The tubulins, the constituents of microtubule, are one of the most promising targets for anticancer agents. Although several vinca alkaloids and taxols are currently being used for cancer treatment, intrinsic toxicity or multi-drug resistance problems with the known drugs have prompted the need for the development of an improved drug. A purine based microtubule inhibitor, myoseverin, has demonstrated unique and promising properties that include low cytotoxicity. The moderate activity of myoseverin requires improvement through intensive derivative synthesis and screening, but modification of the purine structure has intrinsic synthetic difficulties that encumber expeditious diversity generation. To accelerate diversity generation, the more versatile scaffold, triazine, was chosen and a straightforward combinatorial synthesis was developed. The constructed library compounds were screened using a Zebrafish embryo system that yielded new lead compounds, the tubulyzines. Several selected tubulyzines demonstrated similar biological characteristics with myoseverin. In addition, the tubulyzine demonstrated in vitro and in vivo anti-angiogenesis effects. The binding site of tubulyzine in tubulin has been elucidated as a novel GDP binding site, and a computer simulation model of the binding mode has been constructed. The goal of this proposal is to discover improved tubulyzine compounds as clinically useful cancer drug candidates by extensive library synthesis and high-throughput screening. In addition, the action mechanism of this new class of compounds will be determined using several affinity matrix methods.
The specific aims are (1) To design and construct a triazine library using a novel orthogonal solid phase chemistry pathway. (2) Identify highly efficient novel microtubule effectors through rapid biological testing followed by screening as anti-cancer agents. (3) Rational design of a stronger tubulin binder and to identify other cellular targets of tubulyzine.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Lees, Robert G
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New York University
Schools of Arts and Sciences
New York
United States
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