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Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors
Author(s) -
Singh Mandeep,
Wang Siwen,
Joo Hyun,
Ye Zhihan,
Christison Krege M.,
Hekman Ryan,
Vierra Craig,
Xue Liang
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13741
Subject(s) - chemistry , phenanthroline , g quadruplex , telomerase , stereochemistry , dna , selectivity , duplex (building) , stacking , combinatorial chemistry , biochemistry , biophysics , crystallography , gene , biology , organic chemistry , catalysis
Abstract In this paper, we report the synthesis of a phenanthroline and neomycin conjugate ( 7 ). Compound 7 binds to a human telomeric G‐quadruplex ( G1 ) with a higher affinity compared with its parent compounds (phenanthroline and neomycin), which is determined by several biophysical studies. Compound 7 shows good selectivity for G‐quadruplex (G4) DNA over duplex DNA. The binding of 7 with G1 is predominantly enthalpy‐driven, and the binding stoichiometry of 7 with G1 is one for the tight‐binding event as determined by ESI mass spectrometry. A plausible binding mode is a synergistic effect of end‐stacking and groove interactions, as indicated by docking studies. Compound 7 can inhibit human telomerase activity at low micromolar concentrations, which is more potent than previously reported 5‐substituted phenanthroline derivatives.