Design And Synthesis Of Combretastatin A-4 Derivatives As Novel Multi-Target Inhibitor

Combretastatin A-4?CA-4?is a kind of natural stilbene compound,which was isolated from the Combretum caffrum.It has a wide range of anti-tumor activity,and its mechanism of action is related to inhibition of tubulin polymerization,and with a concise chemical structure,attracting many scientific researchers to study its structure modification and antitumor activity of CA-4.In this paper,based on the structure of sulfatase inhibitors and CA-4,through computer-assisted technology,the binding sites and binding methods of tubulin were studies by molecular docking.It was found that the sulfamate-modified Combretastatin A-4derivative could inhibit tubulin and sulfatase.Triphenyl?3,4,5-trimethoxybenzyl?phosphonium bromide and aldehyde were used as reaction materials to synthesize a series of cis-trans isomerism CA-4 analogs as substrates by the Witting reaction.Under basic conditions,the substrate is reacted with sulfamate to synthesize the target product,which is then reduced to give the corresponding single-bond product.Moreover,the structure-activity relationship of the target product was studied,and it was found that the sulfamate derivative of Combretastatin A-4 has universal biological activity.The anti-tumor efficacy of compound 30is about 5-40 times that of CA-4,while it also showed similar anti-tumor activity as CA-4P.And compound 30(IC₅₀=6.160?M)also showed comparable sulfatase potency to the positive control sulfatase inhibitor,estrone-3-O-sulfamate(EMATE,IC₅₀=5.008?M).Compound 30 takes into account inhibition of tubulin and sulfatase inhibitory activity,it is a promising to become a novel multi-target drug and continue to deeply study.