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Total Synthesis and Biological Evaluation of Grassypeptolide A
Author(s) -
Liu Hui,
Liu Yuqing,
Wang Zhuo,
Xing Xiangyou,
Maguire Anita R.,
Luesch Hendrik,
Zhang Hui,
Xu Zhengshuang,
Ye Tao
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201203667
Subject(s) - downregulation and upregulation , cell cycle , poly adp ribose polymerase , steric effects , cell growth , apoptosis , chemistry , cell cycle checkpoint , cyclin , cyclin b1 , cleavage (geology) , cyclin dependent kinase 1 , cell , microbiology and biotechnology , polymerase , biochemistry , stereochemistry , biology , dna , gene , paleontology , fracture (geology)
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.