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

Abstract

Quinoxaline antibiotics intercalate dsDNA and exhibit antitumor properties. However, they are difficult to synthesize and their structural complexity impedes a clear mechanistic understanding of DNA binding. Therefore design and synthesis of minimal-intercalators, using only part of the antibiotic scaffold so as to retain the key DNA-binding property, is extremely important. Reported is a unique example of a monomeric quinoxaline derivative of a 6-nitroquinoxaline-2,3-diamine scaffold which binds dsDNA by two different modes. While benzyl derivatives bound DNA in a sequential 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 DNA binding modes and would be useful in designing functionally important monomeric quinoxaline DNA binders and benchmarking molecular simulations.

Imidazolyl‐Naphthalenediimide‐Based Threading Intercalators of DNA

“…[24] Remarkably,c omplete displacemento fb oth QCy-DT and TC was observed;t his confirmed threading intercalation by NIm6 ( Figure 2D). [24] Remarkably,c omplete displacemento fb oth QCy-DT and TC was observed;t his confirmed threading intercalation by NIm6 ( Figure 2D).…”

“…Finally,w ep erformed the NIm6-titratingd ye displacement assay but with EtBr and Hoechst replaced with out recently delevoped probesQ Cy-DT [6e] (groove binder, l ex = 530 nm, l em = 680 nm) andT C [5b] (intercalator, l ex = 530 nm, l em = 640 nm). [24] Remarkably,c omplete displacemento fb oth QCy-DT and TC was observed;t his confirmed threading intercalation by NIm6 ( Figure 2D). Overall,I m-NDIc onjugates interacted with DNA through intercalation (NDI core) andg roovebinding (Im), thus demonstrating threading intercalation.…”

Cleavage of Abasic Sites in DNA by an Aminoquinoxaline Compound: Augmented Cytotoxicity and DNA Damage in Combination with an Anticancer Drug Chlorambucil in Human Colorectal Carcinoma Cells

“…This binding event leads to histone eviction from in vitro assembled nucleosomes similar to the anticancer drug Doxorubicin. 35 , 36 Moreover, the derivatives of 1d (nitroquinoxaline) were also able to kill certain Gram-positive and Gram-negative bacterial cells causing bacterial DNA damage and morphological alteration of bacterial cells. 37 Besides, quinoxaline derivatives of 1d also bind to HCV RNA at the internal ribosome entry site and inhibit HCV-mediated translation and replication.…”

Synthesis and antimycobacterial activity of disubstituted benzyltriazoles

“…The benzyl moiety also plays an important role in biochemical and pharmacological processes and is herein envisaged as a partner to 1,2,3-triazole. Incorporated into a quinoxaline scaffold it acts as a DNA intercalation switch, resulting in anticancer properties (Mahata et al 2016). On the other hand, when incorporated into polyamine it contributes to the inhibition of Plasmodium falciparum's essential polyamine biosynthetic pathway (El Bissati et al 2019).…”