Synthesis and biological evaluation of novel 2-aralkyl-5-substituted-6-(4 `-fluorophenyl)-imidazo2,1-b]1,3,4]thiadiazole derivatives as potent anticancer agents

Levamisole, the imidazo2,1-b]thiazole derivative has been reported as a potential antitumor agent. In the present study, we synthesized, characterized and evaluated biological activity of its novel analogues with substitution in the aralkyl group and on imidazothiadiazole molecules with same chemical backbone but different side chains namely 2-aralkyl-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]thiadiazoles (SCR1), 2-aralkyl-5-bromo-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]-thiadiaz oles (SCR2), 2-aralkyl-5-formyl-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]-thiadia zoles (SCR3) and 2-aralkyl-5-thiocyanato-6-(4'-fluorophenyl)-imidazo2,1-b]1,3,4]-th iadiazoles (SCR4) on leukemia cells. The cytotoxic studies showed that 3a, 4a, and 4c exhibited strong cytotoxicity while others had moderate cytotoxicity. Among these we chose 4a (IC50, 8 mu M) for understanding its mechanism of cytotoxicity. FACS analysis in conjunction with mitochondrial membrane potential and DNA fragmentation studies indicated that 4a induced apoptosis without cell cycle arrest suggesting that it could be used as a potential chemotherapeutic agent. (C) 2011 Elsevier Masson SAS. All rights reserved.

Interactions of Antithyroid Drugs and Their Analogues with Halogens and their Biological Implications

The selenium analogue of antithyroid drug methimazole (MSeI) reacts with molecular bromine to produce two different types of novel complexes depending upon the molar ratio of MSeI to Br-2 in the reaction medium: Dicationic diselenide complex with two Br- ions as counterions is produced in the reaction of MSeI with 0.5 equiv of Br-2 (MSeI/Br-2, 1.0:0.5), whereas a stable 10-Se-3 hypervalent ``T-shaped'' complex featuring a linear Br-Se-Br moiety was produced when MSeI was treated with Br-2 in an equimolar ratio (MSeI/Br-2, 1.0:1.0). A substitution at the free N-H group in MSeI alters its reactivity toward iodine/bromine. For example, the N,N-disubstituted selones exclusively produce the corresponding 10-Se-3 hypervalent ``T-shaped'' complexes in the reaction with I-2. In the presence of the lectoperoxidase/H2O2/I- system, N,N-dimethylimidazole-2-selone produces the corresponding dicationic diselenide with two I- counterions as the final metabolite. The formation of ionic species in these reactions is confirmed by single crystal X-ray diffraction studies and in some cases by Fourier transform-Raman spectroscopic investigations.

Sub-micrometre spherical particles of TiO2, ZrO2, and PZT by nebulized spray pyrolysis of metal-organic precursors

Nebulized spray pyrolysis of metal-organic precursors in methanol solution has been employed to prepare powders of TiO2, ZrO2 and PbZr0.5Ti0.5O3 (PZT). This process ensures complete decomposition of the precursors at relatively low temperatures. The particles have been examined by scanning and transmission electron microscopy as well as X-ray diffraction. As prepared, the particles are hollow agglomerates of diameter 0.1-1.6 mu m, but after heating to higher temperatures the ultimate size of the particles comprising the agglomerates are considerably smaller (0.1 mu m or less in diameter) and crystalline.

A perspective of biological supramolecular electron transfer

Electron transfer is an essential activity in biological systems. The migrating electron originates from water-oxygen in photosynthesis and reverts to dioxygen in respiration. In this cycle two metal porphyrin complexes possessing circular conjugated system and macrocyclic pi-clouds, chlorophyll and hems, play a decisive role in mobilising electrons for travel over biological structures as extraneous electrons. Transport of electrons within proteins (as in cytochromes) and within DNA (during oxidative damage and repair) is known to occur. Initial evaluations did not favour formation of semiconducting pathways of delocalized electrons of the peptide bonds in proteins and of the bases in nucleic acids. Direct measurement of conductivity of bulk material and quantum chemical calculations of their polymeric structures also did not support electron transfer in both proteins and nucleic acids. New experimental approaches have revived interest in the process of charge transfer through DNA duplex. The fluorescence on photoexcitation of Ru-complex was found to be quenched by Rh-complex, when both were tethered to DNA and intercalated in the base stack. Similar experiments showed that damage to G-bases and repair of T-T dimers in DNA can occur by possible long range electron transfer through the base stack. The novelty of this phenomenon prompted the apt name, chemistry at a distance. Based on experiments with ruthenium modified proteins, intramolecular electron transfer in proteins is now proposed to use pathways that include C-C sigma-bonds and surprisingly hydrogen bonds which remained out of favour for a long time. In support of this, some experimental evidence is now available showing that hydrogen bond-bridges facilitate transfer of electrons between metal-porphyrin complexes. By molecular orbital calculations over 20 years ago. we found that "delocalization of an extraneous electron is pronounced when it enters low-lying virtual orbitals of the electronic structures of peptide units linked by hydrogen bonds". This review focuses on supramolecular electron transfer pathways that can emerge on interlinking by hydrogen bonds and metal coordination of some unnoticed structures with pi-clouds in proteins and nucleic acids, potentially useful in catalysis and energy missions.

