Synthesis and mechanistic studies of novel spin-labeled combretastatin derivatives as potential antineoplastic agents.
Two series (14a-d and 21a-h) of novel spin-labeled combretastatin derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines (K562, SGC-7901, Hela and HepG-2). Simultaneously, a representative compound 21a was selected to investigate the antitumor mechanisms of these synthetic compounds. The results indicated that some of the compounds showed significant cytotoxicity against four tumor cell lines in vitro and were more active than etoposide, a clinically available anticancer drug. Among the newly synthesized compounds, 21a, 21b and 21c displayed the greatest cytotoxicity against three tested tumor cell lines (HEPG-2, BGC-832 and Hela), with IC(50) values ranging from 0.15 to 1.05 μM, compared with values of 0.014-0.403 μM for 3-amino-deoxycombretastatin A-4 (3). In addition, the mechanistic analysis revealed that compound 21a effectively interfered with tubulin dynamics to prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually, dose dependent apoptosis.
School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. yqliu@lzu.edu.cn
Ying-Qian
YQ
Liu
Xiao-Jing
XJ
Li
Chun-Yan
CY
Zhao
Xiang
X
Nan
Jing
J
Tian
Susan L
SL
Morris-Natschke
Zhi-Jun
ZJ
Zhang
Xiao-Ming
XM
Yang
Liu
L
Yang
Lin-Hai
LH
Li
Xing-Wen
XW
Zhou
Kuo-Hsiung
KH
Lee
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D008938:Mitosis / Q000187:drug effects; D013113:Spin Labels; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity
D000970:Antineoplastic Agents; D001632:Bibenzyls; D013113:Spin Labels; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin