In this study, eighteen novel steroidal-furoxan derivatives with 3-glycosyl or 3-methoxy moiety (12a-c, 13a-c, 17a-c, 26a-c, 27a-c and 28a-c) were synthesized and their anti-proliferative activity was evaluated against eight drug-sensitive and three drug-resistant cancer cell lines HeLa, A2780, LNCaP, PC-3, MDA-MB-231, MCF-7, SW480, A549, MCF-7/ADR, A2780/CDDP and A2780/T. Most of them displayed significant anti-cancer potency in vitro with IC50 values at the nanomole level. Among them, 3-methoxy steroidal-furoxan hybrids expressed much better activity than that of 3-glycosyl substitute ones, while estrane and 5 alpha-H-androstane scaffold were slightly more favorable to the improvement of anti-proliferative activity. Especially, compounds 27c and 28b showed the strongest cytotoxicity with IC50 values of 0.0007-0.034 and 0.0011-0.008 mu M, respectively in five drug-sensitive cancer cell lines. Furthermore, 3-glycoconjugates 13a, 13c, 17b and 3-methoxy compounds 27a, 27c, 28b displayed lower toxicity in nontumorigenesis cells HOSEC and expressed a good selectivity against malignant cells in vitro. Preliminary study of pharmacology showed that the introduction of glucose at 3-position in steroidal core seems unable to use glucose transporters to improve the selectivity against proliferation of malignant cells, while the NO-releasing capacity might explain the potent anti-neoplastic activity of these compounds. And compound 28b could induce the apoptosis and hardly affected the cell cycle of A2780. Then, the further study of these steroidal-furoxan hybrids merits to explore and develop a desirable anti-cancer candidate.
[1]Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
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