Imidazolyl‐Naphthalenediimide‐Based Threading Intercalators of DNA

Abstract

Intercalation by threading is anticipated to feature in DNA-binding molecules for developing DNA-targeted diagnostics and therapeutics. We investigated the role of an imidazolyl moiety in threading intercalators of DNA by employing a number of imidazolyl-naphthalenediimide conjugates. Threading intercalation was studied by UV spectroscopy, competitive binding fluorescent dye displacement, circular dichroism, isothermal calorimetry, and computational analysis. NIm6 was found to be a strong candidate, with good half-life, as revealed by dissociation kinetic analysis. Computational studies supported intercalation of the naphthalene core between base pairs and binding of the imidazolyl moieties in the adjacent grooves (threading mechanism) through electrostatic and hydrogen-bonding interactions. The interaction of the positively charged imidazolium moieties with the negatively charged phosphate backbone of DNA contributed to the favorable enthalpy change, as revealed by the experimental and computational data. Threading intercalation by NIm6 caused significant retardation of DNA in an electrophoretic mobility shift assay. The biological significance of potent imidazolyl naphthalenediimide conjugates was demonstrated by the inhibition of topo- isomerase I activity and cytotoxicity against HeLa cells.

A DNA-NDI Hybrid to Efficiently Detect Histone in Parts per Trillion (ppt) Level

“…The plots of fluorescence quenching of DNA‐bound EtBr and DAPI by NDIs are in good agreement with linear Stern‐Volmer Equation. K sv , the Stern‐Volmer quenching constant, a measure of the quenching efficiency, was found to be highest in case of NDI2 (for both EtBr and DAPI displacement) indicating stronger binding in this case ,. Moreover, higher K sv values for EtBr displacement than for DAPI, suggests that these NDIs ( NDI1‐4 ) preferentially intercalate in DNA and then presumably also binds in the grooves through ionic interaction between cationic side groups of NDIs and phosphates of DNA …”

“…To this end, naphthalene diimides (NDI) with appropriate functionalization were found to be an excellent probe to intercalate with DNA double strands . Several detailed studies on NDI‐DNA interaction have been reported by Iverson and Wilson . A direct consequence of DNA‐binding by all these NDI derivatives is the drastic fall in fluorescence quantum yield of NDIs .…”

“…Several detailed studies on NDI‐DNA interaction have been reported by Iverson and Wilson . A direct consequence of DNA‐binding by all these NDI derivatives is the drastic fall in fluorescence quantum yield of NDIs . We envisioned that this quenching of emission upon binding with DNA can be utilized to create new sensor for proteins capable of binding with DNA, such as histone.…”

“…To get insight into the structural changes in DNA upon binding with NDI2 followed by treatment with histone, circular dichroism (CD) spectra were recorded. The CD spectra of DNA alone presented in Figure exhibits two characteristic peaks, one positive band around 280 nm complemented to π‐π stacking of the bases and a negative band around 245 nm for helicity ,. Up on addition of NDI2 , DNA generates an induced CD (ICD) signal near 350–400 nm region along with increase in π‐π stacking peak.…”

Naphthalenediimide-Linked Bisbenzimidazole Derivatives as Telomeric G-Quadruplex-Stabilizing Ligands with Improved Anticancer Activity

“…A number of di- and tetrasubstituted derivatives of NDI have been extensively studied for stabilizing the G-quadruplex. 25 − 27 Four side chains on NDI make its structure too sterically hindered and rigid to bind to quadruplex grooves. 28 Recently, novel NDI derivatives have been found to show anticancer activities.…”