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

  • Medchemcomm. 2018 Apr 30;9(6):969-981. doi: 10.1039/c8md00077h.
Marina P Savić  1 ,  Jovana J Ajduković  1 ,  Jovana J Plavša  2 ,  Sofija S Bekić  1 ,  Andjelka S Ćelić  2 ,  Olivera R Klisurić  3 ,  Dimitar S Jakimov  4 ,  Edward T Petri  2 ,  Evgenija A Djurendić  1
Affiliations
  • 1. Department of Chemistry, Biochemistry and Environmental Protection , Faculty of Sciences , University of Novi Sad , Trg Dositeja Obradovića 3 , 21000 Novi Sad , Serbia . Email: [email protected].
  • 2. Department of Biology and Ecology , Faculty of Sciences , University of Novi Sad , Trg Dositeja Obradovića 2 , 21000 Novi Sad , Serbia . Email: [email protected].
  • 3. Department of Physics , Faculty of Sciences , University of Novi Sad , Trg Dositeja Obradovića 4 , 21000 Novi Sad , Serbia.
  • 4. Oncology Institute of Vojvodina , Faculty of Medicine , University of Novi Sad , Put Dr Goldmana 4 , 21204 Sremska Kamenica , Serbia.
PMID: 30108986 DOI: 10.1039/c8md00077h
Abstract

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.