BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers.

A single G-quadruplex forming sequence from the human telomere can adopt six distinct topologies that are inter-convertible under physiological conditions. This presents challenges to design ligands that show selectivity and specificity towards a particular conformation. Additional complexity is introduced in differentiating multimeric G-quadruplexes over monomeric species, which would be able to form in the single-stranded 3' ends of telomeres. A few ligands have been reported that bind to dimeric quadruplexes, but their preclinical pharmacological evaluation is limited. Using multidisciplinary approaches, we identified a novel quinoline core ligand, BMPQ-1, which bound to human telomeric G-quadruplex multimers over monomeric G-quadruplexes with high selectivity, and induced the formation of G-quadruplex DNA along with the related DNA damage response at the telomere. BMPQ-1 reduced tumor cell proliferation with an IC50 of ∼1.0 µM and decreased tumor growth rate in mouse by half. Biophysical analysis using smFRET identified a mixture of multiple conformations coexisting for dimeric G-quadruplexes in solution. Here, we showed that the titration of BMPQ-1 shifted the conformational ensemble of multimeric G-quadruplexes towards (3+1) hybrid-2 topology, which became more pronounced as further G-quadruplex units are added.

Oligo(ethylene glycol)-Functionalized Ratiometric Fluorescent Probe for the Detection of Hydrazine in Vitro and in Vivo.

Hydrazine induced toxicity causes serious harm to the health of humans. The detection of N2H4 in vitro and in vivo has attracted a great deal of attention, especially in the context of fluorescent probes. Although some fluorescent N2H4 probes have been reported, only a few operate in purely aqueous media and, as a result, require the use of organic cosolvents which hinders their use in analysis of real samples. In addition, most of the current N2H4 probes are either "off-on" or "on-off" types, in which it is difficult to eliminate interference from background fluorescence commonly occurring in in vitro and in vivo systems. Furthermore, some probes are unable to differentiate hydrazine from other organic amines. To address the above problems, we developed a novel oligo(ethylene glycol)-functionalized fluorescent probe for the detection of N2H4. The probe, which has a donor-π-acceptor (D-π-A)-type structure, is water-soluble, and it can be utilized to selectively detect N2H4 in both colorimetric and ratiometric mode. Furthermore, the probe is able to differentiate hydrazine from other organic amines and can be used to detect hydrazine vapor and for imaging A549 cells and zebrafish.

Selective recognition of c-MYC Pu22 G-quadruplex by a fluorescent probe.

Nucleic acid mimics of fluorescent proteins can be valuable tools to locate and image functional biomolecules in cells. Stacking between the internal G-quartet, formed in the mimics, and the exogenous fluorophore probes constitutes the basis for fluorescence emission. The precision of recognition depends upon probes selectively targeting the specific G-quadruplex in the mimics. However, the design of probes recognizing a G-quadruplex with high selectivity in vitro and in vivo remains a challenge. Through structure-based screening and optimization, we identified a light-up fluorescent probe, 9CI that selectively recognizes c-MYC Pu22 G-quadruplex both in vitro and ex vivo. Upon binding, the biocompatible probe emits both blue and green fluorescence with the excitation at 405 nm. With 9CI and c-MYC Pu22 G-quadruplex complex as the fluorescent response core, a DNA mimic of fluorescent proteins was constructed, which succeeded in locating a functional aptamer on the cellular periphery. The recognition mechanism analysis suggested the high selectivity and strong fluorescence response was attributed to the entire recognition process consisting of the kinetic match, dynamic interaction, and the final stacking. This study implies both the single stacking state and the dynamic recognition process are crucial for designing fluorescent probes or ligands with high selectivity for a specific G-quadruplex structure.

Application of the aza-Diels-Alder reaction in the synthesis of natural products.

