17α-Hydroxylase-C17,20-lyase (P45017α) is a key regulator enzyme of the steroid hormone biosynthesis in both the adrenals and the testes. Inhibition of this enzyme can block androgen synthesis in an early step, and may thereby be useful in the treatment of prostatic carcinoma, which is androgen-dependent in the majority of cases. Abiraterone and its analogues have been found strong inhibitors of P45017α suggesting that steroid derivatives with heterocyclic substituent on the C-17 position may bear such potential.
We investigated inhibitory effect on C17,20-lyase exhibited by newly synthesised androsterone derivatives with heterocyclic 17β substituents. C17,20-lyase inhibition was tested via conversion of 17α-hydroxy-progesterone to androst-4-en-3,17-dione in the homogenate of rat testis in vitro. Incubation was carried out with 14C labeled substrate at 37 °C for 20 min. Following an extraction procedure and isolation by thin layer chromatography, the enzyme product and the residual substrate were quantified by their radioactivities. Ketokonazole, a P45017α inhibitor applied in medical practice was used as a reference compound. Among test compounds the non-substituted tetrahydrooxazolone and tetrahydrooxazinone derivatives were found to be the best C17,20-lyase inhibitors; IC50 values were 4.2 and 6.0 μM, respectively. The N-phenyl-tetrahydrooxazinones did not show substantial inhibition (IC50 >50 μM).
The 17β-exo-heterocyclic androsterone derivatives which proved to be potential C17,20-lyase inhibitors in the present study, also exhibited marked inhibition against prostatic 5α-reductase activity in our previous investigations. This dual effect might be particularly beneficial in the therapy of prostate cancer.