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Flexible Versus Rigid G‐Quadruplex DNA Ligands: Synthesis of Two Series of Bis‐indole Derivatives and Comparison of Their Interactions with G‐Quadruplex DNA
Author(s) -
Prasad Bagineni,
Jamroskovic Jan,
Bhowmik Sudipta,
Kumar Rajendra,
Romell Tajanena,
Sabouri Nasim,
Chorell Erik
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201800078
Subject(s) - stacking , dna , indole test , g quadruplex , chemistry , molecule , small molecule , stereochemistry , flexibility (engineering) , combinatorial chemistry , biophysics , biochemistry , biology , organic chemistry , mathematics , statistics
Small molecules that target G‐quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis‐indole scaffolds. Our synthesized series of bis‐indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c‐MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.