Second Generation G-Quadruplex Stabilizing Trimethine Cyanines

Abstract

G-Quadruplex DNA has been recognized as a highly appealing target for the development of new selective chemotherapeutics, which could result in markedly reduced toxicity toward normal cells. In particular, the cyanine dyes that bind selectively to G-quadruplex structures without targeting 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.

Synthesis and Applications of Selected Fluorine-Containing Fluorophores

“…The aldehyde arm of compound 91 or 92 is intended to afford the dye bridge for the final compounds 93 and 94. This reaction affords the final product at a 49% yield for 93 and 18% yield for 94, as reported earlier by the Henary group [72]. [73].…”

“…The aldehyde arm of compound 91 or 92 is intended to afford the dye bridge for the final compounds 93 and 94. This reaction affords the final product at a 49% yield for 93 and 18% yield for 94, as reported earlier by the Henary group [72]. The reaction in Equation ( 5) utilizes the benz[c,d]indolenine aldehyde intermediate 90 or 91 with water-soluble heterocyclic salt 92 in acetic anhydride under reflux for dye synthesis [72].…”

“…The aldehyde arm of compound 91 or 92 is intended to afford the dye bridge for the final compounds 93 and 94. This reaction affords the final product at a 49% yield for 93 and 18% yield for 94, as reported earlier by the Henary group [72]. (5) The synthesis of polyfluorinated cyanine dyes designed by Braun et al begins with a bromine-containing heterocycle reacting with compounds 95-97 to generate the fluorinated heterocycles necessary in Scheme 19 [73].…”

“…The reaction in Equation (5) utilizes the benz[c,d]indolenine aldehyde intermediate 90 or 91 with water-soluble heterocyclic salt 92 in acetic anhydride under reflux for dye synthesis [ 72 ]. The aldehyde arm of compound 91 or 92 is intended to afford the dye bridge for the final compounds 93 and 94 .…”

“…These compounds begin with the same hemicyanine intermediate 82 and undergo a substitution reaction with different nucleophiles to afford fluorinated dyes 83-89 in yields varying between 16% and 65% based on the nucleophile used. The reaction in Equation ( 5) utilizes the benz[c,d]indolenine aldehyde intermediate 90 or 91 with water-soluble heterocyclic salt 92 in acetic anhydride under reflux for dye synthesis [72]. The aldehyde arm of compound 91 or 92 is intended to afford the dye bridge for the final compounds 93 and 94.…”