TUBULIN STRUCTURE AND FUNCTION AS SITES FOR PHARMACOLOGIC ATTACK

微管蛋白作为药理攻击位点的结构和功能

• 批准号: 4692175
• 负责人: E HAMEL
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4692175
• 关键词: 1,3 benzodioxole; 6 phosphofructokinase; adenosine triphosphate; antimetabolites; antimitotics; carbamates; chemical structure function; cyclic amine; drug design /synthesis /production; drug metabolism; electrofocusing; electron microscopy; enzyme substrate; ethers; guanine nucleotides; guanosine triphosphate; neoplasm /cancer pharmacology; nucleotide analog; plant extracts; polymerization; thiocyanates

The rational development of new antineoplastic agents directed against tubulin, a protein critical for cell division, requires greater understanding of the interactions between the polypeptide subunits of tubulin, its two tightly bound guanine nucleotides, and drugs which inhibit mitosis. Substitution of ATP and ATP analogs for GTP in glycerol-induced polymerization was demonstrated. This will permit structure-function studies of nucleotide interactions at the exchangeable site with more readily available ATP analogs. Degradation of the nonexchangeable GTP of tubulin by phosphofructokinase was observed, representing the first approach to this nucleotide which does not require the denaturation of the protein. Studies on the interactions of a large group of antimitotic agents with tubulin continued. The classes of compounds examined were combretastatin congeners; derivatives of 6-benzyl-1,3-benzodioxole and related compounds; derivatives of 5,6-diarylpyridazin-3-one; 2,4-dichlorobenzylthiocyanate; and alkyl carbamates of aromatic amines. A microtubule-associated protein which causes the formation of microtubule bundles was purified to homogeneity. Microtubule-associated protein(s) with nucleoside monophosphate kinase activity were resolved into components with different substrate specificity, and one component was purified to homogeneity. Maytansine was found to inhibit entry and exit of GDP and GTP at the exchangeable nucleotide binding site. Efforts to separate the Alpha and Beta subunits of tubulin continued, and efforts to prepare GTP analogs derivatized at the Gamma-phosphate were initiated.

针对的新抗塑料剂的合理发展 微管蛋白是一种至关重要的细胞分裂的蛋白质，需要更大 了解多肽亚基之间的相互作用 微管蛋白，其两个紧密结合的鸟嘌呤核苷酸和抑制的药物 有丝分裂。 在甘油诱导的ATP和ATP类似物中替换为GTP 证明了聚合。 这将允许结构功能 可交换位点核苷酸相互作用的研究更多 随时可用的ATP类似物。 不合时宜的GTP的降解 观察到通过磷酸果糖激酶微调蛋白，代表了第一个 该核苷酸的方法不需要变性 蛋白质。 大量抗毒素的相互作用的研究 持有微管蛋白的特工仍在继续。 所检查化合物的类是 combretastatin同类物； 6-苯唑-1,3-苯二氧化二氧化碳的衍生物和 相关化合物； 5,6-二亚吡啶嗪-3-ONE的衍生物； 2,4-二氯苯甲酸；和芳香胺的烷基氨基甲酸酯。 一个 微管相关蛋白，导致微管的形成 捆绑包被纯化为同质性。 微管相关蛋白（S） 将核苷单磷酸激酶活性分辨到成分中 具有不同的底物特异性，一个组件被纯化为 同质性。 发现Maytansine抑制GDP和GTP的进入和退出 在可交换的核苷酸结合位点。 分开alpha的努力 小管蛋白的β亚基继续进行，以及准备GTP类似物的努力 在γ-磷酸盐处衍生化。