Evaluation of A-ring fused pyridine d-modified androstane derivatives for antiproliferative and aldo–keto reductase 1C3 inhibitory activity† †Electronic supplementary information (ESI) available: IR, 1H and 13C NMR and HRMS spectra. CCDC CCDC 1823137–1823139. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8md00077h

• Published in: MedChemComm Vol. 9; no. 6; pp. 969 - 981
• Main Authors: Savić, Marina P., Ajduković, Jovana J., Plavša, Jovana J., Bekić, Sofija S., Ćelić, Andjelka S., Klisurić, Olivera R., Jakimov, Dimitar S., Petri, Edward T., Djurendić, Evgenija A.
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 30.04.2018
• Subjects: Chemistry
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c8md00077h

New A-ring pyridine fused androstanes in d -homo lactone, 17α-picolyl or 17( E )-picolinylidene series were synthesized and validated. New A-ring pyridine fused androstanes in 17a-homo-17-oxa ( d -homo lactone), 17α-picolyl or 17( E )-picolinylidene series were synthesized and validated by X-ray crystallography, HRMS, IR and NMR spectroscopy. Novel compounds 3 , 5 , 8 and 12 were prepared by treatment of 4-en-3-one or 4-ene-3,6-dione d -modified androstane derivatives with propargylamine catalyzed by Cu( ii ), and evaluated for potential anticancer activity in vitro using human cancer cell lines and recombinant targets of steroidal anti-cancer drugs. Pyridine fusion to position 3,4 of the A-ring may dramatically enhance affinity of 17α-picolyl compounds for CYP17 while conferring selective antiproliferative activity against PC-3 cells. Similarly, pyridine fusion to the A-ring of steroidal d -homo lactones led to identification of new inhibitors of aldo–keto reductase 1C3, an enzyme targeted in acute myeloid leukemia, breast and prostate cancers. One A-pyridine d -lactone steroid 5 also has selective submicromolar antiproliferative activity against HT-29 colon cancer cells. None of the new derivatives have affinity for estrogen or androgen receptors in a yeast screen, suggesting negligible estrogenicity and androgenicity. Combined, our results suggest that A-ring pyridine fusions have potential in modulating the anticancer activity of steroidal compounds.