wang, W.-M.; Xu, L.-W.; Yang, K.-W.; Oelschlaeger, P.; He, Y. Rhodanine as a potent scaffold for the development of broad-spectrum metallo-?-lactamase inhibitors. ACS Med. Chem. Lett. 2018. 9. 359-364.
17. Alonso, A.; Sasin, J.; Bottini, N.; Friedberg, I.; Friedberg, I.; Osterman, A.; Godzik, A.; Hunter, T.; Dixon, J.; Mustelin, T. Protein tyrosine phosphatases in the human genome. Cell. 2004. 117. 699-711.
18. He, R.-j.; Yu, Z.-h.; Zhang, R.-y.; Zhang, Z.-y. Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol. Sin. 2014. 35. 1227-1246.
19. Koren, S.; Fantus, I. G. Inhibition of the protein tyrosine phosphatase PTP1B: potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Pract. Res. Endocrinol. Metab. 2007. 21. 621-640.
20. Zhu, S.; Bjorge, J. D.; Fujita, D. J. PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation. Cancer. Res. 2007. 67. 10129-10137.
21. Hoekstra E.; Das A. M.; Swets M.; Cao W.; van der Woude J.; Bruno M. J.; Peppelenbosch M. P.; Kuppen P. J. K.; ten Hagen T. L. M.; Fuhler G. M. Increased PTP1B expression and phosphatase activity in colorectal cancer results in a more invasive phenotype ans worse patient outcome. Oncotarget. 2016. 7. 21922-21938.
22. Lessard, L.; Labbe, D. P.; Deblois, G.; Begin, L. R.; Hardy, S.; Mes-Masson, A.-M.; Saad, F.; Trotman, L. C.; Giguere, V.; Tremblay, M. L. PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer. Cancer. Res. 2012. 72. 1529-1537.
23. Cho, C. Y.; Koo, S.-H.; Wang, Y.; Callaway, S.; Hedrick, S.; Mak, P. A.; Orth, A. P.; Peters, E. C.; Saez, E.; Montminy, M.; Schultz, P. G.; Chanda S. K. Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling. Cell. Metab. 2006. 3. 367-378.
24. Zhang, S.; Liu, S.; Tao, R.; Wei, D.; Chen, L.; Shen, W.; Yu, Z.-H.; Wang, L.; Jones, D. R.; Dong, X. C.; Zhang, Z.-Y. A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes. J. Am. Chem. Soc. 2012. 134. 18116-18124.
25. Xu, M.-J.; Sui, X.; Zhan, R.; Dai, C.; Krantz, S. B.; Zhao, Z. J. PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells. Blood. 2003. 102. 4354-4360.
26. Navarrete-Vazquez, G.; Paoli, P.; Leon-Rivera, I.; Villalobos-Molina, R.; Medina-Franco, J.; Ortiz-Andrade, R.; Estrada-Soto, S.; Camici, G.; Diaz-Coutino, D.; Gallardo-Ortiz, I.; Martinez-Mayorga, K.; Moreno-Diaz, H. Synthesis, in vitro and computational studies of protein tyrosine phosphatase 1B inhibition of a small library of 2-arylsulfonylaminobenzothiazoles with antihyperglycemic activity. Bioorg. Med. Chem. 2009. 17. 3332-3341.
27. Combs, A. P. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer. J. Med. Chem. 2010. 53. 2333-2344.
28. Hidalgo-Figueroa, S.; Estrada-Soto, S.; Ramirez-Espinosa, J. J.; Paoli, P.; Lori, G.; Leon-Rivera, I.; Navarrete-Vazquez, G. Synthesis and evaluation of thiazolidine-2, 4-dione/benzazole derivatives as inhibitors of protein tyrosine phosphatase 1B (PTP-1B): Antihyperglycemic activity with molecular docking study. Biomed. Pharmacother. 2018. 107. 1302-1310.
29. Liu, H.; Sun, D.; Du, H.; Zheng, C.; Li, J.; Piao, H.; Li, J.; Sun, L. Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents. Eur. J. Med. Chem. 2019. 172. 163-173.
30. Bhattarai, B.; Kafle, B.; Hwang, J.-S.; Khadka, D.; Lee, S.-M.; Kang, J.-S.; Ham, S. W.; Han, I.-O.; Park, H.; Cho, H. Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects. Bioorg. Med. Chem. Lett. 2009. 19. 6161-6165.
31. Mahapatra, M. K.; Kumar, R.; Kumar, M. Synthesis, biological evaluation and in silico studies of 5-(3-methoxybenzylidene) thiazolidine-2,4-dione analogues as PTP1B inhibitors. Bioorg. Chem. 2017. 71. 1-9.
32. Chen, Y. T.; Seto, C. T. Divalent and trivalent ?-ketocarboxylic acids as inhibitors of protein tyrosine phosphatases. J. Med. Chem. 2002. 45. 3946-3952.
33. Li, X.; Bhandari, A.; Holmes, C. P.; Szardenings, A. K.?, ?-Difluoro-?-ketophosphonates as potent inhibitors of protein tyrosine phosphatase 1B. Bioorg. Med. Chem. Lett. 2004. 14. 4301-4306.
