Solution and Solid‐State Analysis of Binding of 13‐Substituted Berberine Analogues to Human Telomeric G‐quadruplexes

Abstract

The interaction between 13-phenylalkyl and 13-diphenylalkyl berberine derivatives (NAX) and human telomeric DNA G4 structures has been investigated by both spectroscopic and crystallographic methods. NAX042 and NAX053 are the best compounds improving the performance of the natural precursor berberine. This finding is in agreement with the X-ray diffraction result for the NAX053-Tel12 adduct, showing the ligand which interacts via π-stacking, sandwiched at the interface of two symmetry-related quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional π-stacking interactions with the DNA residues. The berberine derivatives were also investigated for their cytotoxic activity towards a panel of human cancer cell lines. Compounds NAX042 and NAX053 affect the viability of cancer cell lines in a dose-dependent manner.

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

“…Specifically, the red shift and hypochromism of the absorption band along with the pronounced increase of the emission intensity are typical for quadruplexbound ligands [17][18][19][20][21][22]. Moreover, the resulting binding constants are in the same range as the ones reported for the resembling derivatives [33][34][35][36][37][38][39][40][41][42]. Notably, the analysis of the binding isotherms revealed the formation of 2:1 or 1:1 complexes (ligand/G4-DNA) ( Table 1), both of which are also well-established for berberines [33][34][35][36][37][38][39][40][41][42].…”

“…Especially berberine derivatives that carry additional substituents with varying alkyl chain lengths in the 9-and 13-position show enhanced binding properties and high selectivity towards telomeric G-quadruplex DNA [34][35][36][37]. Representative examples of this class of compounds are the 9-O-aminoalkyl-substituted and 9-O-pyridinium-N-alkyl-substituted derivatives 1b n and 1c n or the 13-phenylalkyl-substituted substrates 1d n or 1e n (Scheme 1) [38][39][40][41][42]. In the latter cases, the binding properties depend on the length of the alkyl chain.…”

“…In the latter cases, the binding properties depend on the length of the alkyl chain. For example, the aminohexyl-substituted derivative 1b 6 and the phenylpropyl-substituted compound 1d 3 have the highest affinity to G-quadruplex DNA, whereas the deriva-tives with other alkyl chain lengths have a lower affinity [38]. Along the same line, the influence of the length and substituents of the side chains at the G4-DNA ligands have been assessed for quinolinium [43], indoloquinoline [44,45], phenanthroline [46], phenothiazine [47], and thiazole orange [48] derivatives.…”

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…The 13-phenylalkyl and 13-diphenylalkyl BBR derivative NAX compounds were determined to result in telomeric DNA G-quadruplexes. The NAX042 and NAX053 compounds were examined in terms of telomeric G-quadruplexes in this system (Ferraroni et al, 2016). NAX042 and NAX053 were the best compounds in terms of simulating the interaction with human telomeric DNA G4 structures.…”

Discovery of C-9 Modified Berberine Derivatives as Novel Lipid-Lowering Agents

“…Compound 2i-2k were prepared according to the reported procedures, respectively [28][29][30] . BBR (2 g, 5.4 mmol) was added into 5 M sodium hydroxide aqueous solution (20 mL) at room temperature, and then acetone (2 mL) was added dropwise into the above solution.…”