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

Balaji Babu, Hope College
Lauren Lee, Hope College
Lauren Lee, Hope College
Raymond Strobel, Hope College
Olivia Brockway, Hope College
Alexis Nickols, Hope College
Robert Sjoholm, Hope College
Samuel Tzou, Hope College
Sameer Chavda, Hope College
Dereje Desta, Hope College
Gregory S. Fraley, Hope College
Adam Siegfried, Clemson University
William Pennington, Clemson University
Rachel Hartley, University of Texas Health Science - San Antonio
Cara Westbrook, University of Texas Health Science - San Antonio
Susan Mooberry, University of Texas Health Science - San Antonio
Konstantinos Kiakos, UCL Cancer Institute
John A. Hartley, UCL Cancer Institute
Moses Lee, Hope College


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-mu M 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 mu M). This compound initiates microtubule depolymerization with an EC50 value of 1.8 mu Min A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.