Popis: |
Objective: Novel agents to treat metastatic prostate cancer include a class of drugs which function primarily by inhibiting the action of the CYP17 enzyme, which results in decreased androgen synthesis. Abiraterone and related molecules have been shown to decrease expression of the androgen receptor (AR) and to inhibit its transcriptional activity in addition to CYP17 inhibition. The structure-activity relationships (SAR) governing AR down regulation are less well understood than CYP17 and AR inhibition, so we designed abiraterone derivatives with the goal of better understanding the SAR of AR down regulation. Methods: We synthesized 17 abiraterone derivatives with unsaturated, cyclic and acyclic substituents containing hydrogen bond acceptors at C16 and C17 positions. We examined the ability of these compounds to inhibit CYP17 and AR, and to decrease AR expression. Results: While abiraterone was the most potent AR down regulator, we found that a hydrogen bond acceptor on an unsaturated nitrogen or oxygen, 4 to 6 angstroms from C17 is required for AR down-regulation, but a heterocyclic ring is not necessary, as shown by the activity of compounds 4, 8, and 10. The size and shape of substituents on active AR down regulators indicates that the binding site near C17 is significantly larger than the pyridine ring in abiraterone. We found no correlation between the ability of a compound to down regulate AR and its ability to inhibit CYP17 or AR transcriptional activity. AR transcriptional activity was inhibited most potently by molecules with hydrogen bond donors 2-3 angstroms from C17. Molecules with C16 substituents could inhibit AR transcription but were inactive as AR down regulators, as indicated by compounds 5, 13, and 14. CYP17 inhibitors had an unsaturated nitrogen (pyridine or hydrazine) oriented away from the steroid backbone and perpendicular to the C16-C17 bond. Conclusion: We determined the SAR for AR down regulation. The complete lack of correlation between SARs for AR down regulation and AR or CYP17 inhibition suggests distinct mechanisms of actions for these activities. The SAR for AR down regulation suggests that additional hydrogen bond acceptor side chains 4-6 angstroms from C17 could enhance the activity of abiraterone. |