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

Abstract

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.

The Sulfamate Small Molecule CAIX Inhibitor S4 Modulates Doxorubicin Efficacy

“…In this study doxorubicin treatment was only effective in reducing tumor growth in the MDA-MB-231 xenografts, whereas no effect was observed in the FaDu, HT29 –CAIX high and HT29 –CAIX low tumor models. This difference between models is unlikely caused by any intrinsic variation in doxorubicin sensitivity, as no differences were observed in vitro or in previous reports [ 33 ]. The tumor microenvironment might therefore be responsible for this difference in doxorubicin response.…”

Donor–acceptor single cocrystal of coronene and perylene diimide: molecular self-assembly and charge-transfer photoluminescence

“…According to our previous study, 26 assembly of PTCDI-C6 molecules takes two orientations within one monoclinic crystal cell, as usually observed for other PTCDIs that have tertiary or quaternary carbon atoms directly linked to the imide nitrogen atoms. 5,27 Within the PTCDI-C6 crystal, the stacking molecules twist by an appropriate angle to minimize the steric hindrance of cyclohexyl groups. But with the inserting of coronene molecules, the distance between the two PTCDI-C6 molecules was almost doubled, thus diminishing the steric hindrance of side groups.…”

Fragment-based design of small molecule PCSK9 inhibitors using simulated annealing of chemical potential simulations

“…Golunski[69] and co-workers hypothesized that doxorubicin toxicity could be reduced without loss of efficacy by disrupting its π-π self-recognition with pentoxifylline (S2 Fig)–an aromatic molecule known to breakup π-π -stacking. Hartlieb[70] and colleagues attacked this problem differently—they showed that disruption of the π-stacking of 2,9-diazaperopyrenium by adding a functional group that causes a steric clash with the neighboring molecule, results in increased anti-cancer potency (S2 Fig). These investigators solved the crystal structures of the homo-aggregates and demonstrated that biological activity increased as stacking decreased.…”