Synthesis and biological activities of 2-amino-1-arylidenamino imidazoles as orally active anticancer agents.
2-Amino-1-arylidenaminoimidazoles, a novel class of orally (po) active microtubule-destabilizing anticancer agents, were synthesized. The compounds were designed from a hit compound identified in a drug discovery platform by using cancer cell-based high throughput screening assay. Selective synthesized compounds exerted cell cytotoxicity against human cancer cells. The underlying mechanisms for the anticancer activity were demonstrated as interacting with the tubulins and inhibiting microtubule assembly, leading to proliferation inhibition and apoptosis induction in the human tumor cells. Furthermore, two compounds showed in vivo anticancer activities in both po and intravenously (iv) administered routes and prolonged the life spans of murine leukemic P388 cells-inoculated mice. These new po active antimitotic anticancer agents are to be further examined in preclinical studies and developed for clinical uses.
Li
Wen-Tai
WT
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli 35053, Taiwan, ROC.
Hwang
Der-Ren
DR
Song
Jen-Shin
JS
Chen
Ching-Ping
CP
Chuu
Jiunn-Jye
JJ
Hu
Chih-Bo
CB
Lin
Heng-Liang
HL
Huang
Chen-Lung
CL
Huang
Chiung-Yi
CY
Tseng
Huan-Yi
HY
Lin
Chu-Chung
CC
Chen
Tung-Wei
TW
Lin
Chi-Hung
CH
Wang
Hsin-Sheng
HS
Shen
Chien-Chang
CC
Chang
Chung-Ming
CM
Chao
Yu-Sheng
YS
Chen
Chiung-Tong
CT
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007093:Imidazoles; D014404:Tubulin