Two-face, two-turn α-helix mimetics based on a cross-acridine scaffold: analogues of the Bim BH3 domain.
The design of a cross-acridine scaffold mimicking the i, i+3, i+5, and i+7 residues distributed over a two-face, two-turn α-helix is described. Docking studies and 2D (1)H, (15)N HSQC NMR spectroscopy provide compelling evidence that compound 3 d accurately reproduces the arrangement of four hotspots in the Bim BH3 peptide to permit binding to the Mcl-1 and Bcl-2 proteins (Ki 0.079 and 0.056 μM, respectively). Furthermore, the hotspot mutation could also be mimicked by individual or multiple deletions of side chains on the scaffold.
State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, 2 Linggong Road, Dalian 116012 (P.R. China).
Xiangqian
X
Li
Ziqian
Z
Wang
Yingang
Y
Feng
Ting
T
Song
Pengchen
P
Su
Chengbin
C
Chen
Gaobo
G
Chai
Ying
Y
Yang
Zhichao
Z
Zhang
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry*; D000072224:Bcl-2-Like Protein 11; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry*; D062105:Molecular Docking Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism
D000166:Acridines; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2
Mcl-1; acridines; helical structures; peptidomimetics; two-face