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首页> 外文期刊>Anti-Cancer Drug Design >Synthesis of new homochiral bispyrrolidines as potential DNA cross-linking antitumour agents.
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Synthesis of new homochiral bispyrrolidines as potential DNA cross-linking antitumour agents.

机译：合成新的高手性双吡咯烷类化合物作为潜在的DNA交联抗肿瘤剂。

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We are seeking to develop more effective bifunctional alkylating agents as antitumour agents. We previously synthesized conformationally restricted nitrogen mustards containing one piperidine ring, then bispiperidine derivatives were designed and prepared with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. A bispiperidine with the shortest bridge of two carbon atoms was the most reactive bifunctional alkylating agent. In order to extend this work and investigate the effects of a change in the size of the heterocyclic systems, new bispyrrolidine salts 17-23 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-8 carbon atoms were synthesized from L-proline so that only the LL-enantiomers were produced. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. All of the bispyrrolidines were efficient cross-linkers of naked DNA apart from those with three-carbon (18) and four-carbon (19) bridges, in contrast to the results with the bispiperidines. A piperazine derivative 24 with two potential alkylating sites was also shown to be an efficient cross-linker, as was an alicyclic compound 25 with six carbon atoms between the two alkylating sites. Compounds 26 and 30 with an extra carbon atom between the nitrogen and the leaving group were not cross-linkers, as expected if aziridinium ion formation is crucial for cross-linking ability. The preformed aziridine 27 with a further alkylating site was an efficient cross-linker. Compounds 28-29 with only one potential alkylating centre were not cross-linkers of DNA. None of the compounds, however, produced significant cytotoxicity in human tumour cells in vitro.
机译：我们正在寻求开发更有效的双功能烷基化剂作为抗肿瘤剂。我们先前合成了含有一个哌啶环的受构象限制的氮芥，然后设计并制备了具有两个环之间碳链长度不同的双哌啶衍生物，并研究了这些系统中的结构活性关系。具有两个碳原子最短桥的双哌啶是反应性最高的双官能烷基化剂。为了扩展这项工作并研究杂环系统大小变化的影响，新的双吡咯烷盐17-23在2位带有氯甲基基团，并在2-8个碳原子的两个氮原子之间架桥由L-脯氨酸合成，从而仅产生LL-对映体。游离碱经偶氮鎓离子形成而设计为双官能烷基化剂，两个烷基化位点之间的距离不同。与使用双哌啶的结果相反，所有双吡咯烷都是裸DNA的有效交联剂，具有三碳（18）和四碳（19）桥的那些除外。还显示具有两个潜在烷基化位点的哌嗪衍生物24是有效的交联剂，在两个烷基化位点之间具有六个碳原子的脂环族化合物25也是如此。氮与离去基团之间具有额外碳原子的化合物26和30不是交联剂，这是预期的，如果氮丙啶鎓离子的形成对于交联能力至关重要。具有另外的烷基化位点的预形成的氮丙啶27是有效的交联剂。仅具有一个潜在的烷基化中心的化合物28-29不是DNA的交联剂。但是，这些化合物均未在体外对人肿瘤细胞产生明显的细胞毒性。

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