Selective G-quadruplex DNA Stabilizing Agents Based on Bisquinolinium and Bispyridinium Derivatives of 1,8-Naphthyridine

Abstract

Various biologically relevant G-quadruplex DNA structures offer a platform for therapeutic intervention for altering the gene expression or by halting the function of proteins associated with telomeres. One of the prominent strategies to explore the therapeutic potential of quadruplex DNA structures is by stabilizing them with small molecule ligands. Here we report the synthesis of bisquinolinium and bispyridinium derivatives of 1,8-naphthyridine and their interaction with human telomeric DNA and promoter G-quadruplex forming DNAs. The interactions of ligands with quadruplex forming DNAs were studied by various biophysical, biochemical, and computational methods. Results indicated that bisquinolinium ligands bind tightly and selectively to quadruplex DNAs at low ligand concentration (∼0.2-0.4 μM). Furthermore, thermal melting studies revealed that ligands imparted higher stabilization for quadruplex DNA (an increase in the T(m) of up to 21 °C for human telomeric G-quadruplex DNA and >25 °C for promoter G-quadruplex DNAs) than duplex DNA (ΔT(m) ≤ 1.6 °C). Molecular dynamics simulations revealed that the end-stacking binding mode was favored for ligands with low binding free energy. Taken together, the results indicate that the naphthyridine-based ligands with quinolinium and pyridinium side chains form a promising class of quadruplex DNA stabilizing agents having high selectivity for quadruplex DNA structures over duplex DNA structures.

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

“…The aromatic central cores were chosen because of their presence in several G-quadruplex DNA stabilizing agents. [54][55][56][57][58] The rationales for the design of such ligands are as follows: (1) Nitrogen atoms present in the central core and NH of amide bond can form internal H-bonding, which would fix the ligand conformation to crescent shape. 59 This is expected to enhance its accessibility to the top of the G-quartets.…”

“…In contrast, many classes of G-quadruplex selective ligands such as Telomestatin, 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 bisquinolinium compounds (360A, 3AQN), 55 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 correspond to c-MYC DNA (without ligand) were also present ( Figure 4). This clearly indicates that ligand favors end-stacking binding mode and, however, a complete saturation of quadruplex was not attained due to which mixed populations of both quadruplex and quadruplex-ligand co...…”

Dinickel–Salphen Complexes as Binders of Human Telomeric Dimeric G‐Quadruplexes

“…This structure has attracted significant attention due to its proposed role in telomere maintenance and consequently its potential as a target for the development of new anticancer therapies 1, 2, 3, 4. Therefore, a large number of small molecules have been developed over the past two decades with the aim of selectively binding and stabilizing G‐quadruplex DNA 5, 6, 7, 8, 9. Although the structures of single G‐quadruplexes containing four repeats of the 5′‐TTAGGG sequence have been studied in detail,10, 11, 12, 13, 14, 15 less is known about the higher‐order structures formed by longer telomeric sequences 16, 17, 18, 19.…”

“…Though a large number of small molecules have been previously developed as single G‐quadruplex DNA binders,5, 6, 7, 8, 9 comparatively very few have been studied (or indeed specifically designed) as binders for multimeric G‐quadruplex structures 24, 25, 26, 27, 28, 29, 30, 31, 32. This includes a chiral cyclic helicene proposed to bind in the cleft between two human telomeric G‐quadruplexes linked by a TTA spacer 25.…”

Interactions of ruthenium complexes containing indoloquinoline moiety with human telomeric G-quadruplex DNA

“…To-date, various small molecule ligands have been tested and identified as efficient G-quadruplex binding and stabilizing agents [17][18][19][20][21][22][23]. Indoloquinoline and its derivatives, a relatively rare group alkaloids in nature, which has been used as an antimalarial drug in Central and Western Africa for centuries, have also been reported to be a kind of efficient G-quadruplex binder [24][25][26][27].…”