SEMISYNTHETIC PYRROLIZIDINE ALKALOID ANTITUMOR AGENTS

我们的目标是提供改进的抗肿瘤药物，具有更好的治疗效果 指数，模仿吲哚N-氧化物(INO)(1)，这两个逆转录病毒 (2)和Heiotridine(3)N-氧化物家族，并研究其作用机理 这些药物的作用。 蜜酸成分将通过立体定向合成，而 Rtronecine将从现成的野百合碱和 经修改后可提供其他甜蜜。手性分子的位置选择性耦合 将利用甜蜜素中C-7和C-9位的蜜环酸。结构 活动研究将与非常强大和活跃的家庭一起开发 4代表的化合物，以便获得机械论的理解 取代基的影响和手性的影响 酸和甘氨酸。 除了体内筛选外，还将利用体外筛选 之前进行过的。为了区分不同的机制 作用方面，选定药物的烷基化能力将通过 放射性标记化合物与细胞DNA和蛋白质的结合 非标记化合物对DNA链间交联和DNA合成的影响 链的断裂将被确定。将进行直接比较， 在相同的细胞系统中，在体外细胞毒性和在 体外蛋白质和DNA结合和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.