SYNTHESIS OF ANTITUMOR AGENTS

我们建议继续努力， 具有显著抗癌活性的聚酮海洋天然产物 活动 选择用于本发明的特异性合成靶分子可以是： 建议的授权期是tedanacetate（1），C32 H52 O 11，分离自 加勒比海海绵Tedania ignis，aacronine（2），C54 H92 N2）12，来自海兔 海绵中的Aaprosia kurodai和discodermolide（3），C33 H55 NO 8 盘皮藓 这些海产品中的每一种都是 具有独特结构的抗癌剂。 Tedaniline含有作为 多达三个酸和碱敏感的β-羟基部分嵌入在 碳骨架，这是其他大环内酯类天然产物中罕见的特征。 产品. 如图所示，阿克罗宁显示出惊人的生物活性， 将白血病小鼠的平均寿命延长200-550%。 阿克罗宁是结构相关化合物的代表，包括 scytophycins，halichondramides，kabiramide和swinholides。 Discodermolide (3)不仅抑制小鼠P388白血病的体外增殖， 细胞，但也被发现是一种免疫抑制剂十倍 和环孢霉素一样有效 其结构相对简单， 另一个有吸引力的特征及其合成可以构成一种手段， 提供大量的该化合物用于进一步的生物学作用， 问题研究 所提出的1-3的合成广泛使用羟醛缩合反应， 其立体化学过程受双重规则支配 不对称合成 因此，构建了靶分子的片段， 通过单一或多次使用乙酸盐或丙酸盐添加到选定的 醛与几种手性试剂现在可用。 的耦合 片段涉及手性醛和手性酮（两者都是手性的）。 片段），并通过（i）使用第三手性 在羟醛中起立体化学主导作用的组分 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 片段的合成和偶联都是本发明的中心主题。 提议

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.