1044499-66-2Relevant academic research and scientific papers
Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: Methodology and application to a potent fluorescent tubulin inhibitor with anticancer activity
Chinigo, Gary M.,Paige, Mikell,Grindrod, Scott,Hamel, Ernest,Dakshanamurthy, Sivanesan,Chruszcz, Maksymilian,Minor, Wladek,Brown, Milton L.
experimental part, p. 4620 - 4631 (2009/06/06)
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.
