Synthesis and biological evaluation of 2,3-diarylpyrazines and quinoxalines as selective COX-2 inhibitors

Several 2,3-diaryl pyrazines and quinoxalines with 4-sulfamoyl (SO(2)NH(2))/methylsulfonyl (SO(2)Me)-phenyl pharmacophores have been synthesized and evaluated for the cyclooxygenase (COX-1/COX-2) inhibitory activity. Smaller groups such as methoxy, methyl and fluoro when substituted at/around position-4 of the adjacent phenyl ring, have great impact on the selective COX-2 inhibitory activity of the series. Many potential compounds were obtained from a brief structure-activity relationship (SAR) study. Two of these, compounds 11 and 25 exhibited excellent in vivo activity in the established animal model of inflammation. Since compound 25 possessed an amenable sulfonamide group, two of its prodrugs 48 and 49 were also synthesized. Both of them have excellent in vivo potential, and represent a new class of COX-2 inhibitor.     

Understanding high diastereomeric discrimination in formation of oligoribonucleotide phosphorothioate linkages: the first study of pKa-dependent activation in solid-supported coupling of 2'-O-substituted ribonucleoside phosphoramidites

Activation of 2'-O-substituted ribonucleoside phosphoramidites with various activators during solid-supported synthesis of phosphorothioate oligonucleotides was studied. The Rp:Sp diastereomeric composition of resulting phosphorothioate linkage dependent on pKa of activator utilized for coupling.     

Influence of diastereomeric ratios of deoxyribonucleoside phosphoramidites on the synthesis of phosphorothioate oligonucleotides

Extensive investigations on the influence of diastereomeric ratios of deoxyribonucleoside phosphoramidites on stereo-reproducibility of solid phase synthesis of phosphorothioate oligodeoxyribonucleotides via the phosphoramidite approach indicate that the process is stereoreproducible and under inherent process control.     

In vitro shoot propagation of Dendrocalamus strictus nees

Multiple shoots were induced from seedling and axillary buds of mature plants of Dendrocalamus strictus on Murashige and Shoog's medium supplemented with BA and kinetin. About 35–45 shoots were obtained within 20–25 days from a nodal explant of seedling and 3–8 shoots were obtained from a nodal explant of mature plants in the primary culture. The seedling derived cultures were separated into groups of 5–7 and transferred to fresh subculture medium. Rooting of the shoots was achieved under in vitro and ex vitro conditions. 85–90% of rooting was achieved by the ex vitro method using IBA. This revised version was published online in June 2006 with corrections to the Cover Date.     

Crystal structure of an intermolecular 2:1 complex between adenine and thymine. Evidence for both Hoogsteen and ‘quasi-Watson–Crick’ interactions

The titled complex, obtained by co-crystallization (EtOH/25 °C), is apparently the only known complex of the free bases. Its crystal structure, as determined by X-ray diffraction at both 90 K and 313 K, showed that one A–T pair involves a Hoogsteen interaction, and the other a Watson–Crick interaction but only with respect to the adenine unit. The absence of a clear-cut Watson–Crick base pair raises intriguing questions about the basis of the DNA double helix.     

Construction of malate-sensing <Emphasis Type="Italic">Escherichia coli</Emphasis> by introduction of a novel chimeric two-component system

In an attempt to develop a high-throughput screening system for screening microorganisms which produce high amounts of malate, a MalKZ chimeric HK-based biosensor was constructed. Considering the sequence similarity among Escherichia coli (E. coli) MalK with Bacillus subtilis MalK and E. coli DcuS, the putative sensor domain of MalK was fused with the catalytic domain of EnvZ. The chimeric MalK/EnvZ TCS induced the ompC promoter through the cognate response regulator, OmpR, in response to extracellular malate. Real-time quantitative PCR and GFP fluorescence studies showed increased ompC gene expression and GFP fluorescence as malate concentration increased. By using this strategy, various chimeric TCS-based bacteria biosensors can be constructed, which may be used for the development of biochemical-producing recombinant microorganisms.     

Membrane-Active Macromolecules Resensitize NDM-1 Gram-Negative Clinical Isolates to Tetracycline Antibiotics

Gram-negative ‘superbugs’ such as New Delhi metallo-beta-lactamase-1 (bla _NDM-1) producing pathogens have become world’s major public health threats. Development of molecular strategies that can rehabilitate the ‘old antibiotics’ and halt the antibiotic resistance is a promising approach to target them. We report membrane-active macromolecules (MAMs) that restore the antibacterial efficacy (enhancement by >80-1250 fold) of tetracycline antibiotics towards bla _NDM-1 Klebsiella pneumonia and bla _NDM-1 Escherichia coli clinical isolates. Organismic studies showed that bacteria had an increased and faster uptake of tetracycline in the presence of MAMs which is attributed to the mechanism of re-sensitization. Moreover, bacteria did not develop resistance to MAMs and MAMs stalled the development of bacterial resistance to tetracycline. MAMs displayed membrane-active properties such as dissipation of membrane potential and membrane-permeabilization that enabled higher uptake of tetracycline in bacteria. In-vivo toxicity studies displayed good safety profiles and preliminary in-vivo antibacterial efficacy studies showed that mice treated with MAMs in combination with antibiotics had significantly decreased bacterial burden compared to the untreated mice. This report of re-instating the efficacy of the antibiotics towards bla _NDM-1 pathogens using membrane-active molecules advocates their potential for synergistic co-delivery of antibiotics to combat Gram-negative superbugs.