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 synthesi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-03, Vol.53 (6), p.2409-2417
Main Authors: Li, Wen-Tai, Hwang, Der-Ren, Song, Jen-Shin, Chen, Ching-Ping, Chuu, Jiunn-Jye, Hu, Chih-Bo, Lin, Heng-Liang, Huang, Chen-Lung, Huang, Chiung-Yi, Tseng, Huan-Yi, Lin, Chu-Chung, Chen, Tung-Wei, Lin, Chi-Hung, Wang, Hsin-Sheng, Shen, Chien-Chang, Chang, Chung-Ming, Chao, Yu-Sheng, Chen, Chiung-Tong
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
DNA Fragmentation - drug effects
Dose-Response Relationship, Drug
Female
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Inhibitory Concentration 50
Leukemia P388 - drug therapy
Leukemia P388 - pathology
Mice
Mice, Inbred DBA
Mice, Nude
Microtubules - drug effects
Microtubules - metabolism
Models, Chemical
Molecular Structure
Neoplasms - drug therapy
Neoplasms - pathology
Structure-Activity Relationship
Tubulin - metabolism
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm901501s