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Synthesis and Study of Natural and Non-natural Antiproliferative Agents

天然和非天然抗增殖剂的合成与研究

基本信息

批准号：
7195097
负责人：
ANDREW G MYERS
金额：
$ 67.5万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-04-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7195097
关键词：
Affinity Antineoplastic Agents Applications Grants Area Aziridines Binding Binding Proteins Biochemical Biological Biological Factors Biotin Cell Line Chemicals Class Complex Condition Covalent Interaction Cysteine Protease DNA DNA Adducts Development Dimerization Electrophoretic Mobility Shift Assay Enzymes Evaluation Family Generations Glutathione Glyceraldehyde-3-Phosphate Dehydrogenases Goals Hand Human Hydroxyl Radical Indoles Inhibition of Cancer Cell Growth Label Laboratories Lead Learning Libraries Link Macromolecular Complexes Malignant Neoplasms Membrane Molecular Probes Molecular Target Numbers Oxides Oxidoreductase Pathway interactions Pharmaceutical Preparations Phase Physiological Play Polystyrenes Process Property Protease Inhibitor Protein Overexpression Proteins Quinones Radiolabeled Reaction Reading Reagent Research Research Design Role Route Series Serine Site Solid Structural Chemistry Structure Sulfhydryl Compounds Techniques Two-Dimensional Gel Electrophoresis Work adduct analog avrainvillamide aziridine base benzoquinone cancer cell chromophore design improved in vivo indole inhibitor/antagonist inorganic phosphate kedarcidin chromophore knock-down member novel nucleophilic addition programs quinaldic acid quinocarcin radiotracer reconstitution research study saframycin A salinosporamide A stephacidin B tool

项目摘要

DESCRIPTION (provided by applicant): The primary focus of our research continues to be the synthesis and study of complex molecules with proven or potential anti-cancer activity. Efficient laboratory synthetic routes are developed that provide access to new materials with potentially improved properties for study and biological evaluation. The elucidation of the detailed chemical processes that underlie the biological (antiproliferative) activity of the agents we study is a principal goal of our research. Specific synthetic targets include the natural antiproliferative agents avrainvillamide, stephacidin B, salinosporamides, quinocarcin, N1999A2, kedarcidin chromophore, and maduropeptin chromophore. In addition, we will execute a solid-phase split-pool synthesis of a library of ~1,000 saframycin analogs, a small library (~200 compounds) of molecules bearing the 3-alkylidene 3-H- indole-1-oxide function, a novel class of potential enzyme (protease) inhibitors, and a number of structural analogs of quinocarcin, avrainvillamide, and stephacidin B. We will synthesize a large number of analogs of the natural proteasomal inhibitor and antiproliferative agent salinosporamide. By design, the synthetic route under development incorporates three sites of structural variability; the route is also notably short and efficient. A major effort is underway in our laboratory to elucidate the molecular target(s) of the saframycins and, separately, the new class of natural antiproliferative agents represented by avrainvillamide and stephacidin B. We will continue to pursue studies designed to elucidate the details of the interaction of the protein target glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with binary complexes of duplex DNA and saframycins, and the role this interaction may play in the antiproliferative activity of saframycins.

描述（由申请人提供）：我们的主要研究重点仍然是合成和研究具有已证实或潜在抗癌活性的复杂分子。开发了高效的实验室合成路线，为研究和生物评价提供了具有潜在改进性能的新材料。阐明我们所研究的药物的生物（抗增殖）活性背后的详细化学过程是我们研究的主要目标。特异性合成靶点包括天然抗增殖剂avrainvillamide， stephacidin B, salinosporamide, quinocarcin, N1999A2， kedarcidin发色团和maduropeptin发色团。此外，我们将进行固相分裂池合成约1000个萨弗霉素类似物库，一个小库（约200个化合物）具有3-烷基烯- 3-H-吲哚-1-氧化物功能的分子，一类新的潜在酶（蛋白酶）抑制剂，以及喹诺卡素，avrainvillamide和stephacidin b的一些结构类似物。我们将合成大量天然蛋白酶体抑制剂和抗增殖剂salinosporamide的类似物。通过设计，正在开发的合成路线包含三个结构变异性的站点；这条路线也很短，效率很高。我们的实验室正在进行一项主要的工作，以阐明红霉素的分子靶点，以及以avrainvillamide和stephacidin b为代表的新型天然抗增殖药物。我们将继续进行旨在阐明蛋白质靶点甘油醛3-磷酸脱氢酶（GAPDH）与双工DNA和红霉素的二元复合物相互作用的细节的研究。这种相互作用可能在萨芬霉素的抗增殖活性中起作用。