Biological water: Femtosecond dynamics of macromolecular hydration

The unique features of a macromolecule and water as a solvent make the issue of solvation unconventional, with questions about the static versus dynamic nature of hydration and the, physics of orientational and translational diffusion at the boundary. For proteins, the hydration shell that covers the surface is critical to the stability of its structure and function. Dynamically speaking, the residence time of water at the surface is a signature of its mobility and binding. With femtosecond time resolution it is possible to unravel the shortest residence times which are key for the description of the hydration layer, static or dynamic. In this article we review these issues guided by experimental studies, from this laboratory, of polar hydration dynamics at the surfaces of two proteins (Subtilisin Carlsberg (SC) and Monellin). The natural probe tryptophan amino acid was used for the interrogation of the dynamics, and for direct comparison we also studied the behavior in bulk water - a complete hydration in 1 ps. We develop a theoretical description of solvation and relate the theory to the experimental observations. In this - theoretical approach, we consider the dynamical equilibrium in the hydration shell, defining the rate processes for breaking and making the transient hydrogen bonds, and the effective friction in the layer which is defined by the translational and orientational motions of water molecules. The relationship between the residence time of water molecules and the observed slow component in solvation dynamics is a direct one. For the two proteins studied, we observed a "bimodal decay" for the hydration correlation function, with two primary relaxation times: ultrafast, typically 1 ps or less, and longer, typically 15-40 ps, and both are related to the residence time at the protein surface, depending on the binding energies. We end by making extensions to studies of the denatured state of the protein, random coils, and the biomimetic micelles, and conclude with our thoughts on the relevance of the dynamics of native structures to their functions.

Estimation of elasticity map of soft biological tissue mimicking phantom using laser speckle contrast analysis

Scattering of coherent light from scattering particles causes phase shift to the scattered light. The interference of unscattered and scattered light causes the formation of speckles. When the scattering particles, under the influence of an ultrasound (US) pressure wave, vibrate, the phase shift fluctuates, thereby causing fluctuation in speckle intensity. We use the laser speckle contrast analysis (LSCA) to reconstruct a map of the elastic property (Young's modulus) of soft tissue-mimicking phantom. The displacement of the scatters is inversely related to the Young's modulus of the medium. The elastic properties of soft biological tissues vary, many fold with malignancy. The experimental results show that laser speckle contrast (LSC) is very sensitive to the pathological changes in a soft tissue medium. The experiments are carried out on a phantom with two cylindrical inclusions of sizes 6 mm in diameter, separated by 8 mm between them. Three samples are made. One inclusion has Young's modulus E of 40 kPa. The second inclusion has either a Young's modulus E of 20 kPa, or scattering coefficient of mu'(s), = 3.00 mm(-1) or absorption coefficient of mu(a) = 0.03 mm(-1). The optical absorption (mu(a)), reduced scattering (mu'(s)) coefficient, and the Young's modulus of the background are mu(a) = 0.01 mm(-1), mu'(s) = 1.00 mm(-1) and 12kPa, respectively. The experiments are carried out on all three phantoms. On a phantom with two inclusions of Young's modulus of 20 and 40 kPa, the measured relative speckle image contrasts are 36.55% and 63.72%, respectively. Experiments are repeated on phantoms with inclusions of mu(a) = 0.03 mm-1, E = 40 kPa and mu'(s) = 3.00 mm(-1). The results show that it is possible to detect inclusions with contrasts in optical absorption, optical scattering, and Young's modulus. Studies of the variation of laser speckle contrast with ultrasound driving force for various values of mu(a), mu'(s), and Young's modulus of the tissue mimicking medium are also carried out. (C) 2011 American Institute of Physics. doi:10.1063/1.3592352]

