Abstract
G-quadruplex specific targeting molecules, also termed as G4 ligands, are attracting increasing attention for their ability to recognize and stabilize G-quadruplex and high potentiality for biological regulation. However, G4 ligands recognizing G-quadruplex were generally investigated within a dilute condition, which might be interfered with under a cellular crowding environment. Here, we designed and synthesized several new cyclic naphthalene diimide (cNDI) derivatives, and investigated their interaction with G-quadruplex under molecular crowding condition (40% v/v polyethylene glycol (PEG)200) to mimic the cellular condition. The results indicated that, under molecular crowding conditions, cNDI derivatives were still able to recognize and stabilize G-quadruplex structures based on circular dichroism measurement. The binding affinities were slightly decreased but still comparatively high upon determination by isothermal titration calorimetry and UV-vis absorbance spectroscopy. More interestingly, cNDI derivatives were observed with preference to induce a telomere sequence to form a hybrid G-quadruplex under cation-deficient molecular crowding conditions.
Highlights
Over the past two decades, G-quadruplex has been attracting increasing attention for its important and mysterious roles in regulating the enzyme work and gene expression [1,2]
Based on our previously reported cyclic naphthalene diimide with cyclohexane substituent 1 [13], we designed another two new cNDI derivatives, 2 with aromatic ring substituent, and 3 with a simple alkyl chain substituent. Chemical structures of these cNDIs are shown in Figure 1. 1 was considered to cause steric hindrance for NDI to intercalate into double stranded DNA, and favor G-quadruplex specific binding, 2 was expected with better G-quadruplex binding affinity for its aromatic group possibly interacting with DNA base thymidine, and 3, the most simple cyclic substituent, was supposed to be a comparison
The G-quadruplex formation was identified by circular dichroism (CD) measurement, with adding cNDI derivatives 1–3, the intensity shift of cotton effect that derived from cNDIs stacking to G-quartets was considered (Figure 2, Figure S7)
Summary
Over the past two decades, G-quadruplex has been attracting increasing attention for its important and mysterious roles in regulating the enzyme work and gene expression [1,2]. G-quadruplex, formed in the telomere region, was considered an obstruction to interfere with telomerase elongating telomere. Chemical molecules, which can recognize and stabilize G-quadruplex structures that could be involved in G-quadruplex’s regulatory role in biology are considered. Their performance on stabilizing telomere G-quadruplex gives them full potential to become a new type of anti-cancer drug [7,8]. Numerous G-quadruplex (G4) ligands have been reported [9], and some molecules, such as BRACO19 [10], pyridostatin [11], and naphthalene diimides [12], have been comprehensively adopted for biochemical and chemical biology studies. Our group has constructed cyclic naphthalene diimide (cNDI) and cyclic ferrocenylnaphthalene diimide derivatives as the cyclic shape could interfere with their interaction with dsDNA, thereby enhancing their selectivity for G-quadruplex [13,14]
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