title: Synthesis and antitumor evaluation of novel hybrids of phenylsulfonylfuroxan and epiandrosterone/dehydroepiandrosterone derivatives.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yaoqing
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, ZhongShan Hospital, Fudan University, Shanghai, China.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Zhejiang Xianju Pharmaceutical Co. Ltd., Zhejiang, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Ying
authors.affiliation: Zhejiang Xianju Pharmaceutical Co. Ltd., Zhejiang, China.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China. Electronic address: yingchen71@fudan.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000738:Androsterone / Q000031:analogs & derivatives*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives*; D006801:Humans; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D042461:Vascular Endothelial Growth Factor A; D003687:Dehydroepiandrosterone; D000738:Androsterone
keywords: 16,17-Pyrazo-annulated steroids; Anti-cancer; Cytotoxicity; Furoxan; VEGF inhibitor