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Macrocyclic Toolbox from Epothilone Fragment Identifies a Compound Showing Molecular Interactions with Actin and Novel Promoters of Apoptosis in Patient‐derived Brain Tumor Cells
Author(s) -
Dasari Bhanudas,
Fufa Temesgen,
Aeluri Madhu,
Gaddam Jagan,
Deora Girdhar Singh,
Gaunitz Frank,
Kitambi Satish Srinivas,
Arya Prabhat
Publication year - 2016
Publication title -
asian journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.846
H-Index - 44
eISSN - 2193-5815
pISSN - 2193-5807
DOI - 10.1002/ajoc.201600126
Subject(s) - chemistry , fragment (logic) , toolbox , apoptosis , promoter , stereochemistry , microbiology and biotechnology , biochemistry , gene , algorithm , programming language , gene expression , biology , computer science
A simple, practical stereoselective synthesis of the epothilone fragment is developed to obtain a diverse set of expanded 18‐membered macrocyclic compounds. These macrocycles contain the C5–C8 sub‐unit of epothilone and an additional amino acid moiety incorporated in the 18‐membered macrocycle, which allows the synthesis of several analogs with a variation in the chiral side chain. The epothilone fragment was obtained by using an enantiopure epoxide, which was subjected to a regioselective opening, giving the key derivative. Finally, the synthesis of the 18‐membered macrocyclic ring was achieved by employing two key steps: (i) acylation with an N ‐allylated amino acid moiety, and (ii) a ring‐closing metathesis (RCM) approach. Computational studies of the macrocyclic compounds obtained from this study with actin give rise to the proposed molecular interactions with the target protein. Further, the screening of our chemical toolbox from this program (i.e., the final products and several intermediates) identified several compounds as promoters of apoptosis in patient‐derived brain tumor glioma cells.