RESUMO
It is found that G-quadruplexes have important functions in biological systems, such as gene expression. Molecules which can stabilize the G-quadruplex structure may have potential application in regulating the expression of gene. A series of methylazacalix[n]pyridine (n=4, 6, 7, 8, 9) has been tested to stabilize the intermolecular human telomeric G-quadruplex (T12 and H12), intramolecular TBA, c-kit and bcl-2 G-quadruplex by CD denaturation experiments. The results showed that only methylazacalix[6]pyridine (MACP6) can stabilize the intermolecular G-quadruplex formed from the 12bp human telomere. Further studies evidenced that the shape-complementary binding mode was what contributed to the interaction between MACP6 and T12 G-quadruplex.
Assuntos
Calixarenos/farmacologia , DNA/química , Excipientes/farmacologia , Quadruplex G/efeitos dos fármacos , Telômero/efeitos dos fármacos , Dicroísmo Circular , Humanos , Simulação de Acoplamento Molecular , Desnaturação de Ácido Nucleico/efeitos dos fármacos , Telômero/químicaRESUMO
The G-quadruplex ligands database (G4LDB, http://www.g4ldb.org) provides a unique collection of reported G-quadruplex ligands to streamline ligand/drug discovery targeting G-quadruplexes. G-quadruplexes are guanine-rich nucleic acid sequences in human telomeres and gene promoter regions. There is a growing recognition for their profound roles in a wide spectrum of diseases, such as cancer, diabetes and cardiovascular disease. Ligands that affect the structure and activity of G-quadruplexes can shed light on the search for G-quadruplex-targeting drugs. Therefore, we built the G4LDB to (i) compile a data set covering various physical properties and 3D structure of G-quadruplex ligands; (ii) provide Web-based tools for G-quadruplex ligand design; and (iii) to facilitate the discovery of novel therapeutic and diagnostic agents targeting G-quadruplexes. G4LDB currently contains >800 G-quadruplex ligands with â¼4000 activity records, which, to our knowledge, is the most extensive collection of its kind. It offers a user friendly interface that can meet a variety of data inquiries from researchers. For example, ligands can be searched for by name, molecular properties, structures, ligand activities and so on. Building on the reported data, the database also provides an online ligand design module that can predict ligand binding affinity in real time.
Assuntos
Bases de Dados de Compostos Químicos , Desenho de Fármacos , Quadruplex G/efeitos dos fármacos , Internet , Ligantes , Simulação de Acoplamento MolecularRESUMO
Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C-C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.
RESUMO
Molecular folding regulation with environmental stimuli is critical in living and artificial molecular machine systems. Herein, we described a macrocycle, cyclo[4] (1,3-(4,6-dimethyl)benzene)[4](1,3-(4,6-dimethyl)benzene)(4-pyridine). Under 298 K, it has three stable stiff atropisomers with names as 1 (Cs symmetry), 2 (Cs symmetry), and 3 (C4v symmetry). At 393 K, 1 can reversibly transform into 2, but at 473 K, it can irrevocably transform into 3. At 338 K, 3 and (PhCN)2PdCl2 complex to produce the metal-organic cage 4. Only at 338 K does the combination of 1 or 2 and (PhCN)2PdCl2 create a gel-like structure. Heating both gels to 473 K transforms them into 4. In addition to offering a thermally accelerated method for modifying self-assembled systems using macrocyclic building blocks, this study also has the potential to develop the nanoscale transformation material with a thermal response.
RESUMO
Chirality at a supramolecular level is currently attracting great attention attributed to rapid developments in supramolecular chemistry. Herein, we report a new type of chiral self-assembly based on the cyanine dye MTC. The chiral H-aggregates of MTC could form spontaneously from achiral J-aggregates, and could return back to achiral J-aggregates in high concentration on increasing the solution temperature.
RESUMO
G-quadruplex has attracted considerable attention due to their prevalent distribution in functional genomic regions and transcripts, which can importantly influence biological processes such as regulation of telomere maintenance, gene transcription and gene translation. Artificial receptor study has been developed for accurate identification of G-quadruplex from DNA species, since it is important for the G-quadruplex related basic research, clinical diagnosis, and therapy. Herein, fluorescent dye ThT-E, a derivative of the known fluorescence probe Thioflavin T (ThT), was designed and synthesized to effectively differentiate various G-quadruplex structures from other nucleic acid forms. Compared with methyl groups in ThT, three ethyl groups were introduced to ThT-E, which leads to strengthened affinity, selectivity and little inducing effect on the G-quadruplex formation. More importantly, ThT-E could be served as a visual tool to directly differentiate G-quadruplex solution even with naked eyes under illumination of ultraviolet light. Thus, this probe reported herein may hold great promise for high-throughput assay to screen G-quadruplex, which may widely apply to G-quadruplex-based potential diagnosis and therapy.
Assuntos
Benzotiazóis/química , Corantes Fluorescentes/química , Quadruplex G , Técnicas Biossensoriais , DNA/química , Fluorescência , Guanina/química , Humanos , Espectrometria de Fluorescência , Relação Estrutura-AtividadeRESUMO
Nucleic acid based molecular device is a developing research field which attracts great interests in material for building machinelike nanodevices. G-quadruplex, as a new type of DNA secondary structures, can be harnessed to construct molecular device owing to its rich structural polymorphism. Herein, we developed a switching system based on G-quadruplexes and methylazacalix[6]pyridine (MACP6). The induced circular dichroism (CD) signal of MACP6 was used to monitor the switch controlled by temperature or pH value. Furthermore, the CD titration, Job-plot, variable temperature CD and (1)H-NMR experiments not only confirmed the binding mode between MACP6 and G-quadruplex, but also explained the difference switching effect of MACP6 and various G-quadruplexes. The established strategy has the potential to be used as the chiral probe for specific G-quadruplex recognition.
Assuntos
Calixarenos/química , Computadores Moleculares , DNA/química , Quadruplex G , Oligonucleotídeos/química , Dicroísmo Circular , Proteínas de Ligação a DNA/química , Concentração de Íons de Hidrogênio , Modelos Moleculares , Simulação de Acoplamento Molecular , Ressonância Magnética Nuclear Biomolecular , TemperaturaRESUMO
Calixaromatics have attracted much attention on molecular recognition owing to their flexible conformations, cavity structures, versatile recognition properties, and functions. However, conformational control of calixaromatics is still a challenging topic in the field of calixaromatics. Therefore, we explore the possibility to control the chirality of achiral calixaromatics, methylazacalix[6]pyridine (abbreviated as MACP6), by templating of DNA. We have found that MACP6 with opposite chirality can be achieved by controlling the secondary structure of bcl-2 2345 DNA. Furthermore, MACP6 with different chirality has been used to recognize fullerene derivatives in aqueous solution. Our results have provided a possible approach to construct chiral calixaromatics.
RESUMO
A novel trend in G-quadruplex ligand design is to build a binder that is able to not only discriminate G-quadruplex from duplex-DNA, but also among various G-quadruplex structures. Methylazacalix[6]pyridine (MACP6), a new type of azacalixarene with flexible conformation, exhibits induced circular dichroism signals when interacted with most of G-quadruplexes. The intensities of the induced signals are strongly dependent on the topology of G-quadruplexes. Further evidence has shown that these signals can be ascribed to the preferred binding of MACP6 to the loops of G-quadruplexes, which rely on the nature of nucleotides in the loops.