EPOTHILONE AFFINITY LABELS

埃坡霉素亲和标签

• 批准号: 6695917
• 负责人: Gunda I. Georg
• 金额: $ 3.64万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-04 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6695917
• 关键词: affinity labeling; antineoplastic antibiotics; binding sites; chemical synthesis; drug design /synthesis /production; fluorescent dye /probe; macrolide antibiotics; microtubules; paclitaxel; photochemistry; tubulin

Anti-MT drugs continue to receive great interest for their development as potential clinically useful antitumor agents. Several new natural products with taxol-like activity towards tubulin and microtubules have been identified recently. Of these, the epothiones are the most promising and exciting. This group of compounds can be isolated from bacterial source, making large scale production feasible. Epothilone A and B have been shown to be equipotent to taxol in stimulating tubulin assembly and competitively inhibiting [3H]taxol binding to microtubules. The epothilones are also similar to taxol in their anti-cell proliferative activity. However, these compounds have much greater activity toward cells that are resistant to taxol due to the over-expression of the P-glycoprotein multidrug transporter or to the expression of an altered Beta-tubulin. Thus, these compounds have the potential of overcoming two different mechanisms of cell resistance to taxol. Very little is known yet about the interaction of drugs with microtubules. Such information would be useful for designing new and better derivatives. Information obtained on the binding site will also be extremely important for future work on the site directed mutagenesis of the tubulin protein. A variety of approaches can be taken to obtain this information, including those which we are proposing, identification of peptides in the binding site through photo affinity labeling and the use of fluorescence spectroscopy to study detail of the interaction. The results of the tubulin binding studies would suggest that the binding sites for taxol and epothilone are identical. However, the fact that the epothilones are effective cytotoxic agents in cells that are resistant to taxol because of the expression of an altered Beta-tubulin, indicates that the sites may be overlapping rather than identical. It is the plan to prepare epothilone affinity labels through emisynthesis and total synthesis and evaluate them for tubulin assembly activity and cytotoxicity. Fluorescent epothilones will be used to study the interaction with microtubules and tubulin and the epothilone photo affinity will identify the ligand binding sites in the receptor.

抗 MT 药物因其优异的疗效而继续受到人们的极大关注 开发作为潜在的临床有用的抗肿瘤药物。一些 对微管蛋白具有紫杉醇样活性的新天然产物 最近发现了微管。 其中，埃菲硫酮 是最有希望和最令人兴奋的。 这组化合物可以是 从细菌源中分离出来，进行规模化生产 可行的。 埃坡霉素 A 和 B 已被证明与 紫杉醇刺激微管蛋白组装并竞争性抑制 [3H]紫杉醇与微管结合。 埃博霉素也类似 紫杉醇的抗细胞增殖活性。 然而，这些 化合物对耐药细胞具有更大的活性 由于 P-糖蛋白多药过度表达而导致紫杉醇 转运蛋白或改变的β-微管蛋白的表达。 因此， 这些化合物有可能克服两种不同的 细胞对紫杉醇的抵抗机制。 目前对于药物与药物之间的相互作用知之甚少。 微管。 这些信息对于设计新的和 更好的衍生品。 在结合位点上获得的信息将 对于该网站的未来工作也极其重要 微管蛋白的诱变。 可以采取多种方法 为获取这些信息而采取的措施，包括我们正在采取的措施 提出，通过识别结合位点中的肽 光亲和标记和荧光光谱的使用 研究交互的细节。 微管蛋白结合研究的结果表明 紫杉醇和埃博霉素的结合位点是相同的。 然而， 埃博霉素是细胞中有效的细胞毒剂这一事实 由于表达改变而对紫杉醇产生抗性 β-微管蛋白，表明这些位点可能是重叠的，而不是 完全相同的。 计划通过以下方式制备埃坡霉素亲和标签： 半合成和全合成并评估它们的微管蛋白 组装活性和细胞毒性。 荧光埃坡霉素将 用于研究与微管和微管蛋白的相互作用 埃坡霉素光亲和力将识别配体结合位点 受体。

项目成果

Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells.

C25-苄氧基埃坡霉素 C 的全合成和评估，用于微管蛋白组装和对 MCF-7 乳腺癌细胞的细胞毒性。

• DOI: 10.1016/j.bmcl.2008.07.024
• 发表时间: 2008
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Hutt,OliverE;Reddy,BolluS;Nair,SajivK;Reiff,EmilyA;Henri,JohnT;Greiner,JackF;Chiu,Ting-Lan;Vandervelde,DavidG;Amin,ElizabethA;Himes,RichardH;Georg,GundaI
• 通讯作者: Georg,GundaI

Total synthesis and evaluation of C26-hydroxyepothilone D derivatives for photoaffinity labeling of beta-tubulin.

用于 β-微管蛋白光亲和标记的 C26-羟基埃坡霉素 D 衍生物的全合成和评价。

• DOI: 10.1021/jo901752v
• 发表时间: 2010
• 期刊: The Journal of organic chemistry
• 作者: Reiff,EmilyA;Nair,SajivK;Henri,JohnT;Greiner,JackF;Reddy,BolluS;Chakrasali,Ramappa;David,SunilA;Chiu,Ting-Lan;Amin,ElizabethA;Himes,RichardH;VanderVelde,DavidG;Georg,GundaI
• 通讯作者: Georg,GundaI

Cytoskeletal integrity as a drug target.

细胞骨架完整性作为药物靶点。

• DOI: 10.2174/1567205053585837
• 发表时间: 2005
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: Michaelis,ML;Seyb,KI;Ansar,S
• 通讯作者: Ansar,S

Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin.

用于 β-微管蛋白光亲和标记的 22-(3-叠氮基苯甲酰氧基)甲基埃坡霉素 C 的全合成和评价。

• DOI: 10.1016/j.bmcl.2009.04.077
• 发表时间: 2009
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Hutt,OliverE;Inagaki,Jun;Reddy,BolluS;Nair,SajivK;Reiff,EmilyA;Henri,JohnT;Greiner,JackF;VanderVelde,DavidG;Chiu,Ting-Lan;Amin,ElizabethA;Himes,RichardH;Georg,GundaI
• 通讯作者: Georg,GundaI