Article

Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
Organic & Biomolecular Chemistry (Impact Factor: 3.57). 03/2011; 9(8):2975-86. DOI: 10.1039/c0ob00921k
Source: PubMed

ABSTRACT A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.

0 Bookmarks
 · 
91 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Four novel 4-(1H-imidazo[4,5-f]-1,10-phenanthrolin-2-yl)phenol derivatives 1-4 have been synthesized, and their G-quadruplex DNA-binding interactions, telomerase inhibition, antiproliferative activity, cell cycle arrest, and apoptotic induction were studied. All compounds show the preferential h-telo, c-myc, and c-kit2 G-quadruplex binding affinity and the G-quadruplex versus duplex selectivity. In the case of the same G-quadruplex target, the compound 1 exhibits better stabilization effect (ΔTm) than the other three compounds and also gives 80.2% inhibition of telomerase activity at 7.5μM. All compounds can promote selectively the formation of parallel G-quadruplex structure of both c-myc and c-kit2 without addition of any cations. Four compounds display the cytotoxicity activities against HeLa and HepG2 cells by MTT assay with IC50 values of about 10(-6) and 10(-5)M, respectively, and cause a substantial decrease in the G2/M-phase cell population and a significant increase in the number of apoptotic cells.
    Bioorganic & medicinal chemistry 12/2012; · 2.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The interactions of a triangle-shaped [2.2.2]heptamethinecyanine dye , namely 1,5,7-tris-[3-methylbenzothiazol-2-yl]-[2.2.2]heptamethindiium, with quadruplex DNA were studied with photometric and fluorimetric titrations, thermal DNA denaturation, CD and (1)H-NMR spectroscopy. The ligand binds to the quadruplex DNA with moderate affinity (K = 8 × 10(5) M(-1)), mainly by terminal π stacking. Remarkably, the ligand exhibits a selectivity for quadruplex DNA relative to duplex DNA. Whereas the cyanine dye is very weakly fluorescent in aqueous solution, the emission intensity increases by a factor of >100 upon association with quadruplex DNA. Thus, it is shown that trinuclear cyanine derivatives may be employed as selective probes for the fluorimetric detection of quadruplex DNA.
    Organic & Biomolecular Chemistry 11/2012; · 3.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report herein a solvent-free and microwaved-assisted synthesis of several water soluble acyclic pentaheteroaryls containing 1,2,4-oxadiazole moieties (1-7). Their binding interactions with DNA quadruplex structures were thoroughly investigated by FRET melting, fluorescent intercalator displacement assay (G4-FID) and CD spectroscopy. Among the G-quadruplexes considered, attention was focused on telomeric repeats together with the proto-oncogenic c-kit sequences and the c-myc oncogene promoter. Compound 1, and to a lesser extent 2 and 5, preferentially stabilise an antiparallel structure of the telomeric DNA motif, and exhibit an opposite binding behaviour to structurally related polyoxazole (TOxaPy), and do not bind duplex DNA. The efficiency and selectivity of the binding process was remarkably controlled by the structure of the solubilising moieties.
    Chemistry - A European Journal 09/2012; 18(45):14487-96. · 5.93 Impact Factor