Research Article
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In Silico Studies and In Vitro Microsomal Metabolism of Potent MetAP2 Inhibitor and In Vivo Tumor Suppressor for Prostate Cancer: A Thioether-Triazole Hybrid

Year 2023, Volume: 14 Issue: 1, 10 - 23, 01.01.2023

Göknil Coşkun Kaan Birgül Asaf Evrim Evren Ş. Güniz Küçükgüzel Mert Ülgen

https://doi.org/10.31067/acusaglik.1210129
Cited By: 3

Abstract

Background/aim: The in-vitro microsomal metabolism of (S)-3-((2,4,6-trimethylphenyl)thio)-4-(4-fluorophenyl)-5-(1-(6-methoxynaphtalene-2-yl)ethyl)-4H-1,2,4-triazole (SGK636), an anticancer drug candidate was studied using pig microsomal preparations fortified with NADPH to identify the potential S-oxidation and S-dealkylation metabolites.
Materials and methods: In the present study, the sulfoxide metabolite was synthesized, purified and characterized by chromatographic and spectroscopic methods. SGK636, the S-oxidation and S-dealkylation metabolites were then separated by a reversed phase LC-MS, with UV detection and with an HP-TLC system. The results from the in-vitro microsomal metabolic experiments showed that SGK636 produced the corresponding S-oxidation metabolite (sulfoxide) which was observed by LC-MS, LC-MS/MS and HP-TLC with the identical Rt and Rfx100 values and UV/MS spectra in comparison with the authentic compounds, but no any S-dealkylation metabolite was detected.
Results: The present results were proved with molecular docking and molecular dynamic studies. Since sulfoxidation process can be reversible and it may partly explain the low amount of sulfoxide metabolite in our experiment, we also incubated the sulphoxide. No conversion back to the substrate (SGK636) was observed, but it produced the corresponding sulphone metabolite. In order to establish if SGK636 is autooxidized, the substrate was also incubated in buffer under standard incubation conditions, but no any autooxidation was observed into the corresponding sulfoxide. We also did a stability work for SGK636-SO (sulfoxide) in buffer to see any possible autooxidation to sulphone or reduction back to SGK636. No conversion was observed in either way. The substrate seems to be stable to metabolic reactions and to autooxidation which could be an advantage in terms of its pharmacological activity.
Conclusion: The present metabolic and study indicates that SGK 636 underwent S-oxidation. In order to identify the responsible oxydative enzyme, molecular docking and molecular dynamic studies were performed. CYP3A4 was found to be responsible enzyme for S-oxidation.

Keywords

S-oxidation in vitro metabolism thioether 1 2 4-triazole Naproxen.

Supporting Institution

TUBITAK

Project Number

215S009

Thanks

The synthesis and confirmation SGK636 and (S)-Naproxen triazole were supported by a grant of TUBITAK (Project number: 215S009). (+) (S)-Naproxen, was obtained from Deva Ilaç San. Tic. A. S. , Turkey. The pig livers were donated by Acibadem University, Animal Laboratory Centre from the Project by Dr. Mehmet Emin Aksoy; laparoscopic and robotic surgery course, with the 2021-01 ethical approval number. The liver tissue was obtained from the euthanized pig at the end of course. Authors are gratefull to Chemist Ummet Melikoğlu (Acıbadem LABMED employee) for performing LC-MS/MS analyses for the compounds.

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Year 2023, Volume: 14 Issue: 1, 10 - 23, 01.01.2023

Göknil Coşkun Kaan Birgül Asaf Evrim Evren Ş. Güniz Küçükgüzel Mert Ülgen

https://doi.org/10.31067/acusaglik.1210129
Cited By: 3

Abstract

Project Number

215S009

References

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  • 14. Han, M. İ. B., H. ; Cumaoğlu, A.; Küçükgüzel, Ş. G. , Synthesis and characterization of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-Naproxen as anticancer agents. Marmara Pharm. J (now J. Res. Pharm.), 2015, 22 (4), 559-569. https://doi.org/ 10.12991/jrp.2018.98
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  • 16. Birgul, K.; Yildirim, Y.; Karasulu, H. Y.; Karasulu, E.; Uba, A. I.; Yelekci, K.; Bekci, H.; Cumaoglu, A.; Kabasakal, L.; Yilmaz, O.; Kucukguzel, S. G., Synthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives. Eur J Med Chem 2020, 208, 112841. https://doi.org/ 10.1016/j.ejmech.2020.112841
  • 17. Han, M. I.; Atalay, P.; Tunc, C. U.; Unal, G.; Dayan, S.; Aydin, O.; Kucukguzel, S. G., Design and synthesis of novel (S)-Naproxen hydrazide-hydrazones as potent VEGFR-2 inhibitors and their evaluation in vitro/in vivo breast cancer models. Bioorg Med Chem 2021, 37, 116097. https://doi.org/ 10.1016/j.bmc.2021.116097
  • 18. Birgül, K. U., A.I.; Çuhadar, O.;, Koçyiğit, S.; Tiryaki, S.; Mega, T.P.; Orun, O.;, Telci, D.; Yılmaz, Ö.; Yelekçi, K.; Küçükgüzel, Ş.G. , Synthesis and Molecular Modeling of MetAP2 of Thiosemicarbazides, 1,2,4-triazoles, thioethers derived from (S)-Naproxen as Possible Breast Cancer Agents. Journal of Molecular Structure 2022, 132739. https://doi.org/ 10.1016/j.molstruc.2022.132739
  • 19. Han, M. İ., Tunç, C.Ü. Atalay,, P.; Erdoğan, Ö.; Ünal, G.; Bozkurt, M.; Aydın, Ö.; Çevik, Ö.; Küçükgüzel, Ş.G. . , Synthesis, characterization, in vitro and in vivo anticancer activity studies of new (S)-Naproxen thiosemicarbazide/1,2,4-triazole derivatives. New J. Chemistry 2022, in press. https://doi.org/ 10.1039/D1NJ05899A
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  • 21. Kucukguzel, I.; Kucukguzel, S. G.; Rollas, S.; Kiraz, M., Some 3-thioxo/alkylthio-1,2,4-triazoles with a substituted thiourea moiety as possible antimycobacterials. Bioorg Med Chem Lett 2001, 11 (13), 1703-7. https://doi.org/ 10.1016/s0960-894x(01)00283-9
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Details

Primary Language English
Subjects Endocrinology
Journal Section Research Article
Authors

Göknil Coşkun 0000-0001-5168-3866

Kaan Birgül 0000-0003-3963-4687

Asaf Evrim Evren 0000-0002-8651-826X

Ş. Güniz Küçükgüzel 0000-0001-9405-8905

Mert Ülgen 0000-0003-4913-4950

Project Number 215S009
Early Pub Date November 15, 2022
Publication Date January 1, 2023
Submission Date November 25, 2022
Published in Issue Year 2023Volume: 14 Issue: 1

Cite

EndNote Coşkun G, Birgül K, Evren AE, Küçükgüzel ŞG, Ülgen M (January 1, 2023) In Silico Studies and In Vitro Microsomal Metabolism of Potent MetAP2 Inhibitor and In Vivo Tumor Suppressor for Prostate Cancer: A Thioether-Triazole Hybrid. Acıbadem Üniversitesi Sağlık Bilimleri Dergisi 14 1 10–23.

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