Asymmetric Synthesis of 2,3-Dihydro-2-arylquinazolin-4-ones: Methodology and Application to a Potent Fluorescent Tubulin Inhibitor with Anticancer Activity
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- 作者：Gary M. Chinigo ; Mikell Paige ; Scott Grindrod ; Ernest Hamel ; Sivanesan Dakshanamurthy ; Maksymilian Chruszcz ; Wladek Minor ; Milton L. Brown
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：August 14, 2008
- 年：2008
- 卷：51
- 期：15
- 页码：4620-4631
- 全文大小：267K
- 年卷期：v.51,no.15(August 14, 2008)
- ISSN：1520-4804
文摘
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 α,β-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.