Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Novel Smart C2-Symmetrical NDI Derivatives as G-Quadruplex Stabilizing Ligand with a Potential to Differentiate between Topological Structures
Recent evidences of the formation of DNA G-quadruplexes in cells have provided solid support for these structures to be considered as valuable targets against cancer therapy. Three novel symmetric bisubstituted naphthalenediimide G-quadruplex stabilizing ligands; ALI-C3, BBZ-ARO and BBZ-AROCH2 were designed and evaluated as telomerase inhibitors. The unfused aromatic rings containing benzimidazol in ligands allowed a flexible and adaptive conformation to ligand recognition with G-quadruplexes. ΔGfree obtained from MMPBSA calculations and hydrogen bond occupancy after MD Simulations were decisive, as we found that electrostatic interactions (hydrogen bond occupancy) between ligand side chains and DNA grooves played main role not only in the amount of G-quadruplex formed, but also in selecting its topology, as ALI-C3, stabilized preferentially an antiparallel intrastrand 22 mer over BBZ-ARO, stabilizing a parallel interstrand 12 mer G-quadruplex more. Their interactions with telomeric G-quadruplex DNA were studied with competitive FRET melting, SPR and CD spectroscopy suggested that the disubstituted NDI derivatives could strongly bind and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. Moreover, ligands showed also a different ability to inhibit telomerase. The correlation of these findings suggests the intriguing possibility that different G-quadruplex structures could differently inhibit the enzyme. ALI-C3, was found to be most potent telomerase inhibitor (IC50, = 0.7 µM) among three. Hence, easy synthetic access combined with selective recognition of different G-quadruplex conformations, stand out ALI-C3, as lead to be attenuated as anticancer agent.
Alcaro et. al., European Journal of Medicinal Chemistry, 2013, 68, 139-149.
Minarini et. al., European Journal of Medicinal Chemistry, 2012, 57, 417-428.
Vibha et. al., Nucleic Acid Research, 2014(Communicated manuscript).
Chemical Biology Laboratory