The Diels-Alder reaction that involves a nitrogen atom in the diene or dienophile is termed the aza-Diels-Alder reaction. As well as the powerful all-carbon Diels-Alder reaction, the aza-Diels-Alder reaction has also played an important role in the total synthesis of natural products. Herein, we review various natural products using an aza-Diels-Alder reaction as a key step to their total synthesis, and divide the syntheses into inter- and intra-molecular aza-Diels-Alder reactions and a retro-aza-Diels-Alder reaction. Inter- and intra-molecular aza-Diels-Alder reactions involve an imine as an electron deficient dienophile and an imine as an electron deficient azadiene. The significance of the aza-Diels-Alder reaction for the construction of a six-membered ring containing nitrogen is tremendous, but the development of asymmetric, in particular catalytic enantioselective intramolecular aza-Diels-Alder reaction in the total synthesis of natural products remains highly challenging, and will no doubt see enormous advances in the future.

Novel lead compound optimization and synthesized based on the target structure of Xanthomonas oryzae pv. oryzae GlmU.

Bacterial leaf blight, caused by Xanthomonas oryzae pv. oryzae, is one of the most destructive diseases of rice worldwide. N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) was an attractive target for the development of antimicrobial agents. To develop novel, more potent and even more selective inhibitors of the uridyltransferase activity of Xanthomonas oryzae pv. oryzae GlmU (Xo-GlmU), three types of novel target compounds were optimized and synthesized based on the Xo-GlmU structure in this study. The biological testing results showed that all of the target compounds displayed the higher inhibition than the lead compound with the IC50 values in the 10.82-23.31 µM range, and the inhibition rates were increased by 30%-67%. The binding mode and the possible inhibitory mechanism of the target compounds in the active site were also analyzed by the molecular docking based on the uridyltransferase active site of Xo-GlmU.

Clinicopathological significance of Sox2 expression in patients with breast cancer: a meta-analysis.

Sex-determining region Y-box protein 2 (Sox2), an embryonic transcription factor located at chromosome 3q26.33, has been frequently demonstrated to be an important prognostic marker for various tumors, including breast cancer. However, its clinicopathological role in breast cancer has not been fully elucidated. To derive a more precise evaluation, we here performed a meta-analysis focusing on the association between Sox2 expression and various clinicopathological characteristics of breast cancer. Relevant publications were identified and retrieved using PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, and Chinese Biomedical databases. Ten studies with a total of 1713 patients with breast cancer were included in our meta-analysis. Reported odds ratios (OR) and the corresponding 95% confidence intervals (95% CI) were pooled to assess the strengths of the analyzed associations. Our results revealed significant positive associations between Sox2 expression and increased tumor size (pooled OR=2.61, 95% CI=1.91-3.58), histological grade (pooled OR=2.28, 95% CI=1.72-3.03), lymph node metastasis (pooled OR=4.17, 95% CI=1.20-14.45), and the highly aggressive triple-negative phenotype (pooled OR=2.64, 95% CI=1.11-6.29). However, no associations were observed for TNM stage and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 statuses. Overall, the results of this meta-analysis indicate that Sox2 may be considered as a prognostic marker for breast cancer. More well-designed studies with larger sample sizes are warranted to clarify the prognostic significance of Sox2 in breast cancer.

Asymmetric syntheses and bio-evaluation of novel chiral esters derived from substituted tetrafluorobenzyl alcohol.

A series of novel chiral esters derived from tetrafluorobenzyl alcohol were designed and prepared via asymmetric synthesis. The target molecules have been identified on the basis of analytical spectra data. All newly synthesized compounds have been screened their potential insecticidal activity against Plutella xylostella compared with those of fenvalerate and d-trans-phenothrin by standard method, and the respective pairs of enantiomers (3-B1-R/S, 3-C1-R/S, 3-D1-R/S) indicated significantly different activities.

N-nitrourea derivatives as novel potential fungicides against Rhizoctonia solani: synthesis, antifungal activities, and 3D-QSAR.

