Second Generation G‑Quadruplex StabilizingTrimethine Cyanines

G-quadruplex DNA has been recognized as a highly appealing target for the development of new highly selective chemotherapeutics, which could result in markedly reduced toxicity towards normal cells. In particular, the cyanine dyes that bind selectively to G-quadruplex structures without targetting duplex DNA have attracted attention due to their high amenability to structural modifications that allows fine tuning of their biomolecular interactions. We have previously reported pentamethine and symmetric trimethine cyanines designed to effectively bind G-quadruplexes through end stacking interactions. Herein, we are reporting a second generation of drug candidates, the asymmetric trimethine cyanines. These have been synthesized and evaluated for their quadruplex binding properties. Incorporating a benz[c,d]indolenine heterocyclic unit increased overall quadruplex binding and elongating the alkyl length increases the quadruplex-to-duplex binding specificity.