Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim
AbstractA series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl- and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC50 values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation. View Full-Text
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Cheng, C.; Liu, Y.; Balasis, M.E.; Garner, T.P.; Li, J.; Simmons, N.L.; Berndt, N.; Song, H.; Pan, L.; Qin, Y.; Nicolaou, K.C.; Gavathiotis, E.; Sebti, S.M.; Li, R. Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim. Mar. Drugs 2014, 12, 4311-4325.
Cheng C, Liu Y, Balasis ME, Garner TP, Li J, Simmons NL, Berndt N, Song H, Pan L, Qin Y, Nicolaou KC, Gavathiotis E, Sebti SM, Li R. Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim. Marine Drugs. 2014; 12(8):4311-4325.Chicago/Turabian Style
Cheng, Chunwei; Liu, Yan; Balasis, Maria E.; Garner, Thomas P.; Li, Jerry; Simmons, Nicholas L.; Berndt, Norbert; Song, Hao; Pan, Lili; Qin, Yong; Nicolaou, K. C.; Gavathiotis, Evripidis; Sebti, Said M.; Li, Rongshi. 2014. "Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim." Mar. Drugs 12, no. 8: 4311-4325.