ACETYLASE TARGETED ANTINEOPLASTIC ANALOGUES

多胺途径是化疗的合理靶点 干预，因为细胞多胺的消耗导致减少 在细胞生长的速度，并在某些特定的情况下，导致 细胞毒许多有效的多胺生物合成抑制剂具有 已被开发为潜在的抗肿瘤剂，但其中只有一种 化合物已成为临床上有用的药剂。因此，有一个 对多胺抑制剂的设计和合成的持续需求 生物合成双（乙基）多胺代表一类新的 在体外表现出有希望的抗肿瘤作用的多胺类似物， in vivo.有趣的是，观察到的细胞毒性反应似乎是 在重要的人实体瘤范围内具有肿瘤类型特异性。在 响应细胞系，细胞毒性已与倾向 双（乙基）多胺诱导酶亚精胺/精胺-N1- 乙酰基转移酶（SSAT），在催化乙酰基转移酶的限速步骤， 多胺，以及它们下调细胞多胺的能力， 生物合成本提案的总体目标是综合 并研究了一系列不对称取代的 具有潜在的用作抗肿瘤剂的多胺类似物， 工具，以促进对细胞类型的机制的理解 某些多胺类似物显示出特异性细胞毒性。拟议 类似物被设计成作为可逆的、不可逆的、酶激活的 或基于过渡态模拟物的SSAT抑制剂和/或诱导剂，和 导致所提出的类似物的合成路线是足够的 多功能性，以允许选择性官能化， 结构/活动调查。将测定每种类似物的活性 使用先前公开的测定方法针对纯化的人SSAT。 将评价每种类似物的效力和超诱导能力， SSAT在已建立的肺肿瘤细胞模型系统中。活性类似物将 也可用于确定肿瘤细胞特异性的机制， SSAT的超归纳，并作为工具来确定SSAT的要求 用于细胞特异性细胞毒性。这些研究将提供重要的 关于多胺代谢差异的新信息 在细胞类型之间表现出来，也可以提供一些 潜在的重要生物制剂。

The polyamine pathway is a logical target for chemotherapeutic intervention, since depletion of cellular polyamines leads to a decrease in rate of cell growth, and in some specific instances leads to cytotoxicity. A number of potent polyamine biosynthesis inhibitors have been developed as potential antitumor agents, but only one of these compounds has become a clinically useful agent. Thus, there is a continuing need for the design and synthesis of inhibitors of polyamine biosynthesis. The bis(ethyl)polyamines represent a novel class of polyamine analogues which exhibit promising antitumor effects in vitro and in vivo. Interestingly, the observed cytotoxic response appears to be tumor-type specific within the range of important human solid tumors. In responsive cell lines, cytotoxicity has been correlated to the propensity of the bis(ethyl)polyamines to induce the enzyme spermidine/spermine-N1- acetyltransferase (SSAT), the rate limiting step in the catabolism of polyamines, and to their ability to down-regulate cellular polyamine biosynthesis. The overall objectives of this proposal are to synthesize and examine the effects of a series of asymmetrically substituted polyamine analogues for potential use as antineoplastic agents, and as tools to facilitate an understanding of the mechanism of cell-type specific cytotoxicity demonstrated by some polyamine analogs. The proposed analogs are designed to act as reversible, irreversible, enzyme-activated or transition-state mimic-based inhibitors and/or inducers of SSAT, and the synthetic routes leading to the proposed analogues are of sufficient versatility to allow for selective functionalization to facilitate a structure/activity survey. Each analogue will be assayed for activity against purified human SSAT using a previously published assay procedure. Each analogue will be evaluated for potency and the ability to superinduce SSAT in an established lung tumor cell model system. Active analogues will also be used to determine the mechanism of tumor cell specific superinduction of SSAT, and as tools to determine the requirement of SSAT for cell-specific cytotoxicity. These studies should provide significant new information regarding the differences in polyamine metabolism exhibited between cell types, and could also provide a number of potentially important antineoplastic agents.