Potent Antitumor Activities and Structure Basis of the Chiral β-Lactam Bridged Analogue of Combretastatin A-4 Binding to Tubulin.
A series of chiral β-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were synthesized asymmetrically, and their antitumor activities were evaluated in vitro and in vivo. The cocrystal structure of tubulin in complex with compound 9 was determined by X-ray crystallography, which showed that 9 binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was first identified and demonstrated to be critically important for their antiproliferative activities.
School of Pharmacy, Fudan University , Shanghai 201203, China.
Pengfei
P
Zhou
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Yan
Y
Liu
School of Pharmacy, Fudan University , Shanghai 201203, China.
Lu
L
Zhou
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Kongkai
K
Zhu
School of Pharmacy, Fudan University , Shanghai 201203, China.
Kechang
K
Feng
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Hao
H
Zhang
School of Pharmacy, Fudan University , Shanghai 201203, China.
Yuru
Y
Liang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Hualiang
H
Jiang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Cheng
C
Luo
School of Pharmacy, Fudan University , Shanghai 201203, China.
Mingming
M
Liu
School of Pharmacy, Fudan University , Shanghai 201203, China.
Yang
Y
Wang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014404:Tubulin; D047090:beta-Lactams