Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin

Do Yoon Kim, Kyun Hwan Kim, Nam Doo Kim, Ki Young Lee, Cheol Kyu Han, Jeong Hyeok Yoon, Seung Kee Moon, Sung Sook Lee, Baik L. Seong

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Although the structure has been elucidated for the binding of colchicine and podophyllotoxin as potent destabilizer for microtubule formation, very little is known about MDL-27048, a competitive inhibitor for colchicine and podophyllotoxin. The structural basis for the interaction of antimitotic agents with tubulin was investigated by molecular modeling, and we propose binding models for MDL-27048 against tubulin. The proposed model was not only consistent with previous competition experiment data between colchicine and MDL-27048, but further suggested an additional binding cavity on tubulin. Based on this finding from the proposed MDL-tubulin complex, we performed molecular design studies to identify new antimitotic agents. These new chalcone derivatives exerted growth inhibitory effects on all four human hepatoma and one renal epithelial cell lines tested and induced strong cell cycle arrest at G2/M phase. Furthermore, these compounds exhibited a strong inhibitory effect on tubulin polymerization in vitro. Therefore, we suggest that the validated MDL-27048 model would serve as a potent platform for designing new molecular entities for anticancer agents targeted to microtubules.

Original languageEnglish
Pages (from-to)5664-5670
Number of pages7
JournalJournal of Medicinal Chemistry
Volume49
Issue number19
DOIs
Publication statusPublished - 2006 Sep 21

Fingerprint

Tubulin Modulators
Antimitotic Agents
Tubulin
Colchicine
Podophyllotoxin
Microtubules
Chalcone
G2 Phase
Cell Cycle Checkpoints
Polymerization
Cell Division
Antineoplastic Agents
Hepatocellular Carcinoma
Epithelial Cells
Kidney
Cell Line
MDL 27048
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Kim, Do Yoon ; Kim, Kyun Hwan ; Kim, Nam Doo ; Lee, Ki Young ; Han, Cheol Kyu ; Yoon, Jeong Hyeok ; Moon, Seung Kee ; Lee, Sung Sook ; Seong, Baik L. / Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 19. pp. 5664-5670.
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Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin. / Kim, Do Yoon; Kim, Kyun Hwan; Kim, Nam Doo; Lee, Ki Young; Han, Cheol Kyu; Yoon, Jeong Hyeok; Moon, Seung Kee; Lee, Sung Sook; Seong, Baik L.

In: Journal of Medicinal Chemistry, Vol. 49, No. 19, 21.09.2006, p. 5664-5670.

Research output: Contribution to journalArticle

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AU - Seong, Baik L.

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