title: Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein Bim.
abstract: A 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.
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education and State Key Laboratory of Biotherapy, Department of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. chengchunwei666@163.com.
authors: Chunwei
authors: C
authors: Cheng
authors: Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. yan.liu@unmc.edu.
authors: Yan
authors: Y
authors: Liu
authors: Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. maria.balasis@moffitt.org.
authors: Maria E
authors: ME
authors: Balasis
authors: Departments of Biochemistry and Medicine, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer G46, Bronx, NY 10461, USA. thomas.garner@einstein.yu.edu.
authors: Thomas P
authors: TP
authors: Garner
authors: Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. jerry.li@ucsf.edu.
authors: Jerry
authors: J
authors: Li
authors: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. nsimmons@scripps.edu.
authors: Nicholas L
authors: NL
authors: Simmons
authors: Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Norbert.berndt@moffitt.org.
authors: Norbert
authors: N
authors: Berndt
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education and State Key Laboratory of Biotherapy, Department of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. haoright@163.com.
authors: Hao
authors: H
authors: Song
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education and State Key Laboratory of Biotherapy, Department of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. pande179@163.com.
authors: Lili
authors: L
authors: Pan
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education and State Key Laboratory of Biotherapy, Department of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. qinyong@cqu.edu.cn.
authors: Yong
authors: Y
authors: Qin
authors: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@rice.edu.
authors: K C
authors: KC
authors: Nicolaou
authors: Departments of Biochemistry and Medicine, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, 1300 Morris Park Avenue, Forchheimer G46, Bronx, NY 10461, USA. evripidis.gavathiotis@einstein.yu.edu.
authors: Evripidis
authors: E
authors: Gavathiotis
authors: Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. said.sebti@moffitt.org.
authors: Said M
authors: SM
authors: Sebti
authors: Department of Drug Discovery and Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. rongshi.li@unmc.edu.
authors: Rongshi
authors: R
authors: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013440:Sulfides; D051020:bcl-X Protein