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

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

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: marina.savic@dh.uns.ac.rs.
  • 2 Department of Biology and Ecology , Faculty of Sciences , University of Novi Sad , Trg Dositeja Obradovića 2 , 21000 Novi Sad , Serbia . Email: edward.petri@dbe.uns.ac.rs.
  • 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.

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