Acetyl analogs of combretastatin A-4: Synthesis and biological studies

Moses Lee, Balaji Babu, Megan Lee, Lauren Lee, Raymond Strobel, Olivia Brockway, Alexis Nickols, Robert Sjoholm, Samuel Tzou, Sameer Chavda, Dereje Desta, Gregory Fraley, Adam Siegfried, William Pennington, Rachel M. Hartley, Cara Westbrook, Susan L. Mooberry, Konstantinos Kiakos, John A. Hartley

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC50 values in the sub-μM range. Analog 6t has an IC50 of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC50 value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.

Original languageEnglish (US)
Pages (from-to)2359-2367
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number7
DOIs
StatePublished - Apr 1 2011

Keywords

  • Cancer
  • Combretastatin A-4
  • Cytotoxicity
  • Microtubule
  • Trimethoxyphenylacetone
  • Tubulin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Lee, M., Babu, B., Lee, M., Lee, L., Strobel, R., Brockway, O., Nickols, A., Sjoholm, R., Tzou, S., Chavda, S., Desta, D., Fraley, G., Siegfried, A., Pennington, W., Hartley, R. M., Westbrook, C., Mooberry, S. L., Kiakos, K., & Hartley, J. A. (2011). Acetyl analogs of combretastatin A-4: Synthesis and biological studies. Bioorganic and Medicinal Chemistry, 19(7), 2359-2367. https://doi.org/10.1016/j.bmc.2011.02.018