Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors. (26th July 2020)

• Record Type: Journal Article
• Authors: Singh, Mandeep; Wang, Siwen; Joo, Hyun; Ye, Zhihan; Christison, Krege M.; Hekman, Ryan; Vierra, Craig; Xue, Liang
• Is Part Of: Chemical biology & drug design. Volume 96:Number 5(2020)
• Page Start: 1292
• Page End: 1304
• Publication Date: 2020-07-26
• Subjects: DNA‐binding ligands -- G‐quadruplex DNA -- neomycin -- phenanthroline -- telomerase inhibition; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13741
• Languages: English
• ISSNs: 1747-0277

Abstract

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. Abstract : Binding of a human telomerase G‐quadruplex by a phenanthroline‐neomycin conjugate via a synergistic effect.