title: Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth.
abstract: We have exploited the reaction of 1,1'-carbonylbis(2-methylimidazole) (CBMI) with several 17beta-hydroxy androstanes to synthesize a series of novel C17 steroidal carbamates. Structural elucidation features have been provided for the final compounds based on 1D and 2D NMR techniques, IR spectroscopy, and related literature. The new compounds were tested for inhibition of human cytochrome 17alpha-hydroxylase-C17,20-lyase (CYP17) and androgen receptor (AR) binding and function effects. Their inhibitory potential against PC-3 cell proliferation was also evaluated. Compounds 11 and 23 were found to inhibit CYP17 with IC50 values of 17.1 and 11.5 microM, respectively. The carbamate moiety at C17 allowed tight binding of the synthesized compounds to both wild-type (wt-) and mutated AR. When bound to the mutated AR, the compounds were found to have a dual effect, stimulating transcription at low concentrations while almost fully blocking it at the higher concentrations tested, in the presence of the natural androgen dihydrotestosterone (DHT). Compounds 8 and 12 were the most active against PC-3 cell proliferation with EC50 values of 2.2 and 0.2 microM, respectively.
authors.affiliation: Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Rua do Norte, 3000-295 Coimbra, Portugal.
authors.forename: Vânia M A
authors.initials: VM
authors.lastname: Moreira
authors.forename: Tadas S
authors.initials: TS
authors.lastname: Vasaitis
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Guo
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
authors.forename: Jorge A R
authors.initials: JA
authors.lastname: Salvador
mesh_terms: D002219:Carbamates / Q000138:chemical synthesis*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism* / Q000502:physiology; D021241:Spectrometry, Mass, Electrospray Ionization; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D013256:Steroids / Q000138:chemical synthesis*
chemical_list: D002219:Carbamates; D011944:Receptors, Androgen; D013256:Steroids; D013254:Steroid 17-alpha-Hydroxylase