Design, Synthesis and Antitumor Activity of Novel link-bridge and B-Ring Modified Combretastatin A-4 (CA-4) Analogues as Potent Antitubulin Agents

Abstract

A series of 12 novel acylhydrazone, chalcone and amide–bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, 1H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 μM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

“…Acylhydrazone, chalcone and amine-bridged derivatives of CA-4 were synthesized for comparison of their activity towards tubulin. Amongst the metabolites with acylhydrazone bridge with a benzyl at the indole-N position was determined as the most potent antiproliferative agent against several cancer cell lines (IC 50 values between 0.08 and 35.6 µM) with lower cytotoxicity activity on normal human cells as well [69].…”

5-(Furan-2-yl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3- one oxime (6f), a new synthetic compound, causes human fibrosarcoma HT-1080 cell apoptosis by disrupting tubulin polymerisation and inducing G2/M arrest

“…However, the application of CA-4 as an anticancer drug is limited by its low bioavailability, as it tends to isomerize to the thermodynamically more stable and inactive trans-isomer, which decreases its half-life and reduces its activity. Despite the limited bioavailability, the relatively simple structure and the high affinity to the tubulin binding site render CA-4 as an attractive lead compound for the development of new anticancer agents by our group and many other groups (13)(14)(15)(16)(17).…”

Design, synthesis, and biological evaluation of 2,3‐diphenyl‐cycloalkyl pyrazole derivatives as potential tubulin polymerization inhibitors

“…However, CA‐4 has two major defects: chemical instability and poor solubility (Burja et al., ). So, a great many of scientific researchers have carried out structural transformation and prepared the prodrugs of CA‐4 to eliminate these defects (Duan et al., ). As we all known, the combretastatin‐A4 phosphate (CA‐4P), acting as the vascular‐targeting agent (VTA), greatly increased water solubility and bioavailability of CA‐4, showed in vivo activity in all cancer models, and became the first VTA to enter clinical researches worldwide (Garon et al., ; Grisham, Ky, Tewari, Chaplin, & Walker, ).…”

“…of CA-4 to eliminate these defects (Duan et al, 2016). As we all known, the combretastatin-A4 phosphate (CA-4P), acting as the vascular-targeting agent (VTA), greatly increased water solubility and bioavailability of CA-4, showed in vivo activity in all cancer models, and became the first VTA to enter clinical researches worldwide (Garon et al, 2016;Grisham, Ky, Tewari, Chaplin, & Walker, 2018).…”