N‐substituted Piperazinopyridylsteroid Derivatives as Abiraterone Analogues Inhibit Growth and Induce Pro‐apoptosis in Human Hormone‐independent Prostate Cancer Cell Lines

Abstract

Nine new 17-(piperazin-1-yl)pyridin-5-yl)steroids as abiraterone analogues were synthesized. Compounds 5d and 5g showed selective activities against 17α-hydroxylase/C17,20-lyase (CYP17A1) and aromatase (CYP19), respectively. IC50 values of 5d were 5.09 and >50 μm, whereas these values for 5g were >50 μm and 7.40 μm, respectively, for CYP17A1 and CYP19. Molecular modelling highlighted that the inhibitor designed to bind cytochrome P450 haem iron is a necessary condition but not the only rationale to explain inhibitory activity. These abiraterone analogues were then evaluated on hormone-independent prostate cancer cell lines DU-145 and PC-3 and on hormone-dependent breast and prostate cancer cell lines MCF-7 and LNCaP, respectively. Compounds 5e, 5g and 5i have showed potent activities only on hormone-independent prostate cancer cell lines DU-145 and PC-3 with 60-85% inhibition of both cell viability and growth at 10 nm with pro-apoptotic mechanism as illustrated in PC-3 cells by DNA ladder assay and Western blotting of Bax, Casp-3 and its substrate, the poly (ADP-ribose) polymerase. We conclude that hybrid heterocycle steroids could be good lead compounds in the drug design especially against hormone-independent prostate cancer.

The unidirectional hypoxia‐activated prodrug OCT1002 inhibits growth and vascular development in castrate‐resistant prostate tumors

“…It is interesting that abiraterone was markedly effective against PC3 tumors, which are AR‐negative, since its primary action is known to be blockade of androgen synthesis through inhibition of CYP17A1. However, several in vitro studies have demonstrated that the anti‐tumor effect of abiraterone in PC3 cells is not solely associated with blockade of androgen synthesis . Our in vivo studies would confirm these observations.…”

Illuminating cytochrome P450 binding: Ru(ii)-caged inhibitors of CYP17A1

“…The DU145 cells are an aggressive cell line derived from human prostate adenocarcinoma metastatic to the brain and are known to be sensitive to abiraterone. 37 These cells are androgen receptor-negative, but show significant expression of CYP17A1 both at the mRNA and protein levels. 38 The cytotoxic compound thapsigargin (TPG; 10 μM) was used as a positive control.…”

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

“…5aSR -5a-редуктаза; 5b-редуктаза, 3b-HSD -3b-стероиддегидрогеназа. В работе [41] были синтезированы и исследованы производные абиратерона 20-28, содержащие объёмистые заместители в пиридиновом цикле (формула 3).…”

“…Молекулярный докинг показал, что связывание ингибитора 23 в активном центре CYP17A1 существенно отличалось от связывания абиратерона. Соединения 24, 26, 28 подавляли пролиферацию и стимулировали апоптоз только в гормон-независимых клетках карциномы простаты DU-145 и PC-3 [41].…”