Jump to main content
Jump to site search

Issue 6, 2018
Previous Article Next Article

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

Author affiliations

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.

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

Back to tab navigation

Supplementary files

Publication details

The article was received on 09 Feb 2018, accepted on 27 Apr 2018 and first published on 30 Apr 2018


Article type: Research Article
DOI: 10.1039/C8MD00077H
Citation: Med. Chem. Commun., 2018,9, 969-981
  •   Request permissions

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

    M. P. Savić, J. J. Ajduković, J. J. Plavša, S. S. Bekić, A. S. Ćelić, O. R. Klisurić, D. S. Jakimov, E. T. Petri and E. A. Djurendić, Med. Chem. Commun., 2018, 9, 969
    DOI: 10.1039/C8MD00077H

Search articles by author

Spotlight

Advertisements