title: Synthesis of new sarsasapogenin derivatives with cytotoxicity and apoptosis-inducing activities in human breast cancer MCF-7 cells.
abstract: Based on the fact that Timosaponin A-III, a saponin isolated from the rhizome of Anemarrhena asphodeloides, is a promising bioactive lead compound in the treatment of cancer, structural modification at the C3 and C26 positions of sarsasapogenin has always been the focus of our structure-activity investigations. In this paper, we describe the synthesis of a range of new derivatives 5a-5o and the evaluation of their antitumor activities in a panel of six human cancer cell lines using the MTT assay in vitro. The results obtained showed that compounds 5h, 5i, and 5n exhibited significant cytotoxic activities against the six cell lines, being more potent than their parent compound sarsasapogenin. Furthermore, the p-fluorobenzyloxy series of compounds generally exhibited stronger cytotoxicities against all the tested cancer cells compared with the benzyloxy and p-methoxybenzyloxy series, and the substitution of pyrrolidinyl and piperazinyl groups at the C26 position was the preferred option for these compounds to display antitumor activities. Compound 5n exhibited excellent cytotoxic activity against MCF-7 cell line (IC50= 2.95 μM), and was 16.7-fold more potent than sarsasapogenin. Further studies of the cellular mechanism of 5n showed that it arrested MCF-7 cells at the G2/M phase and induced apoptosis and necrosis. All these results show that it is important to carry out structural modification of sarsasapogenin to obtain some promising derivatives with marked antitumor activities, and the representative compound 5n is a lead compound for further research.
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Wenbao
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Zedan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Yao
authors.affiliation: School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Shenyang University of Chemical Technology, Shenyang 110142, People's Republic of China.
authors.forename: Pinyi
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: sjwang_99@163.com.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address: songsj99@163.com.
authors.forename: Shaojiang
authors.initials: S
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D013150:Spirostans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D013150:Spirostans; C046297:sarsasapogenin
keywords: Apoptosis; Cytotoxicity; MCF-7 cells; Sarsasapogenin derivatives