SUPERIOR CHEMOTHERAPEUTIC AGENTS BY RATIONAL DESIGN

摄入许多天然存在的化合物，以及许多合成 药物，在人类和动物中产生“光毒性”，因此， 暴露于光会导致皮肤或视力损伤，或诱导或 癌症的加速。 对这些药物进行合成修饰以避免这种情况 副作用是一项艰巨的任务，因为分子的不确定性 以及这种不期望的光生物活性的机制基础，因此， 很少有人提出可能的方法， 成功地克服了光毒性的这种固有趋势， 药 该提案描述了三种机械衍生的方法， 新型化疗药物的合理合成 减轻光毒性。 这些方法将在综合报告中得到检验 新的化合物有望表现出高抗疟活性，但 无光毒性。 这些化合物的成功不仅会产生新的 迫切需要的抗疟化合物，但也将 证明了一个机械衍生的方法来解决的有效性 在其它不同种类的化合物中的光毒性问题， 也有这种副作用。

Ingestion of many naturally-occurring compounds, as well as many synthetic drugs, produces "phototoxicity" in humans and animals, so that subsequent exposure to light causes skin or vision damage, or induction or acceleration of cancer. To synthetically modify these drugs to avoid this side effect is a difficult task because of uncertainty about the molecular and mechanistic basis for this undesired photobiological activity, so there have been very few suggestions of possible approaches which might be successful in overcoming this inherent tendency towards phototoxicity in a drug. This proposal describes three mechanistically-derived approaches to the rational synthesis of new chemotherapeutic agents of dramatically lessened phototoxicity. These approaches will be tested in the synthesis of new compounds expected to exhibit high antimalarial activity, yet be non-phototoxic. Success with these compounds will not only result in new antimalarial compounds which are desperately needed,but will also demonstrate the validity of a mechanistically-derived approach to solving the problem of phototoxicity in other dissimilar classes of compounds which also suffer from this side effect.