Design, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1, 3,4-oxadiazoline analogs of combretastatin-A4

Lauren Lee, Lyda M. Robb, Megan Lee, Ryan Davis, Hilary Mackay, Sameer Chavda, Balaji Babu, Erin L. O'Brien, April L. Risinger, Susan L. Mooberry, Moses Lee

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

A total of 24 novel 2,5-diaryl-1,3,4-oxadiazoline analogs of combretastatin A-4 (CA-4, 1) were designed, synthesized, and evaluated for biological activities. The compounds represent two structural classes; the Type I class has three methoxy groups on the A ring and the Type II class has a single methoxy group on the A ring. Biological evaluations demonstrate that multiple structural features control the biological potency. Four of the compounds, 2-(3′-bromophenyl)-5-(3″,4″,5″-trimethoxyphenyl) -2-acetyl-2,3-dihydro-1,3, 4-oxadiazoline (91), 2-(2′,5′- dimethoxyphenyl)-5-(3″-methoxyphenyl)-2-acetyl-2,3-dihydro-1,3, 4-oxadiazoline (10h), 2-(3′,4′,5′-trimethoxyphenyl)-5- (3″-methoxyphenyl)-2-acetyl-2,3-dihydro-1,3,4-oxadiazoline (10i), and 2-(3′,5′-dimethoxyphenyl)-5-(3″-methoxyphenyl)-2-acetyl-2, 3-dihydro-1,3,4-oxadiazoline (10j), have potent antiproliferative activities against multiple cancer cell lines. Mechanistic studies indicate that they retain the microtubule disrupting effects of compound 1, including microtubule loss, the formation of aberrant mitotic spindles, and mitotic arrest. Compound 10i inhibits purified tubulin polymerization and circumvents drug resistance mediated by P-glycoprotein and βIII tubulin expression. The oxadiazoline analog 10i is a promising lead candidate worthy of further investigation.

Original languageEnglish (US)
Pages (from-to)325-334
Number of pages10
JournalJournal of Medicinal Chemistry
Volume53
Issue number1
DOIs
StatePublished - Jan 28 2010

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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