High DNA Affinity of a Series of Peptide Linked Diaromatic Guanidinium-like Derivatives

Abstract

In this paper we report the design and synthesis of a new family of asymmetric peptide linked diaromatic dications as potent DNA minor groove binders. These peptide-linked compounds, with a linear core, displayed a much larger affinity than other guanidinium-like derivatives from the same series with curved cores. As a first screening, the DNA affinity of these structures was evaluated by means of thermal denaturation experiments, finding that the nature of the cation (guanidinium vs 2-aminoimidazolinium) significantly influenced the binding strength. Their binding affinity was assessed by implementing further biophysical measurements such as surface plasmon resonance and circular dichroism. In particular, it was observed that compounds 6, 7, and 8 displayed both a strong binding affinity and significant selectivity for AT oligonucleotides. In addition, the thermodynamics of their binding was evaluated using isothermal titration calorimetry, indicating that the binding is derived from favorable enthalpic and entropic contributions.

Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines

“…Since N-phenylbenzamide and 1,3-diphenylurea guanidine and imidazoline derivatives are strong DNA minor groove binders [11,[26][27][28], we were interested in quantitatively evaluating the binding affinity of the new compounds with DNA. Binding to DNA and resultant inhibition of transcription and activity of other DNA-dependent enzymes is thought to contribute to the antiprotozoal activity of dicationic compounds [29].…”

Synthesis of cyclic guanidines: 2-arylamino-1,4,5,6-tetrahydropyrimidines

“…10 Pd 2 (dba) 3 was chosen as the source of catalytic Pd and different bases, solvents and temperatures were examined for their effect on the reaction. A range of ligands 1 -5 ( Figure 1) was investigated but, as previously discovered, 7 we found that Xantphos 5 was the most successful ligand for this coupling process.…”

“…2 Many biologically active molecules containing guanidine or cyclic guanidine functionalities (e.g. the 2-aminoimidazoline system) exhibit a wide range of applications from minor groove binders 3 to potential antidepressant agents. 4 Continuing with our interest in the guanidine system 4 and, in particular, in guanidines embedded in aliphatic rings, the synthesis of 2-arylamino-1,4,5,6-tetrahydropyrimidines, which are compounds that incorporate a cyclic guanidine moiety in a six-membered ring was highly interesting to us.…”

A New Nonpolar N -Hydroxy Imidazoline Lead Compound with Improved Activity in a Murine Model of Late-Stage Trypanosoma brucei brucei Infection Is Not Cross-Resistant with Diamidines

“…Regarding the mode of action of the antitrypanosomal lead compounds I to V, earlier studies have shown that this class of dicationic compounds binds to the DNA minor groove at AT-rich sequences (55)(56)(57)(58). In trypanosomes, the kinetoplast DNA (kDNA) has a high content of AT-rich regions that could be a site of selective action of this kind of compound (59).…”