Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism

Molecular Diversity - The rate of mutability of pathogenic H1N1 influenza virus is a threat. The emergence of drug resistance to the current competitive inhibitors of neuraminidase, such as...     

Removal of a single minor-groove functional group eliminates A-tract curvature

Much of the work in studying the phenomenon of A-tract curvature has involved the insertion of modified residues into the A-tract sequence and then cross-correlation of the structural differences with the resulting curvature effects. In the A-tract sequence d(A-T)5, removal of a single functional group (the O2-carbonyl of the central dT residue) by its replacement with hydrogen completely eliminates the curvature properties. This atom-specific change was accomplished by using the C-nucleoside dm32P in which the O2-carbonyl is replaced with -H but normal Watson-Crick hydrogen bonding is maintained. Similar derivatives with -F (dF62P) or -CH3 (dm62P) when present for the central dT residue also eliminate curvature. Finally, we have shown that the extent of curvature for sequences containing this carbonyl are sensitive to the [Mg2+], while those lacking the carbonyl show little to no Mg2+ dependence, strongly suggesting, we believe, a role for Na+/Mg2+ cooperative interactions in the minor groove to explain the curvature phenomenon.     

Molecular precursors for the preparation of homogenous zirconia-silica materials by hydrolytic sol-gel process in organic media. Crystal structures of [Zr{OSi(O(t)Bu)3}4(H2O)2]·2H2O and [Ti(O(t)Bu){OSi(O(t)Bu)3}3

[Zr(OPr(i))(4)·Pr(i)OH] reacts with [HOSi(O(t)Bu)(3)] in anhydrous benzene in 1:1 and 1:2 molar ratios to afford alkoxy zirconosiloxane precursors of the types [Zr(OPr(i))(3){OSi(O(t)Bu)(3)}] (A) and [Zr(OPr(i))(2){OSi(O(t)Bu)(3)}(2)] (B), respectively. Further reactions of A or B with glycols in 1:1 molar ratio afforded six chemically modified precursors of the types [Zr(OPr(i))(OGO){OSi(O(t)Bu)(3)}] (1A-3A) and [Zr(OGO){OSi(O(t)Bu)(3)}(2)] (1B-3B), respectively [where G = (-CH(2)-)(2) (1A, 1B); (-CH(2)-)(3) (2A, 2B) and (-CH(2)CH(2)CH(CH(3)-)} (3A, 3B)]. The precursors A and B are viscous liquids, which solidify on ageing whereas the other products are all solids, soluble in common organic solvents. These were characterized by elemental analyses, molecular weight measurements, FAB mass, FTIR, (1)H, (13)C and (29)Si-NMR studies. Cryoscopic molecular weight measurements of all the products, as well as the FAB mass studies of 3A and 3B, indicate their monomeric nature. However, FAB mass spectrum of the solidified B suggests that it exists in dimeric form. Single crystal structure analysis of [Zr{OSi(O(t)Bu)(3)}(4)(H(2)O)(2)]·2H(2)O (3b) (R(fac) = 11.9%) as well as that of corresponding better quality crystals of [Ti(O(t)Bu){OSi(O(t)Bu)(3)}(3)] (4) (R(fac) = 5.97%) indicate the presence of a M-O-Si bond. TG analyses of 3A, B, and 3B indicate the formation of zirconia-silica materials of the type ZrO(2)·SiO(2) from 3A and ZrO(2)·2SiO(2) from B or 3B at low decomposition temperatures (≤200 °C). The desired homogenous nano-sized zirconia-silica materials [ZrO(2)·nSiO(2)] have been obtained easily from the precursors A and B as well as from the glycol modified precursors 3A and 3B by hydrolytic sol-gel process in organic media without using any acid or base catalyst, and these were characterized by powder XRD patterns, SEM images, EDX analyses and IR spectroscopy.     

Insulator, semiclassical oscillations and quantum Hall liquids at low magnetic fields

Magneto-transport measurements are performed on two-dimensional GaAs electron systems to probe the quantum Hall (QH) effect at low magnetic fields. Oscillations following the Shubnikov-de Haas (SdH) formula are observed in the transition from the insulator to QH liquid when the observed almost temperature-independent Hall slope indicates insignificant interaction correction. Our study shows that the existence of SdH oscillations in such a transition can be understood based on the non-interacting model.     

