Design, synthesis and biological testing of cyclohexenone derivatives of combretastatin-A4

Jennifer Ruprich, Andrew Prout, John Dickson, Brent Younglove, Lawrence Nolan, Khyati Baxi, Regan LeBlanc, Lori Forrest, Patrice Hills, Herman Holt, Hilary Mackay, Toni Brown, Susan L. Mooberry, Moses Lee

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Sixteen 2-cyclohexenone and 6-(ethoxycarbonyl)-2-cyclohexenone analogs of combretastatin-A4 (CA-4, 1) were synthesized, and their ability to inhibit the growth of two murine cancer cell lines (B16 melanoma and L1210 leukemia) was determined using an MTT assay. One of the cyclohexenone analogs, 8, which contains the same substituents as CA-4 (1) is the most potent (IC50 = 0.91 μ M, L1210). Exposure of A-10 aortic cells to cyclohexenone 8 and its ester congener 7 produced significant reduction in cellular microtubules, with EC50 values of 27 and 37 mM, respectively. Molecular modeling studies indicate that analog 8 adopts a twisted conformation, similar to CA-4, suggesting that conformation and structure are crucial for activity. These compounds are worthy of further investigation as potential tubulin inhibitors in the quest for novel anti-cancer agents.

Original languageEnglish (US)
Pages (from-to)144-148
Number of pages5
JournalLetters in Drug Design and Discovery
Volume4
Issue number2
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Anticancer
  • Combretastatin-A4
  • Cyclohexenone
  • Cytotoxicity
  • Synthesis
  • Tubulin

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Fingerprint Dive into the research topics of 'Design, synthesis and biological testing of cyclohexenone derivatives of combretastatin-A4'. Together they form a unique fingerprint.

Cite this