Specifically targeting mixed-type dimeric G-quadruplexes using berberine dimers

Abstract

Three polyether-tethered berberine dimers (1a-c) were studied for their binding affinity, selectivity and thermal stabilization towards human telomeric dimeric quadruplex DNA (G2T1). Compound 1a with the shortest polyether linker showed the highest affinity (K > 10 M) and 76-508-fold higher selectivity for mixed-type G2T1 over antiparallel G2T1 and three monomeric G-quadruplexes, which are human telomeric monomeric quadruplex G1, c-kit 1 and c-kit 2. Compound 1a induced the formation of quadruplex structures and showed higher thermal stabilization for mixed-type G2T1 than for anti-parallel G2T1, G1 and ds DNA. Spectroscopic studies suggest that compound 1a could bind to mixed-type G2T1 via end-stacking and external binding modes. These results suggest that the polyether linkers in these compounds play an important role in regulating the binding affinity and selectivity towards mixed-type G2T1 and that compound 1a could target mixed-type G2T1 at other genome regions with antiparallel G2T1 and monomeric G-quadruplexes. These results may provide useful guidance for the rational design of selective multimeric G-quadruplex binders and potential anticancer agents.

A Comparative Study on High Selectivities of Human Telomeric Dimeric G‐Quadruplexes by Dimeric G‐Quadruplex Binders

“…Thus, in recent years, the use of small molecules to target multimeric G-quadruplex structures has become am ajor researchf ocus. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Initially,s ome excellent monomeric G-quadruplexb inders, such as tetraphenylethene derivatives (QATPE), [19] cationic porphyrin derivatives (TMPyP4), [20][21][22] threeside-chained triazatruxene derivative( Azatrux), [22] and EPI [23] have been provedt ob ind to multimeric G-quadruplexes through p-p end-stacking, pocket intercalation between two adjacentG -quadruplexes, and external binding. Furthermore, owingt ot he existence of quadruplex-quadruplexi nterfaces in multimeric G-quadruplexes, some multimeric G-quadruplex binders,s uch as triaryl-substituted imidazoles, [24] ac hiral cyclic helicene, [25] and tetrazolylpyrene nucleoside, [26] have specifically intercalated in the pocket, which resulted in an enhancement of the selectivity of their binding towards multimeric G-quadruplexes over the monomeric counterparts.…”

“…Moreover,t hese stud-ies imply that the linkers in these compounds play an important role in regulating the binding affinity and selectivity towards multimeric G-quadruplexes. [16,[28][29][30] On the other hand, as eries of bisquinolinium derivatives of 2,6-pyridodicarboxamide (such as 360 A), [31,32] 1,8-naphthyridine, [33] and 1,10-phenanthroline [34][35][36][37][38] have been reported to show higher binding selectivity towards telomeric G-quadruplex DNA than double-stranded DNA (dsDNA) as well as relatively strong telomerase inhibition. Moreover,t he derivatives of pyridostatins (PDS), as derivatives of 360 A,h ave also been studied as G-quadruplexb indersa nd probes.…”

“…[39][40][41][42] This family of bisquinoliniumd erivatives, which show high binding affinities to human telomeric G-quadruplex DNA and telomerase inhibition, inspired us to establish their affinities and selectivities for multimeric G-quadruplexes.A lthoughadimeric analogue (360 A) 2A has just been reported to bind higher-order G-quadruplexes (especially trimericG -quadruplexes), the adjustment of the length of the linker will possibly result in different binding modes and increaset he selectivity towards higher-order Gquadruplexes. [43] With this in mind, together with our recent research on polyether-tethered berberine dimers 1a-c [29,30] and dinickel-salphen complexes 2a-c, [28] three bisquinolinium dimers (3a-c)w ith different length polyether linkers were designed (Scheme 1), and we have evaluated their abilities to selectively bind and stabilize humant elomeric dimeric quadruplex DNA (G2T1), and we have analyzed their telomerase inhibition and antitumor activity.F urthermore, the interaction of these three kinds of polyether-tethered dimeric G-quadruplex ligands( 1a-c, 2a-c,a nd 3a-c)t owardsG 2T1 has been com-pared to enablet he design of improved dimeric quadruplex bindersa nd potential anticancer reagents that target higherorder G-quadruplexes.…”

A novel square-planar Pt(ii) complex as a monomeric and dimeric G-quadruplex DNA binder

“…16,17,19,21 In contrast, complex 1 had negligible thermal stabilization towards monomeric quadruplexes G1 (DT m ¼ 1. . These results show that complex 1 had the preferential thermal stabilization towards mixed-type G2T1 over G1 and ds DNA.…”

“…However, the presence of complex 1 increased the mobility of the mixed-type G2T1 (lane 5). These results suggest that complex 1 could form a compact complex with G2T1 rather than G1, 14,16 which was further veried by incubating complex 1 with a mixture of G1 and G2T1 and then analysing their gel electrophoresis. Obviously, a mixture of G1 and G2T1 in the absence of complex 1 gave the characteristic bands corresponding to intramolecular G1 and G2T1 (lane 6).…”