title: 3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1.
abstract: Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC(50)=10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Li
authors.forename: Xilong
authors.initials: X
authors.lastname: Chang
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Liang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Guiye
authors.initials: G
authors.lastname: Wu
authors.forename: Shenghui
authors.initials: S
authors.lastname: Xie
authors.forename: Pengchen
authors.initials: P
authors.lastname: Su
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wu
authors.forename: Yingang
authors.initials: Y
authors.lastname: Feng
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000073:Acenaphthenes / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000073:Acenaphthenes; D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D051020:bcl-X Protein