A series of N-nitrourea derivatives bearing various aryl substituents were conveniently obtained via three steps including nitration, carbamic chlorination, and aminolysis reactions. The structures of all newly synthesized compounds were characterized and confirmed by IR, ¹H-NMR, MS, and elemental analysis. The preliminary bioassays indicate that five compounds possess sufficient fungicidal activity against Rhizoctonia solani. Structure-activity relationship (SAR) is also discussed based on the experimental data, and the further quantitative structure-activity relationship (QSAR) was analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

Organocatalytic synthesis and sterol 14alpha-demethylase binding interactions of enantioriched 3-(1H-1,2,4-triazol-1-yl)butyl benzoates.

1H-1,2,4-Triazole reacted with 2-butenal in the presence of diaryl prolinol silyl ether 3 and benzonic acid to give 3-(1H-1,2,4-triazol-1-yl)butanal 4, which was subsequently reduced and then treated with various acyl chloride to generate enantioriched 3-(1H-1,2,4-triazol-1-yl)butyl benzoates 6. Some of triazoles 6 exhibited strong binding interactions with the cytochrome P450-dependent sterol 14alpha-demethylase (CYP51). For example, compound (R)-6f showed the best binding activity with K(d) 0.3381 microM.

2-(1H-Imidazol-1-yl)-3-isopropyl-1-benzothieno[3,2-d]pyrimidin-4(3H)-one.

In the title compound, C(16)H(14)N(4)OS, the three fused rings of the benzothieno[3,2-d]pyrimidinone unit are essentially coplanar, the maximum deviation from the mean plane being 0.067 (3) Å. The dihedral angle between the mean plane of the fused rings and the imidazole ring is 72.00 (3)°. Offset π-π stacking inter-actions involving the fused rings are effective in the stabilization of the crystal structure. The centroid-centroid distances between the thienophene and benzene rings, and between the pyrimidine and benzene rings are 3.67 (1) and 3.93 (1) Å, respectively. There are two intramolecular C-H⋯O interactions.

3-Butyl-2-propyl-amino-1-benzo-thieno[3,2-d]pyrimidin-4(3H)-one.

In the title compound, C(17)H(21)N(3)OS, the propyl and butyl groups are disordered over two positions; site occupation factors are 0.304 (10) and 0.696 (10). The three fused rings are coplanar. In the crystal structure, inter-molecular N-H⋯O and C-H⋯O hydrogen bonds link the mol-ecules. Further stability is provided by offset π-π stacking inter-actions. Adjacent thienophene-pyrimidine and pyrimidine-benzene rings have centroid-centroid distances of 3.96 (1) and 3.55 (2) Å, respectively.

Iminophosphorane-mediated efficient synthesis of new tricyclic 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a]pyrimidin-9-ones.

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with hydrazine to give selectively 6-amino-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones 5. Compounds 5 were further transformed to iminophosphoranes 6 by reaction with triphenylphosphine, hexachloroethane and triethylamine. A tandem aza-Wittig reaction of iminophosphorane 6 with isocyanate or acyl chloride generated previously unreported 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a]pyrimidin-9-ones 10 or 12 in satisfactory yield. X-ray structure analysis of 10 g verified the proposed structure and the reaction selectivity.

Application of bis(iminophosphorane) in heterocyclic synthesis: new entries to symmetrically or unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones.

The bis(carbodiimides) 4, obtained from bis-aza-Wittig reactions of bis(iminophosphorane) 3 with 2 equiv of aromatic isocyanates, were reacted with secondary amine to give symmetrically substituted 2,7-diaminothieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-dione 6 in the presence of a catalytic amount of EtO(-)Na(+). Reactions of 4 with phenols or ROH in the presence of a catalytic amount of potassium carbonate or RO(-)Na(+) gave symmetrically substituted 2,7-diaryl(alkyl)oxythieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 6 in satisfactory yields. However, iminophosphoranes 9 were obtained via reaction of bis(iminophosphorane) 3 with 1 equiv of aromatic isocyanate and subsequent reaction with an amine in the presence of a catalytic amount of EtO(-)Na(+). Further reaction of iminophosphoranes 9 with aromatic isocyanates and various nucleophile generated unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 12 in good yields.