title: 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.
authors.affiliation: Université de Caen/Basse-Normandie, Esplanade de la Paix, 14032, Caen cedex, France; UFR des Sciences Pharmaceutiques, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), CNRS INC3M - SFR ICORE 146, Bd Becquerel, F-14032, Caen cedex, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Brossard
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shozeb M
authors.initials: SM
authors.lastname: Haider
authors.forename: Miriam
authors.initials: M
authors.lastname: Sgobba
authors.forename: Mohamed
authors.initials: M
authors.lastname: Khalid
authors.forename: Rémi
authors.initials: R
authors.lastname: Legay
authors.forename: Martine
authors.initials: M
authors.lastname: Duterque-Coquillaud
authors.forename: Philippe
authors.initials: P
authors.lastname: Galera
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: Patrick
authors.initials: P
authors.lastname: Dallemagne
authors.forename: Safa
authors.initials: S
authors.lastname: Moslemi
authors.forename: Laïla
authors.initials: L
authors.lastname: El Kihel
mesh_terms: D000736:Androstenes; D000737:Androstenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001141:Aromatase / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053837:DNA Cleavage / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D010879:Piperazines / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000737:chemistry; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000736:Androstenes; D000737:Androstenols; D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D013256:Steroids; D001141:Aromatase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; C023666:pyridine
keywords: CYP17A1; CYP19; abiraterone analogues; hormone-dependent cancer; hormone-independent cancer; hybrid heterocycle steroids; prostate cancer; steroidal alkaloid analogues