SYNTHESIS OF ANTITUMOR AGENTS

抗肿瘤剂的合成

• 批准号: 2330762
• 负责人: SATORU MASAMUNE
• 金额: $ 21.11万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-08 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2330762
• 关键词: aldehydes; antineoplastics; biological products; chemical structure function; drug design /synthesis /production; ketones; lactones; macrolide antibiotics; saltwater environment; stereochemistry

We propose to continue our efforts directed towards to==the synthesis of polyketide marine natural products which exhibit notable anticancer activities. The specific synthetic target molecules selected for the proposed grant period are tedanolide (1), C32H52O11, isolated from Caribbean sponge Tedania ignis, aplyronine (2), C54H92N2)12, from sea hare Aplysia kurodai, and discodermolide (3), C33H55NO8, from the marine sponge Discodermia dissoluta. Each of these marine products is a potent anticancer agent possessing a unique structure. Tedanolide contains as many as three acid-and base-sensitive beta-hydroxy moieties embedded in the carbon framework, a feature rarely seen in other macrolide natural products. Aplyronine exhibits striking biological activity as illustrated by a 200-550% extension of the average lifetime of leukemic mice. Aplyronine is a representative of structurally related compounds including scytophycins, halichondramides, kabiramide and swinholides. Discodermolide (3) not only inhibits the in vitro proliferation of murine P388 leukemia cells, but has also been found to be an immunosuppressive agent ten times as potent as cyclosporine. The relative simplicity of its structure is another attractive feature and its synthesis may constitute a means of providing substantial quantities of this compound for further biological studies. The proposed syntheses of 1-3 extensively use aldol reactions, the stereochemical courses of which are governed by the rule of double asymmetric synthesis. Thus, fragments of a target molecule are constructed by single or multiple use of acetate or propionate additions to a selected aldehyde with several chiral reagents now available. The coupling of fragments involves a chiral aldehyde and a chiral ketone (both of which are fragments) and is executed either (i) by the use of a third chiral component which plays a stereochemically dominant role in the aldol reaction or (ii) by exploiting certain types of structural features existing in the reactants. The selection of chiral reagents to be used in both the synthesis and coupling of fragments is a central theme of this proposal.

我们建议继续努力，争取……的综合 具有显著抗癌作用的聚酮类海洋天然产物 活动。所选的特定合成目标分子 建议的授权期为tedanolide(1)，C32H52O11，分离自 加勒比海绵Tedania Ignis，Aplyronine(2)，C54H92N2)12，来自海兔 和盘状纤毛虫(Discodermolide)C33H55NO8 溶解盘皮病。这些海产品中的每一种都是一种强有力的 具有独特结构的抗癌剂。泰丹内酯含有AS 多达三个对酸和碱敏感的β-羟基嵌入在 碳骨架，这是其他天然大环内酯中罕见的特征 产品。如图所示，阿普利罗宁具有显著的生物活性 白血病小鼠的平均寿命延长了200-550%。 阿普利罗宁是结构上相关的化合物的代表，包括 镰刀菌素、灯盏花素、卡比拉胺和猪假日。米氏盘状物 (3)不仅抑制小鼠P388白血病细胞的体外增殖 细胞，但也被发现是一种十倍的免疫抑制剂 和环孢素一样有效。它的结构相对简单，是 另一个吸引人的特征及其合成可以构成一种手段 提供了大量的这种化合物用于进一步的生物 学习。 建议的1-3的合成广泛使用了Aldol反应， 其立体化学课程受双重规则支配 不对称合成。因此，构建了目标分子的片段 通过单次或多次使用醋酸酯或丙酸添加到选定的 乙醛和几种手性试剂现已上市。的耦合性 碎片涉及手性醛和手性酮(这两种物质都是 片段)，并且(I)通过使用第三手性 在羟醛化合物中起立体化学主导作用的成分 反应或(Ii)通过利用某些类型的结构特征 存在于反应物中。手性试剂的选择 片段的合成和耦合都是这方面的一个中心主题 求婚。