Cross-taxon surrogacy of biodiversity in the Indian Garhwal Himalaya

Biodiversity surveys were conducted in 13, 10x50 m(2) plots located between 1400 to 3100 in abode mean sea level in a range of habitats in temperate mixed Oak and Coniferous forests through sub-alpine to the alpine grasslands in Chamoli district of Uttaranchal state in the Indian Garhwal Himalaya. Cross-taxon congruence in biodiversity (alpha-diversity and beta-diversity) across macrolichens, mosses, liverworts, woody plants (shrubs and trees) and ants was investigated, so as to examine the extent to which these group, of organisms can function as Surrogates for each other. Although woody plants provided a major substrate for macrolichens and mosses, there was no species-specific association between them. Woody plant species richness was highly positively correlated with mosses (r(2) = 0.63, P < 0.001) but the relationship, as not particularly very strong with lichens and liverworts. While there was a significant correlation in the species turnover (β-diversity) of macrolichens with mosses (r(2) = 0.21 P < 0.005). the relationship was relatively poor with the woody plants. On the other hand. negative correlations emerged in the species richness of ants with those of macrolichens, mosses and woody plants (r(2) = -0.44 P < 0.05). but most of the complementarity (turnover) relationships among them were positive, Since diversity between taxonomic hierarchies within the group was consistently significantly positively correlated in all these taxa, the higher taxonomic categories Such as genus and family may be employed as surrogates for rapid assessment and monitoring of species diversity, Although no single group other than macrolichens has emerged as a good indicator of changes in species richness in all other groups, some concordant relationships between them conform to the hypothesis that species assemblages of certain taxonomic groups could still be used as surrogates for efficient monitoring of species diversity in other groups whose distribution may further predict the importance of conserving overall biodiversity in landscapes such as the Garhwal Himalaya. (C) 2002 Elsevier Science Ltd. All rights reserved.

Search for sub-mm, mm and radio continuum emission from extremely red objects

We present the results of sub-mm, mm (850 mum, 450 mum and 1250 mum) and radio (1.4 and 4.8 GHz) continuum observations of a sample of 27 K-selected Extremely Red Objects, or EROs, (14 of which form a complete sample with K < 20 and I - K > 5) aimed at detecting dusty starbursts, deriving the fraction of UltraLuminous Infrared Galaxies (ULIGs) in ERO samples, and constraining their redshifts using the radio-FIR correlation. One ERO was tentatively detected at 1250 mum and two were detected at 1.4 GHz, one of which has a less secure identification as an ERO counterpart. Limits on their redshifts and their star forming properties are derived and discussed. We stacked the observations of the undetected objects at 850 mum, 1250 mum and 4.8 GHz in order to search for possible statistical emission from the ERO population as a whole, but no significant detections were derived either for the whole sample or as a function of the average NIR colours. These results strongly suggest that the dominant population of EROs with K < 20 is not comprised of ULIGs like HR 10, but is probably made of radio-quiet ellipticals and weaker starburst galaxies with L < 10(12) L . and SFR < few hundred M. yr(-1).

Reconstructing Solid Model from 2D Scanned Images of Biological Organs for Finite Element Simulation

This work presents a methodology to reconstruct 3D biological organs from image sequences or other scan data using readily available free softwares with the final goal of using the organs (3D solids) for finite element analysis. The methodology deals with issues such as segmentation, conversion to polygonal surface meshes, and finally conversion of these meshes to 3D solids. The user is able to control the detail or the level of complexity of the solid constructed. The methodology is illustrated using 3D reconstruction of a porcine liver as an example. Finally, the reconstructed liver is imported into the commercial software ANSYS, and together with a cyst inside the liver, a nonlinear analysis performed. The results confirm that the methodology can be used for obtaining 3D geometry of biological organs. The results also demonstrate that the geometry obtained by following this methodology can be used for the nonlinear finite element analysis of organs. The methodology (or the procedure) would be of use in surgery planning and surgery simulation since both of these extensively use finite elements for numerical simulations and it is better if these simulations are carried out on patient specific organ geometries. Instead of following the present methodology, it would cost a lot to buy a commercial software which can reconstruct 3D biological organs from scanned image sequences.

