title: Total Syntheses and Biological Activities of Vinylamycin Analogues.
abstract: Natural depsipeptide vinylamycin was reported to be an antibiotic previously. Herein we report vinylamycin to be active against K562 leukemia cells (IC50= 4.86 μM) and be unstable in plasma (t1/2= 0.54 h). A total of 24 vinylamycin analogues with modification of the OH group and chiral centers were generated via a combinatorial approach. The lead compound 1a was subsequently characterized as having the following: no antimicrobial activity, significantly higher plasma stability (t1/2= 14.3 h), improved activity against K562 leukemia cells (IC50= 0.64 μM), and up to 75% cell inhibition without significant toxicities in K562 cells xenograft zebrafish model. Furthermore, compound 1a maintained its activity against the breast cancer cell line MCF-7 under hypoxic conditions. In comparison, the activity of gemcitabine in the same hypoxic in vitro model of MCF-7 cells was 15-fold lower. Therefore, the present results demonstrate that 1a has great potential as an anticancer agent.
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Jinghan
authors.initials: J
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Beijia
authors.initials: B
authors.lastname: Kuang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.|High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine , Tianjin 300457, People's Republic of China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Guo
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Ding
authors.affiliation: School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, People's Republic of China.
authors.forename: Jiangnan
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Science and Technology, Tianjin University , Tianjin, 300072, People's Republic of China.
authors.forename: Shende
authors.initials: S
authors.lastname: Jiang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Luyuan
authors.initials: L
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Hunter Biotechnology, Inc., F1A, building 5, no. 88 Jiangling Road, Binjiang Zone, Hangzhou, Zhejiang Province 310051, People's Republic of China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Hunter Biotechnology, Inc., F1A, building 5, no. 88 Jiangling Road, Binjiang Zone, Hangzhou, Zhejiang Province 310051, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xia
authors.affiliation: Hunter Biotechnology, Inc., F1A, building 5, no. 88 Jiangling Road, Binjiang Zone, Hangzhou, Zhejiang Province 310051, People's Republic of China.
authors.forename: Chun-Qi
authors.initials: CQ
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Yue
authors.identifier: 0000-0002-1317-7097
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D020014:K562 Cells; D015027:Zebrafish
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D047630:Depsipeptides; C402693:vinylamycin