Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: Methodology and application to a potent fluorescent tubulin inhibitor with anticancer activity

Gary M. Chinigo, Mikell Paige, Scott Grindrod, Ernest Hamel, Sivanesan Dakshanamurthy, Maksymilian Chruszcz, Wladek Minor, Milton L. Brown

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

For several decades the 2,3-dihydroquinazolinone (DHQZ) heterocycle has been known to possess a variety of important biological and medicinal properties. Despite the many interesting facets of these molecules, synthetic access to nonracemic DHQZ analogues has remained elusive. Herein, we disclose a synthetic route that allows access to either enantiomer of a variety of DHQZ derivatives. We illustrate the utility of this chemistry with the asymmetric preparation and biological evaluation of a new chiral fluorescent tubulin binding agent with extremely potent antiproliferative properties against human cancer cells. A computational rationale for the increased potency of the (S)-enantiomer over the (R)-enantiomer is given, based on the crystal structure of αβ-tubulin complexed with colchicine. Taking advantage of the inherent fluorescence of these molecules, confocal images of GMC-5-193 (compound 7) in the cytoplasm of human melanoma cells (MDA-MB-435) cells are presented.

Original languageEnglish
Pages (from-to)4620-4631
Number of pages12
JournalJournal of Medicinal Chemistry
Volume51
Issue number15
DOIs
StatePublished - 14 Aug 2008
Externally publishedYes

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