Synthesis and antitumor evaluation of novel hybrids of phenylsulfonylfuroxan and epiandrosterone/dehydroepiandrosterone derivatives

•Synthesis of hybrids with 16,17-pyrazo-annulated steroids and phenylsulfonylfuroxan.•The newly synthesized compounds were evaluated as anti-cancer agents.•Preliminary structure activity relationship was demonstrated. Thirteen novel furoxan-based nitric oxide (NO) releasing hybrids (14a–e, 15a–e, 17...

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Bibliographic Details
Published in:Steroids 2015-09, Vol.101, p.7-14
Main Authors: Huang, Yaoqing, Liu, Mingming, Meng, Lanfang, Feng, Pan, Guo, Yalan, Ying, Minghua, Zhu, Xiuyan, Chen, Ying
Format: Article
Language:English
Subjects:
16,17-Pyrazo-annulated steroids
Androsterone - analogs & derivatives
Anti-cancer
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry Techniques, Synthetic
Cytotoxicity
Dehydroepiandrosterone - analogs & derivatives
Furoxan
Humans
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacology
Vascular Endothelial Growth Factor A - antagonists & inhibitors
VEGF inhibitor
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Summary:•Synthesis of hybrids with 16,17-pyrazo-annulated steroids and phenylsulfonylfuroxan.•The newly synthesized compounds were evaluated as anti-cancer agents.•Preliminary structure activity relationship was demonstrated. Thirteen novel furoxan-based nitric oxide (NO) releasing hybrids (14a–e, 15a–e, 17b–d) of 16,17-pyrazo-annulated steroidal derivatives were synthesized and evaluated against the MDA-MB-231, HCC1806, SKOV-3, DU145, and HUVEC cell lines for their in vitro anti-proliferative activity. Most of the compounds displayed potent anti-proliferative effects. Among them, 17c exhibited the best activity with IC50 values of 20–1.4nM against four cell lines (MDA-MB-231, SKOV-3, DU145, and HUVEC), and 1.03μM against a tamoxifen resistant breast cancer cell line (HCC1806). Furthermore, five compounds (14a, 15a, 17b–d) were selected to screen for VEGF inhibitory activity. Compounds 15a, 17b,c showed obviously better activity than 2-Methoxyestradiol (2-ME) on reducing levels of VEGF secreted by MDA-MB-231 cell line. In a Capillary-like Tube Formation Assay, compounds 17b,c exhibited a significant suppression of the tubule formation in the concentration of 1.75nM and 58nM, respectively. The preliminary SAR showed that steroidal scaffolds with a linker in 3-position were favorable moieties to evidently increase the bioactivities of these hybrids. Overall, these results implied that 17c merited to be further investigated as a promising anti-cancer candidate.
ISSN:0039-128X
1878-5867
DOI:10.1016/j.steroids.2015.05.003