Monodisperse sub-10 nm gold nanoparticles by reversing the order of addition in Turkevich method - The role of chloroauric acid

The Turkevich method for synthesizing gold nanoparticles, using sodium citrate as the reducing agent, is renowned for its ability to produce biocompatible colloids with mean size >10 nm. Here we show that monodisperse gold nanoparticles in the 5-10 nm size range can be synthesized by simply reversing the order of addition of reactants, i.e. adding chloroauric acid to citrate solution. Kinetic studies and electron microscopic characterization revealed that the reactivity of chloroauric acid, initial molar ratio of citrate to chloroauric acid (MR), and reaction mixture pH play an important role in producing monodisperse gold nanoparticles. Reversing the order of addition also enhanced the stabilization of nanoparticles at high MR values. Remarkably, the system exhibits a `memory' of the order of addition, even when the timescale of mixing is much shorter than the timescale of synthesis. (C) 2011 Elsevier Inc. All rights reserved.

Haptic Feedback for Injecting Biological Cells using Miniature Compliant Mechanisms

We present a real-time haptics-aided injection technique for biological cells using miniature compliant mechanisms. Our system consists of a haptic robot operated by a human hand, an XYZ stage for micro-positioning, a camera for image capture, and a polydimethylsiloxane (PDMS) miniature compliant device that serves the dual purpose of an injecting tool and a force-sensor. In contrast to existing haptics-based micromanipulation techniques where an external force sensor is used, we use visually captured displacements of the compliant mechanism to compute the applied and reaction forces. The human hand can feel the magnified manipulation force through the haptic device in real-time while the motion of the human hand is replicated on the mechanism side. The images are captured using a camera at the rate of 30 frames per second for extracting the displacement data. This is used to compute the forces at the rate of 30 Hz. The force computed in this manner is sent at the rate of 1000 Hz to ensure stable haptic interaction. The haptic cell-manipulation system was tested by injecting into a zebrafish egg cell after validating the technique at a size larger than that of the cell.

Synthesis, biological studies of linear and branched arabinofuranoside-containing glycolipids and their interaction with surfactant protein A

Oligoarabinofuranoside-containing glycolipids relevant to mycobacterial cell wall components were synthesized in order to understand the functional roles of such glycolipids. A series of linear tetra-, hexa-, octa-and a branched heptasaccharide oligoarabinofuranosides, with 1 -> 2 and 1 -> 5 a-linkages between the furanoside residues, were synthesized by chemical methods from readily available monomer building blocks. Upon the synthesis of glycolipids, constituted with a double alkyl chain-substituted sn-glycerol core and oligosaccharide fragments, biological studies were performed to identify the effect of synthetic glycolipids on the biofilm formation and sliding motilities of Mycobacterium smegmatis. Synthetic glycolipids and arabinofuranosides displayed an inhibitory effect on the growth profile, but mostly on the biofilm formation and maturation. Similarly, synthetic compounds also influenced the sliding motility of the bacteria. Further, biophysical studies were undertaken, so as to identify the interactions of the glycolipids with a pulmonary surfactant protein, namely surfactant protein A (SP-A), with the aid of the surface plasmon resonance technique. Specificities of each glycolipid interacting with SP-A were thus evaluated. From this study, glycolipids were found to exhibit higher apparent association constants than the corresponding oligosaccharide portion alone, without the double alkyl group-substituted glycerol core.

Intercalative pyrimido[4',5':4,5]thieno(2,3-b)quinolines induce apoptosis in leukemic cells: a comparative study of methoxy and morpholino substitution

DNA intercalating molecules are promising anticancer agents. Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and affect major physiological functions. In the present study, we have characterized two molecules with the same chemical backbone but different side chains, namely 8-methoxy pyrimido[4',5':4,5]thieno (2,3-b)quinoline-4(3H)-one (MPTQ) and 4-morpholino pyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpho-PTQ) at the 8th and 4th position, respectively. Although both MPTQ and morpho-PTQ show similar biophysical properties with high DNA affinity, here we show that they differ in their biological activities. We find that MPTQ is many fold more potent than morpho-PTQ and is cytotoxic against different leukemic cell lines. IC(50) value of methoxy PTQ was estimated between 2-15 A mu M among the leukemic cells studied, while it was more than 200 A mu M when morpho-PTQ was used. Cell cycle analysis shows an increase in sub-G1 phase, without any particular cell cycle arrest. Annexin V staining in conjunction with comet assay and DNA fragmentation suggest that MPTQ induces cytotoxicity by activating apoptosis. Thus the observed low IC(50) value of MPTQ makes it a promising cancer chemotherapeutic agent.