Synthesis, structural analysis and antiproliferative activity of some novel D-homo lactone androstane derivatives

Abstract

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-3b-yl acetate 1 into the 5a-hydroxy-17-oxa-D-homoandrostane-6,16-dion-3b-yl acetate (4). After the dehydration of 4, the newly synthesized 6-keto-androst-4-ene-3b-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 4b,5b-epoxy derivative 12.Structures were confirmed by IR, 1 H NMR, 13 C 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 (ER2, MDA-MB-231) breast cancer cells over estrogen-dependent (ER+, MCF-7) breast cancer cells.

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

“…19,20 Rational modification of steroid hormones is a proven strategy for the development of improved treatments for hormone-dependent and other cancers. 5,21 For example, addition of a lactone ring to the steroid nucleus is associated with dramatic changes in bioactivity vs. parent compounds, and has led to identification of potential cytotoxic agents 22 and compounds that modulate steroid signaling pathways including inhibitors of 5α-reductase, 23 aromatase 24 and AKR1C3. 25 Testolactone, a steroidal D-lactone, was one of the first steroids used in clinical treatment and prevention of hormonedependent tumors such as breast cancer, 26 while the steroidal D-lactone EM1401 is a selective inhibitor of human AKR1C3.…”

Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties

“…All of the compounds except 5 were as toxic in MRC-5 cells (SF ≤ 1) as in cancer cells ( Table 1 ), or more toxic in MRC-5 cells than in cancer cells, suggesting they may cause serious side effects during treatment. Similarly, poor selectivity is typically observed for anticancer natural product drugs such as paclitaxel and doxorubicin 46 , 47 . That is, despite being very effective, these drugs can cause severe toxicity in cancer patients, including heart toxicity and peripheral neuropathy 48 , 49 .…”

The Structural Diversity and Biological Activity of Steroid Oximes

“…Savić et al, designed and synthesized some novel D-homo lactone androstane derivatives and evaluated their antiproliferative activity against several cancer cell lines [ 49 ]. Among these compounds, the oxime derivative 1t ( Figure 4 ), demonstrated to have high activity ( Table 1 ).…”