Synthesis of Dimeric 2‐Amino‐1,8‐Naphthyridine and Related DNA‐Binding Molecules

Abstract

The synthetic protocols for dimeric 2-amino-1,8-naphthyridine and related compounds are described in this unit. These compounds represent a novel class of compounds that bind selectively to mismatched base pairs. The compounds consist of two main components: the heterocycles and a linker. Connecting two heterocycles by a linker was found to modulate the binding selectivity. This unit describes the synthesis of dimeric 2-amino-1,8-naphthyridine (which binds to the G-G mismatch), naphthyridine-azaquinolone (for the G-A mismatch), N-alkyl naphthyridine dimer (for the C-C mismatch), and naphthyridine carbamate dimer (for G-G mismatches in the (CGG)(n) trinucleotide repeat). Protocols for connecting the short linker to these molecules providing the compounds suitable for immobilization on solid surface are also described.

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

“…[11] We have reported mismatch binding ligands that can stabilize the hairpin secondary structures of dA C H T U N G T R E N N U N G (CAG) n and d-A C H T U N G T R E N N U N G (CGG) n repeats. [12,13] Among the mismatch binding ligands, naphthyridine carbamate dimer (NCD), consisting of two Nalkyloxycarbonyl-2-amino-7-methyl-1,8-naphthyridine heterocycles as a recognition element for nucleotide bases (Scheme 1), strongly bound to dA C H T U N G T R E N N U N G (CGG) n repeats. A surface plasmon resonance (SPR) assay of NCD binding to the TRS by means of an immobilized-NCD sensor showed that NCD bound not only to dA C H T U N G T R E N N U N G (CGG) n but also to dA C H T U N G T R E N N U N G (GAA) n , dA C H T U N G T R E N N U N G (CAG) n , dA C H T U N G T R E N N U N G (GCC) n , and dA C H T U N G T R E N N U N G (CTG) n repeats with decreased efficiency (Figure 1 a).…”

Photoswitchable Unsymmetrical Ligand for DNA Hetero‐Mismatches

“…[10] An improved synthesis of 15 is shown in Scheme 2. The key step is the rearrangement of the N-oxide 11 to the corresponding hydroxymethyl derivative 12.…”

Recognition of Mismatched Base Pairs in DNA

“…13,15,22 The selective binding of ND to the GG mismatch, among seven other mismatches, has been verified by examining the thermal stability of the mismatch-containing duplexes in the presence of ND. In general, ligand binding to DNA increases the thermal stability of the duplex, making the temperature required for denaturation of a duplex to a single strand higher than that in the absence of the ligand.…”

“…In this article, we describe the inside story of MBLs about the discovery, identifying the function, and the application in genomic science. 22 3. Recognition of Mismatched Base Pairs 3.1 GG Mismatch Recognition.…”