SEMISYNTHETIC PYRROLIZIDINE ALKALOID ANTITUMOR AGENTS

我们的目的是提供改进的抗肿瘤剂，具有更好的治疗效果， 指数，以indicine N-氧化物（INO）（1）为模型， (2)和heliotridine（3）N-氧化物家族，并研究 这些药物的作用。 将立体特异性地合成necic酸组分，而 倒罗那辛将从容易获得的野百合碱获得， 被改造成能给其他人致命的东西 手性的位点选择性偶联 将利用位于necines的C-7和C-9的necic酸。 结构 活动研究将与非常有效和活跃的家庭一起开展 4所代表的化合物，以获得机械的理解 取代基的影响和手性的影响的necic 酸和necines。 除体内筛选外，还将进行体外筛选 以前进行的。 为了区分各种机制 为了确定作用，所选药物的烷基化能力将通过 放射性标记的化合物与细胞DNA和蛋白质的结合， 非标记化合物对DNA链间交联的影响， 将测定链断裂。 直接比较将由 反应，在相同的细胞系统中，在体外细胞毒性和 体外蛋白质和DNA结合以及DNA链断裂。

Our aim is to provide improved antitumor agents, with better therapeutic indices, modeled after indicine N-oxide (INO) (1), of both the retronecine (2) and heliotridine (3) N-oxide families and to study the mechanism of action of these drugs. The necic acid components will be stereospecifically synthesized, while retronecine will be obtained from the readily available monocrotaline and modified to give other necines. Site selective coupling of the chiral necic acids at C-7 and C-9 of the necines will be utilized. Structure activity studies will be developed with the very potent and active family of compounds represented by 4, in order to obtain mechanistic understanding of the effects of substituents and the effects of chiralities of the necic acids and necines. In vitro screening will be utilized, in addition to the in vivo screening previously undertaken. In order to distinguish between various mechanisms of action, the alkylating ability of selected drugs will be measured by the binding of radioactively labeled compound to cellular DNA and protein and the effects of non-labeled compounds on DNA interstrand crosslinking and strand scission will be determined. Direct comparisons will be made of responses, in the same cell systems, between in vitro cytotoxicity and in vitro protein and DNA binding and DNA strand scission.