A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

Natalie G Barnes; Anthony W Parker; Amjed A Ahmed Mal Ullah; Patricia A Ragazzon; John A Hadfield

doi:10.1016/j.bmc.2020.115684

A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors

Bioorg Med Chem. 2020 Oct 1;28(19):115684. doi: 10.1016/j.bmc.2020.115684. Epub 2020 Aug 5.

Authors

Natalie G Barnes¹, Anthony W Parker², Amjed A Ahmed Mal Ullah¹, Patricia A Ragazzon¹, John A Hadfield³

Affiliations

¹ Biomedical Research Centre, Kidscan Laboratories, School of Science, Engineering and Environment, University of Salford, Salford, UK.
² Central Laser Facility, Research Complex at Harwell, Rutherford Appleton Laboratory, STFC, Chilton, Oxfordshire OX11 0QX, UK.
³ Biomedical Research Centre, Kidscan Laboratories, School of Science, Engineering and Environment, University of Salford, Salford, UK. Electronic address: j.a.hadfield@salford.ac.uk.

PMID: 32912434
DOI: 10.1016/j.bmc.2020.115684

Abstract

A series of combretastatin derivatives were designed and synthesised by a two-step stereoselective synthesis by use of Wittig olefination followed by Suzuki cross-coupling. Interestingly, all new compounds (2a-2i) showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, 2a, 2b and 2e were the most active across three cancer cell lines. In addition, these compounds inhibited the polymerisation of tubulin in vitro more efficiently than CA-4. They caused cell cycle arrest in G₂/M phase further confirming their ability to inhibit tubulin polymerisation.

Keywords: Cancer; Combretastatin A-4; Microtubules; Tubulin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Polymerization / drug effects
Stereoisomerism
Stilbenes / chemical synthesis
Stilbenes / chemistry
Stilbenes / pharmacology*
Structure-Activity Relationship
Tubulin / metabolism*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*

Substances

Antineoplastic Agents
Stilbenes
Tubulin
Tubulin Modulators
fosbretabulin