Anticancer Activity Expressed by a Library of 2,9-Diazaperopyrenium Dications

Polyaromatic compounds are well-known to intercalate DNA. Numerous anticancer chemotherapeutics have been developed upon the basis of this recognition motif. The compounds have been designed such that they interfere with the role of the topoisomerases, which control the topology of DNA during the cell-division cycle. Although many promising chemotherapeutics have been developed upon the basis of polyaromatic DNA intercalating systems, these candidates did not proceed past clinical trials on account of their dose-limiting toxicity. Herein, we discuss an alternative, water-soluble class of polyaromatic compounds, the 2,9-diazaperopyrenium dications, and report in vitro cell studies for a library of these dications. These investigations reveal that a number of 2,9-diazaperopyrenium dications show similar activities as doxorubicin toward a variety of cancer cell lines. Additionally, we report the solid-state structures of these dications, and we relate their tendency to aggregate in solution to their toxicity profiles. The addition of bulky substituents to these polyaromatic dications decreases their tendency to aggregate in solution. The derivative substituted with 2,6-diisopropylphenyl groups proved to be the most cytotoxic against the majority of the cell lines tested. In the solid state, the 2,6-diisopropylphenyl-functionalized derivative does not undergo π···π stacking, while in aqueous solution, dynamic light scattering reveals that this derivative forms very small (50–100 nm) aggregates, in contrast with the larger ones formed by dications with less bulky substituents. Alteration of the aromaticitiy in the terminal heterocycles of selected dications reveals a drastic change in the toxicity of these polyaromatic species toward specific cell lines.

聚芳香族化合物嵌入DNA的特性已被广泛认知，诸多抗癌化疗药物正是基于这一识别基序开发而来。此类化合物的设计思路为干扰拓扑异构酶（topoisomerases）的功能——拓扑异构酶可在细胞分裂周期中调控DNA的拓扑结构。尽管基于聚芳香族DNA嵌入体系已开发出多款极具潜力的化疗候选药物，但这些候选药物均因存在剂量限制性毒性而未能通过临床试验。本文讨论了一类新型水溶性聚芳香族化合物——2,9-二氮杂苝二阳离子（2,9-diazaperopyrenium dications），并报道了该类二阳离子文库的体外细胞实验研究结果。研究发现，多款2,9-二氮杂苝二阳离子对多种癌细胞系的活性与多柔比星（doxorubicin）相当。此外，本文还报道了这类二阳离子的固态结构，并将其在溶液中的聚集倾向与各自的毒性谱相关联。向这类聚芳香族二阳离子引入大位阻取代基，可降低其在溶液中的聚集趋势。其中，带有2,6-二异丙基苯基取代基的衍生物对绝大多数受试癌细胞系的细胞毒性最强。在固态状态下，该2,6-二异丙基苯基功能化衍生物未发生π-π堆积（π···π stacking）；而在水溶液中，动态光散射实验结果显示，该衍生物仅形成尺寸极小（50–100 nm）的聚集体，与之形成鲜明对比的是，取代基位阻更小的二阳离子会形成更大尺寸的聚集体。对部分二阳离子的末端杂环芳香性进行改造后，这类聚芳香族物种对特定细胞系的毒性发生了显著变化。