Highly sensitive LC-MS/MS-ESI method for simultaneous quantitation of albendazole and ricobendazole in rat plasma and its application to a rat pharmacokinetic study

A highly sensitive and specific LC-MS/MS-ESI method was developed for simultaneous quantification of albenadazole (ABZ) and ricobendazole (RBZ) in rat plasma (50 μL) using phenacetin as an internal standard (IS). Simple protein precipitation was used to extract ABZ and RBZ from rat plasma. The chromatographic resolution of ABZ, RBZ and IS was achieved with a mobile phase consisting of 5 m m ammonium acetate (pH 6) and acetonitrile (20:80, v/v) at a flow rate of 1 mL/min on a Chromolith RP-18e column. The total chromatographic run time was 3.5 min and the elution of ABZ, RBZ and IS occurred at 1.66, 1.50 and 1.59 min, respectively. A linear response function was established for the ranges of concentrations 2.01-2007 and 6.02-6020 ng/mL for ABZ and RBZ, respectively. The intra- and inter-day precision values for ABZ and RBZ met the acceptance as per FDA guidelines. ABZ and RBZ were stable in battery of stability studies, viz. bench-top, auto-sampler and freeze-thaw cycles. The developed assay was applied to a pharmacokinetic study in rats.     

Thermoanalytical studies of oxovanadium(IV)hydroxamate complexes

The thermal decomposition behavior of oxovanadium(IV)hydroxamate complexes of composition [VO(acac)(C₆H₅C(O)NHO)] (I), [VO(C₆H₅C(O)NHO)₂] (II), [VO(acac)(4-ClC₆H₄C(O)NHO)] (III), [VO(4-ClC₆H₄C(O)NHO)₂] (IV) (where acac = (CH₃COCHCOCH₃ ^–) synthesized from the reactions of VO(acac)₂ with equi- and bimolar amounts of potassium benzohydroxamate and potassium 4-chlorobenzohydroxamate in THF + MeOH solvent medium has been studied by TG and DTA techniques. TG curves indicated that complexes I, II, and IV undergo decomposition in single step to yield VO₂ as the final residue, while complex III decomposes in two steps to yield VO(acac) as the likely intermediate and VO₂ as the ultimate product of decomposition. The formation of VO₂ has been authenticated by IR and XRD studies. From the initial decomposition temperatures, the order of thermal stability for the complexes has been inferred as IV > I > III > II.     

Role of Intracellular Iron in Switching Apoptosis to Ferroptosis to Target Therapy-Resistant Cancer Stem Cells

Iron is a crucial element required for the proper functioning of the body. For instance, hemoglobin is the vital component in the blood that delivers oxygen to various parts of the body. The heme protein present in hemoglobin comprises iron in the form of a ferrous state which regulates oxygen delivery. Excess iron in the body is stored as ferritin and would be utilized under iron-deficient conditions. Surprisingly, cancer cells as well as cancer stem cells have elevated ferritin levels suggesting that iron plays a vital role in protecting these cells. However, apart from the cytoprotective role iron also has the potential to induce cell death via ferroptosis which is a non-apoptotic cell death dependent on iron reserves. Apoptosis a caspase-dependent cell death mechanism is effective on cancer cells however little is known about its impact on cancer stem cell death. This paper focuses on the molecular characteristics of apoptosis and ferroptosis and the importance of switching to ferroptosis to target cancer stem cells death thereby preventing cancer relapse. To the best of our knowledge, this is the first review to demonstrate the importance of intracellular iron in regulating the switching of tumor cells and therapy resistant CSCs from apoptosis to ferroptosis.     

Chiral ligand exchange chromatography on polygalactomannan (Guaran)

Summary The Chiral discriminating properties of the legume seed (Cyamopsis tetragonalobus) polysaccharide, guaran, has been investigated by this laboratory. Due to the presence of cis-hydroxyl groups in its molecule, guaran a galactomannan, forms tetracoordinated polymeric complexes with boron, resulting in cross-linking and gelling. Ligand exchange between the polymeric boron complex and a low molecular weight chiral diol can take place with stereoselectivity. The principle has been applied for the resolution of (±) mandelic acid by using ligand exchange chromatography.