The Benzyl Moiety in a Quinoxaline‐Based Scaffold Acts as a DNA Intercalation Switch

Abstract

Quinoxaline antibiotics intercalate dsDNAa nd exhibit antitumor properties.H owever,t hey are difficult to synthesize and their structural complexity impedes ac lear mechanistic understanding of DNAbinding.Therefore design and synthesis of minimal-intercalators,u sing only part of the antibiotic scaffold so as to retain the key DNA-binding property,isextremely important. Reported is aunique example of am onomeric quinoxaline derivative of a6 -nitroquinoxaline-2,3-diamine scaffold which binds dsDNAbytwo different modes.W hile benzyl derivatives bound DNAi nasequential fashion, with intercalation as the second event, nonbenzyl derivatives showed only the first binding event. The benzyl intercalation switch provides important insights about molecular architecture which control specific DNAb inding modes and would be useful in designing functionally important monomeric quinoxaline DNAb inders and benchmarking molecular simulations.

DNA Structural Alteration Leading to Antibacterial Properties of 6-Nitroquinoxaline Derivatives

“…Here we have designed a series of monoquinoxaline based derivatives (Figure C) from the modification of the scaffold 3g (Figure B) . In order to achieve this, two sets of compounds were designed by changing the substituents at C-2 and C-3 positions of the 6-nitroquinoxaline moiety, all of which were subjected to antibacterial evaluation (Figure C).…”

“…The structural change of DNA induced by intercalators is reflected in the mobility of supercoiled plasmid DNA in agarose gel . Previously we have shown that compound 3g (with mandatory benzyl moiety) shows gel shift of pBR322 plasmid DNA indicating DNA intercalation . To investigate the structural change of DNA induced by the designed quinoxaline molecules, we have studied the agarose gel shift assay of supercoiled plasmid DNA (pCDNA3.1) by the most potent analogues ( 3a , 3u , and 3q ) and compound 3d , which does not show any antibacterial activity.…”

“…DNA structural change induced by small molecules can also be determined by change in the circular dichroism (CD) spectra of DNA . Appearance of an induced CD (ICD) has a direct relation to the structural change and superstructure formation, which is mediated by close association of DNA bound nitroquinoxaline scaffold. , Titrating calf thymus DNA (CT-DNA) with increasing concentrations of 3a , 3q , or 3u leads to decrease in the typical B-DNA CD peak at 265 nm (Figure A–C). A negative ICD also appeared at 320–325 nm wavelength indicating DNA intercalation induced structural change.…”

“…(A) Structure of triostin A, a known DNA intercalator. (B) N 2 -benzyl- N 3 -(3-(dimethylamino)­propyl)-6-nitroquinoxaline-2,3-diamine ( 3g ), a previously reported DNA intercalator . (C) Two sets of compounds were evaluated for the antibacterial activity.…”

“…In our previous study, we showed that a 6-nitroquinoxaline scaffold, 3g (Figure B), intercalates into DNA preferentially in GC-rich sequences through complex cooperative binding events . Considering the importance of the structural integrity of bacterial genome in its survival, we have synthesized a series of monoquinoxaline based derivatives by substitutional tuning of 3g that possesses the distinct ability to induce change in the native DNA structure.…”