Design,synthesis and activity evaluation of aryl formamides as Bax agonists
Direct activation of Bax by small molecules could exert the equipotent potency to multi-targeting BH3 mimetics.By introducing basic groups targeting Bax D142 or E146 and structural modification on 4-substituted groups to promote'opening'of the α1-α2 loop and the 5-substituted groups occupying the bottom pocket,a series of Bax agonists with aryl formamide(C1-C18)were designed and synthesized based on compound BMC233 obtained from virtual screening.Methyl 4-(aminomethyl)benzoate was used as the starting material,which occurred the condensation reaction with different carboxylic acids in turn,followed by the hydrolysis reaction to give a 4-substituted benzoic acid intermediate.After its condensation reaction with a benzenesulfonamide intermediate obtained by nucleophilic substitution reaction to give compounds C1-C8.Taking methyl 4-bromo-lH-pyrrole-2-carboxylate as the starting material,nucleophilic substitution,Suzuki coupling,hydrolysis and condensation with different amines were carried out in turn to give compounds C9-C18.A total of eighteen aryl formamide compounds were designed and synthesized,all of which were not reported in the literatures,and their structures were confirmed by 1H-NMR,13C-NMR and HR-ESI-MS.The activities of the target compounds were tested at molecular level and cell level.Among them,compound C13 had fragile inhibitory activity against Bcl-2/Bcl-XL/Mcl-1(IC50＞200 p.mol·L-1),and presented higher antiproliferative activity against a variety of solid tumor cell lines than the positive control BTSA1.
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