Developments of Combretastatin A-4 Derivatives as Anticancer Agents

Abstract

Tubulin protein is one of several members of a small family of globular proteins. It offers a potential target for anticancer drug design and development. Combretastatin A-4 (CA-4) is a potent anticancer and antiangiogenesis natural substance isolated from Combretum caffrum. Modifications on the CA-4 structure have led to a great number of novel CA-4 derivatives as potent tubulin inhibitors and high cytotoxic anticancer agents is becoming an interesting field, leading to a breakthrough in the treatment of cancer. In this review, the recent developments of novel CA-4 derivatives via the modifications on the A- and B-ring and the double bond as anticancer agents are discussed.

Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

“…Therefore, the search for new antimicrotubule agents exhibiting improved biopharmaceutical profiles and pharmacodynamics is still recognized as of utmost importance. To that end, tens of thousands of derivatives and analogs based on modifications of the ring B and the ethenyl bridge of CA-4 were synthesized and screened for anticancer activity [5,6]. However, only a few modifications were made on the trimethoxyphenyl (TMP) moiety (ring A, Fig.…”

Synthesis and biological evaluation of 5,6,7-trimethoxy-1-benzylidene-3,4-dihydro-naphthalen-2-one as tubulin-polymerization inhibitors

“…ing results in human cancer clinical trials, fueling continued 27 research in novel colchicine site inhibitors (CSIs) [7,8].…”

“…1) [6,7]. A large number of modifications of CA-4 focused on 32 the linking bridge and B ring, respectively [6,7,[9][10][11][12][13][14].…”

“…1) [6,7]. A large number of modifications of CA-4 focused on 32 the linking bridge and B ring, respectively [6,7,[9][10][11][12][13][14]. There also 33 some modifications focused on combining the linking bridge 34 with A ring or B ring [15][16][17].…”

“…Compound 1a showed lower 93 inhibition activity of tumor cell growth relative to 22b, which 94 suggested that the change of the connection between the six-95 membered ring from the B ring to the A ring reduced its biological 96 activity. Like other CA-4 like tubulin polymerization inhibitors [6,7], the substitute on the B ring has an obvious effect on biological 98…”