Synthesis of potent cytotoxic epidithiodiketopiperazines designed for derivatization
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acs.joc.9b03371.pdf
Description
Published version
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2.51 MB
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Author(s)
Olsson, Chase Robert
Payette, Joshua N.
Cheah, Jaime
Movassaghi, Mohammad
Date Issued
March 2020
Journal
The journal of organic chemistry
Publisher
American Chemical Society (ACS)
Citation
Olsson, Chase R., Joshua N. Payette, Jaime Cheah, and Mohammad Movassaghi, "Synthesis of potent cytotoxic epidithiodiketopiperazines designed for derivatization." The journal of organic chemistry 85, 7 (March 2020): p. 4648-62 doi 10.1021/acs.joc.9b03371 ©2020 Author(s)
Version
Final published version
Abstract
We describe our design, synthesis, and chemical study of a set of functional epidithiodiketopiperazines (ETPs) and evaluation of their activity against five human cancer cell lines. Our structure-activity relationship-guided substitution of ETP alkaloids offers versatile derivatization while maintaining potent anticancer activity, offering exciting opportunity for their use as there are no examples of complex and potently anticancer (nM) ETPs being directly used as conjugatable probes or warheads. Our synthetic solutions to strategically designed ETPs with functional linkers required advances in stereoselective late-stage oxidation and thiolation chemistry in complex settings, including the application of novel reagents for dihydroxylation and cis-sulfidation of diketopiperazines. We demonstrate that complex ETPs equipped with a strategically substituted azide functional group are readily derivatized to the corresponding ETP-triazoles without compromising anticancer activity. Our chemical stability studies of ETPs along with cytotoxic evaluation of our designed ETPs against A549, DU 145, HeLa, HCT 116, and MCF7 human cancer cell lines provide insights into the impact of structural features on potency and chemical stability, informing future utility of ETPs in chemical and biological studies. ©2020
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1021/acs.joc.9b03371
