title: Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors.
abstract: The B-cell lymphoma-2 (Bcl-2) family proteins are attractive targets for cancer therapy. In our previous work, the structure-activity relationship of WL-276 was studied. According to the results, rhodanine derivatives show potent binding affinity for Bcl-2 and Mcl-1 protein and show weaker activity against Bcl-XLprotein. Based on the previous results, a new class of indole-3-carboxylic acid-based derivatives were designed and synthesized as Bcl-2/Mcl-1 dual inhibitors. Among them, compound 17 has a Kivalue of 0.26μM for Bcl-2 protein and is better than WL-276. Furthermore, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Kivalue of 72nM. Especially, compound 31 can selectively acting on Bcl-2 and Mcl-1 protein but not Bcl-XLprotein, which has great significance for developing dual inhibitors targeting Bcl-2 and Mcl-1 protein, as well as specific antitumor abilities in cells.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, PR China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
authors.forename: Renshuai
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
authors.forename: Minyong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: haofangcn@sdu.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005454:Fluorescence Polarization; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C012382:indole-3-carboxylic acid
keywords: Anti-tumor; Bcl-2/Mcl-1; Indole-3-carboxylic acid-based derivatives; Inhibitors