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.

Parasitic diseases affect millions of people and animals, predominantly in the tropics, in-cluding visitors to tropical countries and other areas. Efficient and low-cost treatments for infections caused by various parasites are not yet available. Antiparasitic drugs have some drawbacks, such as toxicity and the development of resistance by parasites. This has motivated many researchers to fo-cus on the discovery of safe, effective and affordable antiparasitic drugs, both among drugs already available for other diseases and new compounds synthesized or isolated from natural sources. Fur-thermore, steroid and triterpenoid compounds attract the attention of pharmacologists, chemists and biochemists owing to their broad application in the treatment of various diseases. Isolation of ster-oid and triterpenoid compounds from natural sources with antiparasitic efficacy is an attractive choice for scientists. On the other hand, these compounds can be transformed into more potent forms by modifying the basic skeleton. This review presents a collection of isolated and synthesized steroid and triterpenoid compounds from 2018 to 2021 that have been reported to be effective against certain parasitic protozoa and helminths. A total of 258 compounds have been identified with antimalarial, antitrypanosomal, antileishmanial, anti-Toxoplasma, and/or anthelmintic activity. The described investigations of antiparasitic compounds may be helpful for further drug develop-ment.

An efficient synthesis of several A,B-modified D-homo lactone androstane derivatives is reported. The synthetic scheme shows the transformation of 17-oxa-D-homoandrost-5-en-16-on-3β-yl acetate 1 into the 5α-hydroxy-17-oxa-D-homoandrostane-6,16-dion-3β-yl acetate (4). After the dehydration of 4, the newly synthesized 6-keto-androst-4-ene-3β-yl acetate derivative 5 was oximinated to give the 6-hydroximino derivative 6, which was converted to A,B-condensed isoxazole derivatives 7 and 8. Compound 4 was also converted (via 6(E)- and 6(Z)-hydroximino derivatives 9 and 10) to the B-seco-cyano derivative 11 under a Beckmann fragmentation, while compound 5 was transformed to the 4β,5β-epoxy derivative 12. Structures were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS, and for 7 and 8 by X-ray crystallography. All compounds were tested in vitro on six malignant cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) and one non-tumor MRC-5 cell line. Significant antiproliferative activity was observed for specific compounds against prostate (PC-3), cervical (HeLa) and colon (HT-29) cancer cells, while no compounds showed antiproliferative activity to non-cancerous control cells (MRC-5). Interestingly, 1–8 displayed selective antiproliferative activity against estrogen-independent (ER−, MDA-MB-231) breast cancer cells over estrogen-dependent (ER+, MCF-7) breast cancer cells.