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

Abstract

New A-ring pyridine fused androstanes in 17a-homo-17-oxa (d-homo lactone), 17α-picolyl or 17()-picolinylidene series were synthesized and validated by X-ray crystallography, HRMS, IR and NMR spectroscopy. Novel compounds ,, and 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 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 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.

Novel alkylaminoethyl derivatives of androstane 3-oximes as anticancer candidates: synthesis and evaluation of cytotoxic effects

“…O-Alkylated oximes derivatized with an alkylaminoethyl side chain have also been reported as effective candidates for cytotoxic drugs. In view of these ndings and in continuation of our previous work 7, [24][25][26][27] on the synthesis and biological activity of androstane derivatives, we have synthesized novel oxime-ether derivatives in 17a-(pyridin-2-yl) methyl series (4-10) and in (17E)-(pyridin-2-yl)methylidene series (14)(15)(16)(17)(18)(19)(20), by the reaction of androst-4-ene 3E-oxime 2 and 12, using various alkylaminoethyl chlorides. The biological effects of these new compounds were then studied in vitro on several types of human steroid-converting CYPs and on human cancer cell lines.…”

Pyridine Moiety: Recent Advances in Cancer Treatment

“…AKR1C2, is also known as bile acid binding protein and preferentially reduces Dihydrotestosterone (DHT) to the weak metabolite 5α-androstane-3α,17βdiol (3α-diol) without conversion of 3α-diol to DHT in the PC-3 cell line [95][96][97] . Savic et al [98] synthesized and validated new A ring pyridine fused androstanes in 17a-homo-17-oxa (D-homo lactone), 17α-picolyl or 17(E)-picolinylidene series for potential antitumor activity in vitro using human tumor cell lines and recombinant targets of steroidal antitumor drugs. SAR revealed that pyridine fusion to position 3, 4 of the A ring intensely enhance affinity of 17α-picolyl compounds for cytochrome (CYP) 17 while conferring selective anti-proliferative activity against PC-3 cells.…”

Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic Ketones with Propargylamine

“…Among 24 substrates, the desired products were not detected in the reaction mixture only for 7 ketones: ethyl 2-oxocyclohexanecarboxylate 22f, 32 dihydrothiophen-3(2H)-one 22j, 2-fluorocyclohexanone 22t, monoprotected 1,3-cyclohexanedione 22s, furan-2,4(3H,5H)-dione 22u, and α,β-unsaturated cyclic ketones 22v and 22w. 33,34 In other cases, the desired fused pyridines formed in 5−65% yields (see Table 2). Interestingly, among all ketones, the best results were obtained for the sixmembered species: the yields were ca.…”