title: Total synthesis and biological evaluation of grassypeptolide A.
abstract: Herein, we describe in full our investigations into the synthesis of grassypeptolide A (1) in 17 linear steps with an overall yield of 11.3 %. In particular, this work features the late-stage introduction of sensitive bis(thiazoline) heterocycles and 31-membered macrocyclization conducted at the sterically congested secondary amide site in superb conversion (72 % yield). Biological evaluation indicated that grassypeptolide A significantly inhibited cancer cell proliferation in a dose-dependent manner. It induced cancer cell apoptosis, which was associated with increased cleavage of poly(ADP-ribose) polymerase (PARP) and decreased expression of bcl-2 and bcl-xL. Furthermore, grassypeptolide A also caused cell cycle redistribution by increasing cells in the G1 phase and decreasing cells in the S and G2 phases. In addition, cell cycle arrest was correlated with downregulation of cyclin D and upregulation of p27 and p21.
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiangyou
authors.initials: X
authors.lastname: Xing
authors.forename: Anita R
authors.initials: AR
authors.lastname: Maguire
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhengshuang
authors.initials: Z
authors.lastname: Xu
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D002455:Cell Division; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008386:Marine Biology; D015394:Molecular Structure; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; C555839:grassypeptolide A; D011065:Poly(ADP-ribose) Polymerases