Synthesis and Evaluation of a Novel Class of G-Quadruplex-Stabilizing Small Molecules Based on the 1,3-Phenylene-Bis(piperazinyl benzimidazole) System

Abstract

Achieving stabilization of telomeric DNA in G-quadruplex conformation by various organic compounds has been an important goal for the medicinal chemists seeking to develop new anticancer agents. Several compounds are known to stabilize G-quadruplexes. However, relatively few are known to induce their formation and/or alter the topology of the preformed quadruplex DNA. Herein, four compounds having the 1,3-phenylene-bis(piperazinyl benzimidazole) unit as a basic skeleton have been synthesized, and their interactions with the 24-mer telomeric DNA sequences from Tetrahymena thermophilia d(T(2)G(4))(4) have been investigated using high-resolution techniques such as circular dichroism (CD) spectropolarimetry, CD melting, emission spectroscopy, and polyacrylamide gel electrophoresis. The data obtained, in the presence of one of three ions (Li(+), Na(+), or K(+)), indicate that all the new compounds have a high affinity for G-quadruplex DNA, and the strength of the binding with G-quadruplex depends on (i) phenyl ring substitution, (ii) the piperazinyl side chain, and (iii) the type of monovalent cation present in the buffer. Results further suggest that these compounds are able to abet the conversion of the intramolecular quadruplex into parallel stranded intermolecular G-quadruplex DNA. Notably, these compounds are also capable of inducing and stabilizing the parallel stranded quadruplex from randomly structured DNA in the absence of any stabilizing cation. The kinetics of the structural changes induced by these compounds could be followed by recording the changes in the CD signal as a function of time. The implications of the findings mentioned above are discussed in this paper.

Stabilization and Structural Alteration of the G-Quadruplex DNA Made from the Human Telomeric Repeat Mediated by Tröger’s Base Based Novel Benzimidazole Derivatives

“…This profile is similar to the CD spectral profile of the parallel G4DNAs formed by a number of human and nonhuman telomeric sequences. 28,30,46,49,50 These results suggest that both TBBz1 and TBBz2 are capable of interacting with the preformed G4DNA in K + solution without causing any structural alteration. But the ligands are capable of directing the folding of the randomly structured Hum 21 sequence into the parallel-stranded G4DNA at low concentrations when the G-quadruplex is formed in 100 mM K + solution in the presence of the ligands.…”

“…The UV−vis spectral titrations involving either of the ligands with the preformed G4DNA resulted in hypochromicity, which indicates a specific binding and strong stacking type of interactions of the ligands with the G4DNA. 28 On the other hand, we observed insignificant hypochromicity in the case of the duplex DNA with each of the above ligands ( Figure S6, Supporting Information).…”

“…IR: 3353. 8, 2955.41, 2925.77, 1494.19, 1463.4, 1377.55, 1216.83 To a freshly prepared solution of 4-(4-methylpiperazin-1-yl)benzene-1, 2-diamine (6, 103 mg, 0.5 mmol) 28 was added dialdehyde (3, 69.5 mg, 0.25 mmol). To this solution was added sodium metabisulfite (Na 2 S 2 O 5 , 2 equiv dissolved in minimum quantity of water).…”

Fluorescence Light-Up Probe for Parallel G-Quadruplexes

“…40 For example, Hoechst 33258, a well-known minor groove binding ligand routinely used for staining nuclear DNA, contains a bisbenzimidazole core linked in a head-to-tail manner, 41 which has also been reported to bind G4s with lower affinity than to duplex DNA. 42,43 Inspired by the good selectivity toward G4s of the V-shaped bisbenzimidazole derivatives, 36,37 we attempted to develop a highly specific probe for G4s based on the bisbenzimidazole structure. By fusing a fluorophore, carbazole into the scaffold of a bisbenzimidazole derivative, we synthesized a crescent-shaped molecule, 9-methyl-3,6-bis[5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl]-9H-carbazole (BPBC) (Scheme 1).…”

Molecular Design of Synthetic Benzimidazoles for the Switchover of the Duplex to G-quadruplex DNA Recognition

“…Because the angular shaped 3b was a stronger inhibitor than the linear isomer 3a, we focused our attention on 1,3-substituted 'V'-shaped molecules with appropriate modifications in the central aromatic nucleus and incorporated an end piperazine moiety to get the optimum out of such molecular entities. [17] We introduced four ligands (4a-d) and each of them (Fig. 3) showed better binding structure of the G-tetrad with the interatomic distances obtained from crystal structure.…”