Brown, A.W., Fisher, M., Tozer, G.M. et al. (2 more authors) (2016) Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4. Journal of Medicinal Chemistry, 59 (20). pp. 9473-9488. ISSN 0022-2623
Abstract
The combretastatins are an important class of tubulin-binding agents. Of this family, a number of compounds are potent tumor Vascular Disrupting Agents (VDAs) and have shown promise in the clinic for cancer therapy. We have developed a modular synthetic route to combretastatin analogs based on a pyrazole core through highly-regioselective alkyne cycloaddition reactions of sydnones. These compounds show modest to high potency against human umbilical vein endothelial cell proliferation. Moreover, evidence is presented that these novel VDAs have the same mode of action as CA4P and bind reversibly to β-tubulin - believed to be a key feature in avoiding toxicity. The most active compound from in vitro studies was taken forward to an in vivo model and instigated an increase in tumor cell necrosis.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2016 American Chemical Society. This is an author produced version of a paper subsequently published in Journal of Medicinal Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Department of Chemistry (Sheffield) |
Funding Information: | Funder Grant number CANCER RESEARCH UK (CRUK) C43420/A14234 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 11 Oct 2016 13:49 |
Last Modified: | 01 May 2020 09:02 |
Published Version: | http://dx.doi.org/10.1021/acs.jmedchem.6b01128 |
Status: | Published |
Publisher: | American Chemical Society |
Refereed: | Yes |
Identification Number: | 10.1021/acs.jmedchem.6b01128 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:105872 |