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

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

来源：Bioorganic & Medicinal Chemistry, 2011, 19(7): 2359-2367.

DOI：10.1016/j.bmc.2011.02.018

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

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 IC(50) values in the sub-mu M range. Analog 6t has an IC(50) 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 EC(50) value of 1.8 mu Min A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity.

• 出版日期2011-4-1