New progesterone derivatives as inhibitors of 5alpha-reductase enzyme and prostate cancer cell growth.
In this study we report the synthesis and pharmacological evaluation, in vivo as well as in vitro, of four new progesterone derivatives 4-7. The evaluation in vivo was carried out on gonadectomized male hamsters that were injected subcutaneously daily with 1 mg/Kg of testosterone (T) and/or 1 mg/Kg of finasteride, or with 2 mg/Kg of the novel compounds. It was observed that when testosterone (T) and finasteride or compound 4 were injected together, the weight of the prostate decreased significantly as compared to that oftestosterone-treated animals. Compounds 5-7 did not show any in vivo activity. The 5alpha-reductase inhibitory activity of the novel compounds was determined in vitro using human prostate homogenates; the steroids 4-7 inhibited the 5alpha-reductase activity with IC50 values lower than that for the reference compound finasteride. 3. The effect of compounds 4-7 on the growth of lymphocytes and prostate cancer culture cells line was that steroid 4 inhibited the growth of both cells lines at a concentration of 50 microM and showed a cytotoxic effect whereas compounds 5-7 showed a much lower inhibition. Nevertheless steroids 4-7 didn't exhibit any toxic effects in vivo since the animals remained alive during the six days of treatment.
Cabeza
Marisa
M
Department of Biological Systems and Animal Production, Metropolitan University-Xochimilco, Mexico, DF Mexico. marisa@correo.xoc.uam.mx
Bratoeff
Eugene
E
Heuze
Ivonne
I
Rojas
Arely
A
Terán
Nayely
N
Ochoa
Martha'
M
Ramírez-Apan
Teresa
T
Ramírez
Elena
E
Pérez
Victor
V
Gracia
Isabel
I
D000818:Animals; D045744:Cell Line, Tumor; D042944:Cholestenone 5 alpha-Reductase / Q000737:chemistry*; D006224:Cricetinae; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D008297:Male; D008647:Mesocricetus; D008956:Models, Chemical; D011374:Progesterone / Q000031:analogs & derivatives* / Q000737:chemistry*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013256:Steroids / Q000737:chemistry; D013739:Testosterone / Q000494:pharmacology
D013256:Steroids; D013739:Testosterone; D011374:Progesterone; D018120:Finasteride; D042944:Cholestenone 5 alpha-Reductase