RESUMEN
AGRO100 (also known as AS1411) is a G-rich oligonucleotide that has long been established as a potent anti-cancer aptamer. However, the structure of AGRO100 remained unresolved, due to the co-existence of multiple different G-quadruplex conformations. We identified a DNA sequence named AT11, derived from AGRO100, which formed a single major G-quadruplex conformation and exhibited a similar anti-proliferative activity as AGRO100. The solution structure of AT11 revealed a four-layer G-quadruplex comprising of two propeller-type parallel-stranded subunits connected through a central linker. The stacking between the two subunits occurs at the 3Î-end of the first block and the 5Î-end of the second block. The structure of the anti-proliferative DNA sequence AT11 will allow greater understanding on the G-quadruplex folding principles and aid in structural optimization of anti-proliferative oligonucleotides.
Asunto(s)
Antineoplásicos/química , Aptámeros de Nucleótidos/química , G-Cuádruplex , Oligodesoxirribonucleótidos/química , Células A549 , Antineoplásicos/farmacología , Aptámeros de Nucleótidos/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Oligodesoxirribonucleótidos/farmacologíaRESUMEN
Aside from the well-known double helix, DNA can also adopt an alternative four-stranded structure known as G-quadruplex. Implications of such a structure in cellular processes, as well as its therapeutic and diagnostic applications, have been reported. The G-quadruplex structure is highly polymorphic, but so far, only right-handed helical forms have been observed. Here we present the NMR solution and X-ray crystal structures of a left-handed DNA G-quadruplex. The structure displays unprecedented features that can be exploited as unique recognition elements.
Asunto(s)
ADN/química , Conformación de Ácido Nucleico , Cristalografía por Rayos X , Espectroscopía de Resonancia MagnéticaRESUMEN
The development of a fluorescent probe capable of detecting and distinguishing the wide diversity of G-quadruplex structures is particularly challenging. Herein, we report a novel BODIPY-based fluorescent sensor (GQR) that shows unprecedented selectivity to parallel-stranded G-quadruplexes with exposed ends and four medium grooves. Mechanistic studies suggest that GQR associates with G-quadruplex grooves close to the end of the tetrad core, which may explain the dye's specificity to only a subset of parallel structures. This specific recognition favours the disaggregation of GQR in aqueous solutions thereby recovering the inherent fluorescence of the dye. Due to its unique features, GQR represents a valuable tool for basic biological research and the rapid discovery of novel, specific ligands that target similar structural features of G-quadruplexes.
Asunto(s)
Técnicas Biosensibles/métodos , Colorantes Fluorescentes/química , G-Cuádruplex , Ligandos , Oligonucleótidos/química , Oligonucleótidos/genética , Telómero/químicaRESUMEN
Phen-DC3 is a highly promising compound that specifically targets G-quadruplexes, with potent biological effects observed in vivo. We used NMR spectroscopy to solve the structure of the complex formed between Phen-DC3 and an intramolecular G-quadruplex derived from the c-myc promoter. Structural information revealed that Phen-DC3 interacts with the quadruplex through extensive π-stacking with guanine bases of the top G-tetrad. On the basis of our structure, modifications are proposed for the development of this compound for selective targeting of a specific G-quadruplex conformation.
Asunto(s)
ADN/química , G-Cuádruplex , Compuestos de Quinolinio/química , Sitios de Unión , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , SolucionesRESUMEN
Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through π-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs.
Asunto(s)
G-Cuádruplex , Oxazoles/química , Telómero/química , Humanos , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , SolucionesRESUMEN
A new direct coupling of cyclic enamides with aryl boronic acids via Pd(ii)-catalyzed C-H functionalization has been achieved with good yields (up to 90%).
RESUMEN
It does get in! A fluoride-assisted direct cross-coupling of cyclic enamides with trialkoxy aryl silanes by a palladium-catalyzed C--H activation leads to a wide range of enamides in yields of up to 95 %.