SYNTHESIS OF GUANINE QUADRUPLEX LIGAND AND PARTITION COEFFICIENT MEASUREMENTS OF ANIONS

Abstract

Guanine quadruplexes (G4s) are secondary architectures of nucleic acids which have gained much attention in the medicinal world for many years. They are present in telomeres and oncogene promoters and found in both DNA and RNA. Stabilizing these G4s by organic binders (ligands) may inhibit the telomerase enzyme, shorten the telomeres, and impede cancer cell growth. Likewise, these G4 binding ligands may also repress the activity of oncogenes. My thesis aims to explore the synthesis of G4 stabilizing ligands and determine the partition coefficients of permanent salts as a means to rank counter-anions in terms of their hydrophilicity. The latter study would be valuable since many G4 binders are cationic and therefore accompanied by anions. The first part of the thesis reports the attempted first steps in the synthesis of two G4 ligands. One is organic (acridine-based), and the other one was designed to generate a coordination binder (terpyridine). None of these two G4 ligands were successfully synthesized. Four steps in the terpyridine synthesis, and one reaction in the acridine ligand synthesis, were investigated. The second part of the thesis was initially inspired by the data previously obtained by Linclau and his group using fluorine nuclear magnetic resonance spectroscopy for logP determination. Control experiments were reproduced, and the logP of six salts of N-benzyl-3-fluoropyridinium was studied. Ion-exchange chromatography was applied to produce the five new salts, and nuclear magnetic resonance was used to determine (i) the efficiency of anion conversion and (ii) LogP values. Reliable logP values would be of interest in the selection of anions, as counter-anions to cationic potential drugs, in the context of improved cell uptake.