A Small Molecule Affecting the Replication of Trinucleotide Repeat d(GAA)_n

Abstract

A newly designed ligand, methylcarbamoylnaphthyridine dimer (MCND), was synthesized and characterized. Ligand binding to d(GAA)(10) was investigated by UV thermal denaturation, circular dichroism spectroscopy, surface plasmon resonance, and cold-spray-ionization time-of-flight mass spectrometry. The results indicated that MCND bound to the d(GAA)(n) repeat to form a stable hairpin structure with a major binding stoichiometry of 3:1. The most likely binding site was identified as the G-G mismatch in the AGA/AGA triad. The polymerase stop assay showed that MCND binding to the d(GAA)(n) repeat effectively interfered with the extension of the primer at the first two GAA sites on the template with both prokaryotic Taq DNA polymerase and human DNA polymerase alpha.

Cyclic mismatch binding ligand CMBL4 binds to the 5′-T-3′/5′-GG-3′ site by inducing the flipping out of thymine base

“…Detail synthesis (Supplementary Figure S4) and characterization of CMBL4 are given in the Supplementary data. We also prepared control compound naphthyridine carbamate dimer ( NCD) (30) and MCND (36) and 2-( N -methoxycarbonyl)amino-7-aminomethyl-1,8-naphthyridine ( monomer) (30) using previously reported procedure to evaluate the effect on interaction with nucleic acid upon macrocyclization. Conformational analysis of CMBL4 was carried out using Amber* force field with mixed torsional/low mode sampling method (Maestro version 10.0.013, Schrödinger Inc.).…”

“…Linkers connecting two heterocycles play an important role in offering a conformation that is suitable for the simultaneous binding of two heterocycles to the target nucleotide bases (36). Due to the increased conformational freedom of two heterocycles connected by a long linker, the necessary conformational changes for the binding should be accompanied by the penalty of entropy loss.…”

Naphthyridine-based lanthanide complexes worked as magnetic resonance imaging contrast for guanosine 5′-monophosphate in vivo

“…Synthesis of N-(7-methyl- [1,8]naphthyridin-2-yl)-acetamide 36 2-amino-7-methylnaphthyridine (2.5g, 15.7 mmol) was dissolved in 25 mL dry acetic anhydride and refluxed 8 h. Solvent was removed under vacuum. The crude product was purified by column chromatography using 50% ethyl acetate in petroleum ether to give pale yellow solid (2.2 g, 70% yield): 1 37,38 Solution of N-(7-Methyl- [1,8]naphthyridin-2-yl)-acetamide (0.88 g, 4.00 mmol), NBS (0.84 g, 4.80 mmol), and benzoyl peroxide in a mixture of chloroform and acetonitrile (5:4) was heated to reflux. Reactions were monitored by TLC.…”

Electrochemical Investigation of Interaction between a Bifunctional Probe and GG Mismatch Duplex

“…The bifunctional electrochemical probe (FecNC) was synthesized according to previous work. 20 All the oligonucleotides were purchased from the Invitrogen Corp. (China) with HPLC purification. The base sequences are as follows:…”

“…[19][20][21] Recently, we designed a new bifunctional electrochemical probe for the electrochemical detection of GG mismatch duplexes and CGG trinucleotide repeat DNA in solution. 6,22,23 In the presence of the bifunctional electrochemical probe FecNC (Scheme 1), GG mismatch in aqueous solution was detected by a naked gold electrode because of different diffusibility between free and DNA-bound FecNC.…”