) The overall goal of this proposal is to provide combinatorial chemistry support for the Cell Cycle (project 1 ), Spatial Distribution (Project 2), and Anti-Apoptosis Targets (project 3) as well as the in vitro/in vivo Testing (Core D), DNA Microarray (Core B) and Cell Fluorescence Biomarkers (Core E) Programs. Chemical synthesis will be heavily guided by interactions with these Projects, devoting 20% of our effort to each, as well as 20% to Core D and 10% each to Cores B and F (Informatics ). Specifically, we have three major chemistry aims: 1. The solid phase parallel synthesis of libraries of alkene peptide isosteres as part of the development of libraries of serine/threonine and other cell cycle phosphatase inhibitors. 2. The fluorous phase parallel synthesis of libraries of the kinase inhibitor wortmannin. We already have 50 9 of wortmannin available as starting material for analog syntheses. 3. The rapid preparation of focused analog libraries of bioactive compounds from the NCI collection that are being identified as promising leads in our three NCDDG project areas. This program will apply both solid and fluorous phase rapid synthesis techniques. Combined, these three combinatorial chemistry programs have a goal of approximately 9 libraries/y of 300 compounds each for biological evaluation. In addition, some scale up for samples that go into advanced animal testing will be needed. We will prepare ca. 0.5 g of 8 compounds/y that are tested in animals. Of the projected 30 leads that are studied in cell culture screen and hollow fiber assays in mice, we will prepare ca. 100 mg each.
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