Evaluation of A-ring fused pyridine d-modified androstane derivatives for antiproliferative and aldo-keto reductase 1C3 inhibitory activityElectronic 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

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. New A-ring pyridine fused androstanes in d -homo lactone, 17α-picolyl or 17( E )-picolinylidene series were synthesized and validated.