SYNTHESIS OF ANTITUMOR NATURAL PRODUCTS

抗肿瘤天然产物的合成

• 批准号: 2633730
• 负责人: SAMUEL J DANISHEFSKY
• 金额: $ 40.64万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-03-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2633730
• 关键词: antineoplastics; breast neoplasms; camptothecin; chemical synthesis; colon neoplasms; drug design /synthesis /production; gastrointestinal neoplasms; paclitaxel; synthetic tumor antigen

DESCRIPTION: It is stated that the long term goals of this project involve the development of new chemistry to be used in synthesis as well as in the preparation of target structures for the purposes of investigating their biological activity and modes of action. The focus in terms of biological profile in this program is to center on three types of agents. It is noted that the first is a group of cytotoxic natural products. The PI indicates that selectivity of such systems would reside in the enhanced vulnerability of rapidly dividing cells to the various actions of cytotoxic agents and that in this category, he will be addressing synthetic, mechanistic, and SAR issues related to (A) taxol, (B) the epothilones, (C) enediyne related hybrids, (D) ET-743, and (E) camptothecin. He notes that his attentions will also be directed to cytotoxic agents known to be implicated in cell cycle modulation and that these goal structures include (F) radicicol, (G) herbimycin, (H) xestocyclamine, and (I) tryprostatin. The PI indicates that in addition, he hopes to be following up some dramatic leads in the area of agents which might potentially reverse the multidrug resistance (MDR) phenotype and that compounds in this class include (J) the ardeemins, and (K) the gypsetins, as well as related pyrolo indole based natural products. He reports that another natural product target, CP 225,917 (L) poses a difficult and attractive structure given reports that it is a farnesyl transferase inhibitor. The third area is to involve the synthesis of fully synthetic antitumor antigens. The PI notes that the concept involves previous observations that novel carbohydrate patterns are expressed at the cell surface of transformed cells and that these tend to be bound to the cell membrane, either through involvement as glycoproteins, or as glycolipids. He states that the thought is that synthetic versions of these tumor antigens might elicit an immune response leading to antibody formation, complement fixation and cell lysis and that minimally, such tumor antigens could be used in very early diagnosis as a devise for early screening of antibody formation. It is noted that the tumor antigens which will be addressed are (M) a breast tumor antigen, (N) a gastric tumor antigen, and (O) a colon cancer antigen. In the area of chemical methodology, the PI is to explore in some detail, the scope of transition metal mediated furanylation reactions, new strategies in ring construction, new departures in diastereoselective and enantioselective synthesis and the synthesis of neoglycoconjugates including neoglycoproteins.

说明：据指出，该项目的长期目标包括 新化学的发展将用于合成以及 目标结构的制备，以研究其 生物活性和作用方式。 在生物学方面， 在这个程序中的配置文件是集中在三种类型的代理。 应注意 第一种是一组细胞毒性天然产物。 PI显示 这种系统的选择性将存在于增强的脆弱性中， 快速分裂的细胞对细胞毒性剂的各种作用， 在这一类别中，他将讨论合成、机械和SAR 与（A）紫杉醇，（B）埃博霉素，（C）烯二炔有关的问题 杂交物，（D）ET-743和（E）喜树碱。 他注意到他的注意力 本发明还涉及已知与细胞凋亡有关的细胞毒性剂 循环调节，并且这些目标结构包括（F）根赤霉素，（G） 除莠霉素、（H）昔司环胺和（I）曲前列素。 PI表示，此外，他希望能够跟进一些戏剧性的 可能逆转多药耐药的药物领域的领先者 耐药（MDR）表型，这类化合物包括（J） ardeemins，和（K）gypsetins，以及相关的基于吡咯并吲哚的 天然产品。 他报告说，另一种天然产品的目标，CP 225，917（L）构成了一个困难和有吸引力的结构，因为有报道称， 是法尼基转移酶抑制剂。 第三个领域是让 全合成抗肿瘤抗原的合成。 PI指出， 这一概念涉及到以前的观察，即新的碳水化合物模式是 在转化细胞的细胞表面表达，并且这些倾向于 结合到细胞膜上，或者通过作为糖蛋白参与，或者 糖脂 他指出，这种想法是， 这些肿瘤抗原可能引发免疫反应， 形成、补体固定和细胞裂解，并且最低限度地，这种肿瘤 抗原可用于非常早期的诊断， 抗体形成的筛选。 值得注意的是， 将涉及的是（M）乳腺肿瘤抗原，（N）胃肿瘤抗原， 抗原，和（O）结肠癌抗原。 在化学领域， 方法论，PI是探讨在一些细节，范围的过渡 金属介导的呋喃化反应，环构建中的新策略， 在非对映选择性和对映选择性合成中的新的偏离和 包括新糖蛋白的新糖缀合物的合成。