New benzothieno[2,3-c]pyridines as non-steroidal CYP17 inhibitors: design,synthesis, anticancer screening,apoptosis induction,and in silico ADME profile studies |
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| Authors: | Nadia A Khalil Eman M Ahmed Ashraf F Zaher Eman A Sobh Samiha A El-Sebaey Mona S El-Zoghbi |
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| Institution: | aPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt;bPharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt;cPharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt |
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| Abstract: | A series of 1]benzothieno2,3-c]pyridines was synthesised. Most compounds were chosen by NCI-USA to evaluate their anticancer activity. Compounds 5a–c showed prominent growth inhibition against most cell lines. 5c was selected at five dose concentration levels. It exhibited potent broad-spectrum anticancer activity with a GI50 of 4 nM–37 µM. Cytotoxicity of 5a–c was further evaluated against prostate, renal, and breast cancer cell lines. 5c showed double and quadruple the activity of staurosporine and abiraterone, respectively, against the PC-3 cell line with IC50 2.08 µM. The possible mechanism of anti-prostate cancer was explored via measuring the CYP17 enzyme activity in mice prostate cancer models compared to abiraterone. The results revealed that 5c suppressed the CYP17 enzyme to 15.80 nM. Moreover, it was found to be equipotent to abiraterone in testosterone production. Cell cycle analysis and apoptosis were performed. Additionally, the ADME profile of compound 5c demonstrated both good oral bioavailability and metabolic stability. |
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| Keywords: | Cancer CYP17 enzyme inhibitors apoptosis |
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