Synthesis and evaluation of agelastatin derivatives as potent modulators for cancer invasion and metastasis
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nihms904287.pdf
Description
Accepted version
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896.19 KB
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Author(s)
Antropow, Alyssa Hope
Xu, Kun
Buchsbaum, Rachel J.
Movassaghi, Mohammad
Date Issued
July 2017
Journal
Journal of Organic Chemistry
Publisher
American Chemical Society (ACS)
Citation
Antropow, Alyssa H., et al., "Synthesis and evaluation of agelastatin derivatives as potent modulators for cancer invasion and metastasis." Journal of Organic Chemistry 82, 15 (July 2017): p. 7720-31 doi 10.1021/acs.joc.7b01162 ©2017
Version
Author's final manuscript
Abstract
The synthesis of new agelastatin alkaloid derivatives and their anticancer evaluation in the context of the breast cancer microenvironment is described. A variety of N1-alkyl and C5-ether agelastatin derivatives were accessed via application of our strategy for convergent imidazolone synthesis from a common thioester along with appropriately substituted urea and alcohol components. These agelastatin derivatives were evaluated in our three-dimensional coculture assay for the effects of mammary fibroblasts on associated breast cancer cells. We have discovered that agelastatin alkaloids are potent modulators for cancer invasion and metastasis at noncytotoxic doses. Herein, we discuss the increased potency of (-)-agelastatin E as compared to (-)-agelastatin A in this capacity, in addition to identification of new agelastatin derivatives with activity that is statistically equivalent to (-)-agelastatin E. The chemistry described in this report provides a platform for the rapid synthesis of agelastatin derivatives with excellent potency (50-100 nM) as modulators for cancer invasion and metastasis.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/acs.joc.7b01162
