Novel N-Methylated Cyclodepsipeptide Prodrugs for Targeted Cancer Therapy
- 8 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (2), 991-1000
- https://doi.org/10.1021/acs.jmedchem.0c01387
Abstract
Coibamide A (1) is a highly N-methylated cyclodepsipeptide with low nanomolar antiproliferative activities against various cancer cell lines. In previous work, we discovered a simplified analogue, [MeAla3-MeAla6]-coibamide (1a), which exhibited the same inhibitory abilities as coibamide A. Herein, to reduce the whole-body toxicity and improve the solubility of 1a, two novel peptide–drug conjugates RGD-SS-CA (2) and RGD-VC-CA (3) were designed, synthesized, and evaluated. Composed of cyclodepsipeptide 1a, a tumor-homing RGD motif, and a conditionally labile linker, the conjugates are expected to release 1a tracelessly in specific tumor microenvironments. Compared with RGD-VC-CA (3), RGD-SS-CA (2) proved to be superior in in vitro drug release and cytotoxicity tests. Notably, intravenous injection of RGD-SS-CA (2) into mice-bearing human tumor xenografts induced significant tumor growth suppression with negligible toxicity. Therefore, as a novel prodrug of the coibamide A analogue, conjugate 2 has great potential for further exploration in cancer drug discovery.Keywords
Funding Information
- Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20170818153538196, JCYJ20170818162642882)
- National Natural Science Foundation of China (21672254, 21778068, 21977111)
- Natural Science Foundation of Guangdong Province (2018B030308001, 2019A1515012073)
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