Synthesis and Evaluation of 2,3-Dihydroquinazolinones as Dual of Angiogenesis and Cancer Cell Proliferation
Chinigo, Gary Michael, Department of Chemistry, University of Virginia
McGarvey, Glenn, Department of Chemistry, University of Virginia
Mandell, James, Department of Pathology, University of Virginia
III Dual inhibitors of cancer cell proliferation and angiogenesis have recently shown remarkable potential for the clinical treatment of several cancers. Inspired by this success, we have employed traditional medicinal chemistry techniques to develop a 2,3-dihydroquinazolin-4- one lead molecule with promising anti-proliferative and anti-angiogenic activity. These molecules, which we originally derived from thalidomide, have evolved into an extremely effective (sub-nanomolar) prospective drug candidate for the treatment of cancer. Described herein is an account of the many structural modifications made to this lead compound along with the corresponding effects on competitive 3 H colchicine displacement from tubulin, microtubule depolymerization, and cytotoxicity toward several human cancer and endothelial cell lines. From these evaluations we were able to design 3 rd generation analogs with significantly enhanced potency. Subsequent animal testing suggests these molecules are relatively non-toxic, bio-available, and efficacious at treating tumors in vivo – evidence which supports the possibility of our most active analogs being evaluated clinically. In addition to the SAR studies, we were compelled to develop synthetic methods enabling us to synthesize the enantiomers of these molecules. Exploration of several different approaches eventually led us to a chiral auxiliary based method of synthesis. Preliminary success led to a more thorough exploration of the scope and limitations of this methodology, and ultimately to the synthesis of the R and S enantiomers of both the lead and our most active molecule. Related X- ray crystal structure and biological studies conclusively point to the S isomer as the biologically active enantiomer. Finally, by using molecular modeling in conjunction with all the data gathered thus far, we have developed a hypothesis regarding the likely mode of interaction between tubulin and the molecules in this study.
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PHD (Doctor of Philosophy)
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