title: Phenanthroline-bis-oxazole ligands for binding and stabilization of G-quadruplexes.
abstract: G-quadruplexes (G4) are found at important genome regions such as telomere ends and oncogene promoters. One prominent strategy to explore the therapeutic potential of G4 is stabilized it with specific ligands.
  
  
  
  We report the synthesis of new phenanthroline, phenyl and quinoline acyclic bisoxazole compounds in order to explore and evaluate the targeting to c-myc and human telomeric repeat 22AG G4 using FRET-melting, CD-melting, NMR, fluorescence titrations and FID assays.
  
  
  
  The design strategy has led to potent compounds (Phen-1 and Phen-2) that discriminate different G4 structures (human telomeric sequences and c-myc promoter) and selectively stabilize G4 over duplex DNA. CD studies show that Phen-2 binds and induces antiparallel topologies in 22AG quadruplex and also binds c-myc promotor, increasing their Tmin about 12°C and 30°C respectively. In contrast, Phen-1 induces parallel topologies in 22AG and c-myc, with a moderate stabilization of 4°C for both sequences. Consistent with a CD melting study, Phen-2 binds strongly (K=106to 107M-1) to c-myc and 22AG quadruplexes.
  
  
  
  Phen-1 and Phen-2 discriminated among various quadruplex topologies and exhibited high selectivity for quadruplexes over duplexes. Phen-2 retains antiparallel topologies for quadruplex 22AG and does not induce conformational changes on the parallel c-myc quadruplex although Phen-1 favors the parallel topology. NMR studies also showed that the Phen-2 binds to the c-myc quadruplex via end stacking.
  
  
  
  Overall, the results suggest the importance of Phen-2 as a scaffold for the fine-tuning with substituents in order to enhance binding and stabilization to G4 structures. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Medeiros-Silva
authors.affiliation: INSERM, U1212, CNRS, UMR 5320, IECB, F-33600 Pessac, France; Univ. Bordeaux, ARNA laboratory, F-33000 Bordeaux, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Guédin
authors.affiliation: INSERM, U1212, CNRS, UMR 5320, IECB, F-33600 Pessac, France; Univ. Bordeaux, ARNA laboratory, F-33000 Bordeaux, France.
authors.forename: Gilmar F
authors.initials: GF
authors.lastname: Salgado
authors.affiliation: INSERM, U1212, CNRS, UMR 5320, IECB, F-33600 Pessac, France; Univ. Bordeaux, ARNA laboratory, F-33000 Bordeaux, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
authors.forename: João A
authors.initials: JA
authors.lastname: Queiroz
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
authors.forename: Eurico J
authors.initials: EJ
authors.lastname: Cabrita
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal. Electronic address: carlacruz@fcsaude.ubi.pt.
authors.forename: Carla
authors.initials: C
authors.lastname: Cruz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002942:Circular Dichroism; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes / Q000187:drug effects; D006151:Guanosine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009691:Nucleic Acid Denaturation; D010080:Oxazoles / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013329:Structure-Activity Relationship; D016615:Telomere / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008024:Ligands; C489427:MYC protein, human; D010080:Oxazoles; D010618:Phenanthrolines; D016271:Proto-Oncogene Proteins c-myc; D006151:Guanosine
keywords: Circular dichroism; Drug design; Fluorescence titrations; Fret-melting; G-quadruplex; Phenanthroline ligands