34. Wang, Q.; Zhu, M.; Zhu, R.; Lu, L.; Yuan, C.; Xing, S.; Fu, X.; Mei, Y.; Hang, Q. Exploration of ?-aminophosphonate N-derivatives as novel, potent and selective inhibitors of protein tyrosine phosphatases. Eur. J. Med. Chem. 2012. 49. 354-364.
35. Patel, D.; Jain, M.; Shah, S. R., Bahekar, R.; Jadav, P.; Joharapurkar, A.; Dhanesha, N.; Shaikh, M.; Sairam K. V. V. M.; Kapadnis, P. Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors. Bioorg. Med. Chem. Lett. 2012. 22. 1111-1117.
36. Campochiaro, P. A.; Sophie, R.; Tolentino, M.; Miller, D. M.; Browning, D.; Boyer, D. S.; Heier, J. S.; Gambino, L.; Withers, B.; Brigell, M. Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2. Ophthalmology. 2015. 122. 545-554.
37. Campochiaro, P. A.; Peters, K. G. Targeting Tie2 for treatment of diabetic retinopathy and diabetic macular edema. Curr. Diab. Rep. 2016. 16. 126.
38. Shen, J.; Frye, M.; Lee, B. L.; Reinardy, J. L.; McClung, J. M.; Ding, K.; Kojima, M.; Xia, H.; Seidel, C.; Lima e Silva, R.; Dong, A.; Hackett, S. F.; Wang, J.; Howard, B. W.; Vestweber, D.; Kontos, C. D.; Peters, K. G.; Campochiaro, P. A. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J. Clin. Invest. 2014. 124. 4564-4576.
39. Ozen C.; Unlusoy, M. C.; Aliary, N.; Ozturk, M.; Dundar, O. B. Thiazolidinedione or rhodanine a study on synthesis and anticancer activity comparison of novel thiazole derivatives. J. Pharm. Pharm. Sci. 2017. 20. 415-427.
40. Kaur, G.; Gupta, S. K.; Singh, P.; Ali, V.; Kumar, V.; Verma, M. Drug-metabolizing enzymes: role in drug resistance in cancer. Clin. Transl. Oncol. 2020. 22. 1667-1680.
41. Hanna, P. E.; Anders, M. W. The mercapturic acid pathway. Crit. Rev. Toxicol. 2019. 49. 819-929.
42. Hayes, J. D.; Flanagan, J. U.; Jowsey, I. R. Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 2005. 45. 51-88.
43. Hayes, J. D.; Flanagan, J. U.; Jowsey, I. R. Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 2005. 45. 51-88.
44. Shultz, M.; Dutta, S.; Tew, K. D. Inhibitors of glutathione S-transferases as therapeutic agents. Adv. Drug Deliv. Rev. 1997. 26. 91-104.
45. Allocati, N.; Masulli, M.; Ilio, C. D.; Federici, L. Glutathione transferases: substrates, inhibitors and pro-drugs in cancer and neurodegenerative diseases.Oncogenesis. 2018. 7.
46. Sun, L.; Wang, P.; Xu, L.; Gao, L.; Li, J.; Piao, H. Discovery of 1, 3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors. Bioorg. Med. Chem. Lett. 2019. 29. 1187-1193.
47. Sinenko V. O.; Slivchuk, S. R.; Pil’o, S. G.; Raenko, G. F.; Brovarets, V. S. Synthesis of new 1,3-thiazole derivatives from 2(5)-hydroxyalkyl-1,3-thiazole-5(2)-carbaldehydes. Russ. J. Gen. Chem. 2016. 86. 1597-1603.
48. Balchin, D.; Fanucchi, S.; Achilonu, I.; Adamson, R. J.; Burke, J.; Fernandes, M.; Gildenhuys, S.; Dirr, H. W. Stability of the domain interface contributes towards the catalytic function at the H-site of class alpha glutathione transferase A1-1. Biochim. Biophys. Acta. 2010. 1804. 2228-2233.
49. Van der Aar E. M.; Buikema D.; Commandeur J. N.; te Koppele J. M.; van Ommen B.; van Bladeren P. J.; Vermeulen N. P. Enzyme kinetics and substrate selectivities of rat glutathione S-transferase isoenzymes towards a series of new 2-substituted 1-chloro-4-nitrobenzenes. Xenobiotica. 1996. 26. 143-155.
50. Berman H. M.; Westbrook J.; Feng Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne P. E. The Protein Data Bank. Nucleic Acids Res. 2000. 28. 235-242.
51. MarvinSketch 5.2.4, 2009, ChemAxon [Internet]. Available from: http://www.chemaxon.com (accessed on October 22, 2020).
52. Hanwell M. D.; Curtis D. E.; Lonie D. C.; Vandermeersch T.; Zurek E.; Hutchison G. R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 2012. 4. 17.
53. Sanner, M. F. Python: A programming language for software integration and development. J. Mol. Graph. Model. 1999. 17. 57-61.
54. Trott O.; Olson A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 2011. 31. 455-461.

Full-text in PDF  

 

Home