期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 17, 页码 4287-4291出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.07.040
关键词
Hsp90 inhibitors; Anticancer activity; Herbimycin A; C18-deoxy analogue; C15-phenylated analogue
资金
- National Natural Science Foundation of China [21272279]
Benzoquinone ansamycins are important leads for the discovery of novel inhibitors of heat shock protein 90 (Hsp90), a promising target of cancer chemotherapeutics. Intrinsic hepatotoxicity caused by the benzoquinone moiety appeared to be a serious limitation to the development of these compounds. To solve this problem by rational structure optimization, a short series of C18-deoxy analogues of herbimycin A were designed based on putative interactions between the compound and the protein. Chemical synthesis of the target molecules were attempted by following the established synthetic route to the natural product, but resulted in the isolation of four serendipitous C15 phenylated final products. In vitro antiproliferative activity and Hsp90 binding affinity of the compounds were determined, suggesting the C18-oxygen of herbimycin A is removable and bulky lipophilic groups can be accommodated at C15 without loss of activity. (C) 2016 Published by Elsevier Ltd.
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