New progesterone derivatives as inhibitors of 5α-reductase enzyme and prostate cancer cell growth

Abstract

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.

Steroids with a carbamate function at C-17, a novel class of inhibitors for human and hamster steroid 5α-reductase

“…Some carbamates inhibit endothelial cell proliferation in vitro and tumor induced angiogenesis in vivo as well as tumor growth in mice [18]. In view of the fact that recently we have synthesized several progesterone derivatives with an ester moiety at C-17 which showed high activity as 5␣-reductase enzyme inhibitors and prostate cancer cell growth [19], in this paper, we describe the synthesis of two new steroids based on the progesterone skeleton having a carbamate moiety at C-17, compounds 8a and 8b (Fig. 2).…”

Testosterone-Induced Prostate Growth Is Blocked by Co- and Preadministration of Norethisterone Enanthate in Castrated Cynomolgus Monkeys

“…Alternatively, these suggested endocrine interactions might be additionally influenced by an altered 5 ␣ -reductase metabolism, as has been indicated by previous experiments using inhibiting substances [26][27][28] . In a hamster model, in which the effects of progestin derivatives on prostate size were examined, it was suggested that these substances may act as 5 ␣ -reductase inhibitors and thereby avoid dihydrotestosterone-driven prostate growth increase, also interacting with the AR [29,30] . Unexpectedly, after the treatment change of groups with NETE, no significant prostate growth was measured in animals of group I.…”

Synthesis and biological effect of halogen substituted phenyl acetic acid derivatives of progesterone as potent progesterone receptor antagonists

“…Several new halogen substituted phenyl acetic acid ester derivatives of progesterone had been synthesized by our group which act as inhibitors of 5␣-reductase enzyme in human prostate [11]. However, these compounds did not bind to the androgen receptors (unpublished data).…”

“…The uteri from the rabbits were minced and homogenized in equal volume of TEMD buffer plus protease inhibitors (2 mM PMSF, 10 g/ml antipain, 5 mM leupeptin [14]; 40 mM Tris-HCl, 3 mM EDTA and 20 mM sodium molybdate, dithiotreitol 0.5 mM, 10% glycerol at pH 7.4) [11]. The homogenate was centrifuged at 140,000 × g for 1 h at 0 • C in a SW 60 Ti rotor (Beckman Instruments, Palo Alto, CA).…”