Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

Dong Jin Hwang, Jin Wang, Wei Li, Duane Miller

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

A new series of indole analogues based on our earlier lead compound, 2-(1H-indol-5-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine (42), was prepared as tubulin inhibitors in an effort to find a molecule with improved cytotoxic potency and metabolic stability. A series of indolyl-imidazopyridines (IIP) were synthesized and exhibited potent tubulin polymerization inhibitory activity with potent IC50 values ranging from 3 to 175 nM against a panel of human melanoma and prostate cancer cell lines. Among these compounds, the 6-indolyl compound 43 showed improved cytotoxic potency (average IC50 of 9.75 nM vs 55.75 nM) and metabolic stability in human liver microsomes (half-life time was 56.3 min vs. 45.4 min) as compared to previously reported 42. It was also shown to be effective against P-glycoprotein (P-gp) mediated multiple drug resistance (MDR) and taxol resistance.

Original languageEnglish (US)
Pages (from-to)993-997
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number9
DOIs
StatePublished - Sep 10 2015

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Structural optimization
Colchicine
Antineoplastic Agents
Inhibitory Concentration 50
Tubulin Modulators
Binding Sites
Lead compounds
Derivatives
Multiple Drug Resistance
P-Glycoprotein
Liver Microsomes
Tubulin
Paclitaxel
Polymerization
Liver
Half-Life
Melanoma
Prostatic Neoplasms
Cells
Cell Line

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents. / Hwang, Dong Jin; Wang, Jin; Li, Wei; Miller, Duane.

In: ACS Medicinal Chemistry Letters, Vol. 6, No. 9, 10.09.2015, p. 993-997.

Research output: Contribution to journalArticle

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