Design and synthesis of cyclopropylamide analogues of combretastatin-A4 as novel microtubule-stabilizing agents.
A series of novel cyclopropylamide analogues of combretastatin-A4 (CA-4) were designed and synthesized. Most of them had significant in vitro antiproliferative activities, particularly for compounds 7i4, 7c4, 8a4, and 8c4. Moreover, compound 8c4 was also equally potent against paclitaxel resistant cancer cells. Interestingly, the novel cyclopropylamide analogues had different binding mechanisms from CA-4. Instead of inhibiting tubulin polymerization, these CA-4 derivatives were able to stimulate tubulin polymerization. Flow cytometry revealed that compound 8c4 arrested A549 cancer cells in the G2/M phase and resulted in cellular apoptosis. Further immunofluorescence assays revealed that compound 8c4 induced mitotic arrest in A549 cells through disrupting microtubule dynamics. In addition, compound 8c4 also effectively inhibited the tumor growth in the A549 xenograft model without causing significant loss of body weight. Compound 8c4 represents a novel class of microtubule-stabilizing agent and can be used as a promising lead for the development of new antitumor agents.
Department of Medicinal Chemistry, College of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Huan
H
Chen
Yongmei
Y
Li
Chunquan
C
Sheng
Zhiliang
Z
Lv
Guoqiang
G
Dong
Tiantian
T
Wang
Jia
J
Liu
Mingfeng
M
Zhang
Lingzhen
L
Li
Tao
T
Zhang
Dongping
D
Geng
Chunjuan
C
Niu
Ke
K
Li
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D013267:Stilbenes; C058728:fosbretabulin