Abstract
G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a new series of macrocyclic hexaoxazole-type G4 ligand (6OTD) bearing three side chains. One of these ligands, 5b, stabilizes telomeric G4 preferentially over the G4-forming DNA sequences of c-kit and K-ras, due to the interaction of its piperazinylalkyl side chain with the groove of telomeric G4.
Highlights
G-quadruplex (G4) is one of the characteristic higher-order structures of non-B DNAs [1]
The G4 ligands TMPyP4 [16,17], PhenDC3 [18], and pyridostatin [14,19] interact with the G-quartet in G4, whereas TOxaPy [20] and distamycin A [21] recognize the groove in telomeric G4
We have developed a series of macrocyclic hexaoxazoles, called 6OTD [22], as G4 ligands based upon the structure of the natural G4 ligand telomestatin [23,24]
Summary
G-quadruplex (G4) is one of the characteristic higher-order structures of non-B DNAs [1]. We have developed a series of macrocyclic hexaoxazoles, called 6OTD [22], as G4 ligands based upon the structure of the natural G4 ligand telomestatin [23,24]. Among these derivatives, we have recently shown that 4,2-L2H2-6OTD [25] and L2G2-2M2EG-6OTD [26], obtained by altering the Molecules 2019, 24, 263; doi:10.3390/molecules24020263 www.mdpi.com/journal/molecules. We describe the synthesis of a new series of 6OTD derivatives bearing side chains that recognize both the G-quartet and the grooves of G4. One of these ligands, 5b, stabilizes telomeric G4 preferentially over the G4-forming. Selective stabilization of telomeric G4 would lead to the senescence and apoptosis of cancer cells through dissociation of telomeric protective proteins such as TRF2 and POT1 from telomeric DNA [32,33,34,35,36]
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