SYNTHESIS OF ANTITUMOR NATURAL PRODUCTS

说明：该项目的长期目标包括 用于合成和合成的新化学的发展 为研究它们的目的制备目标结构 生物活性和作用方式。在生物学方面的焦点 本计划中的配置文件以三种类型的代理为中心。值得注意的是 第一种是一组具有细胞毒性的天然产物。PI表示 这种系统的选择性将存在于增强的脆弱性中 在细胞毒剂的不同作用下快速分裂细胞 在这一类别中，他将讨论合成、机械和SAR 与(A)紫杉醇、(B)环氧乙烯酮、(C)烯二炔有关的问题 杂交种、(D)ET-743和(E)喜树碱。他指出，他的注意力 也将针对已知与细胞有关的细胞毒剂 这些目标结构包括(F)自由基，(G) 去甲氧西林、(H)异四环胺和(I)尝试前列腺素。 私家侦探表示，此外，他希望跟进一些戏剧性的 可能逆转多种药物的药物领域的线索 抗性(MDR)表型，这类化合物包括(J) Ardeemins，和(K)吉卜赛汀，以及相关的以吡咯吲哚为基础的化合物 天然产品。他报告说，另一个天然产品目标是CP 225,917(L)构成了一个困难而有吸引力的结构，因为有报道称 是一种法尼基转移酶抑制剂。第三个领域是涉及 全合成抗肿瘤抗原的合成。私家侦探指出， 这个概念涉及之前的观察，即新的碳水化合物模式是 在转化细胞的细胞表面表达，这些往往是 结合到细胞膜上，或者作为糖蛋白参与，或者 作为糖脂。他指出，人们的想法是，合成版本的 这些肿瘤抗原可能会引发免疫反应，从而产生抗体。 形成、补体结合和细胞溶解，以及最小的，这样的肿瘤 抗原可用于非常早期的诊断，作为早期诊断的手段。 抗体形成的筛选。值得注意的是，肿瘤抗原 将解决的是(M)乳腺癌抗原，(N)胃癌 抗原，和(O)结肠癌抗原。在化学领域 方法论上，PI是比较详细地探索、过渡的范围 金属介导的呋喃反应，环结构的新策略， 非对映选择性和对映体选择性合成的新进展 含新糖蛋白的新糖偶联物的合成。

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.