Stereoselectivity in the addition of hydrogen chloride to cyclohex-1-enecarbonitrile: Possible role of chlorine lone pair-nitrile π-orbital pseudoallylic A1, 3 interaction

The (overall trans) addition of hydrogen chloride to cyclohex-1- enecarbonitrile in anhydrous alcoholic media proceeds to give cis-2-chlorocyclohexanecarboxylate (together with some cis-2- chlorocyclohexanecarboxamide): no corresponding products with the trans-configuration are detectable. In anhydrous ether the addition proceeds to give a single isomer, presumably cis-, of 2-chlorocyclohexanecarbonitrile, indicating that the configuration of the products may not be equilibrium-controlled in alcoholic media. An examination of the steric factors indicates that the transition state for protonation of the presumed intermediate, 2-chlorocyclohexylidenemethylideneimine, leading to cis-product is favoured if interaction between the lateral π-orbital of the C-N double bond and the lone-pairs on the chlorine atom at the 2-position is large. Consideration of interactions in the transition states meets Zimmerman's criticism that invoking A1, 3 interaction existing in ground states to explain product configuration takes insufficient account of the Curtin-Hammett principle.

Interaction of heterocyclic thiols/thiones eliminated from cephalosporins with iodine and its biological implications

Hydrolysis of beta-lactam antibiotics by beta-lactamases (e. g., metallo-beta-lactamase, m beta l) is one of the major bacterial defense systems. These enzymes can catalyze the hydrolysis of a variety of antibiotics including the latest generation of cephalosporins, cephamycins and imipenem. It is shown in this paper that the thiol/thione moieties eliminated from certain cephalosporins by m beta l-mediated hydrolysis readily react with molecular iodine to produce ionic compounds having S-I bonds. While the reaction of MTT with iodine produced the corresponding disulfide, MDT and DMETT produced the charge-transfer complexes MDT-I-2 and DMETT-I-2, respectively. Addition of two equivalents of I-2 to MDT produced a novel cationic complex having an almost linear S-I+-S moiety and I-5(-) counter anion.However, this reaction appears to be highly solvent dependent. When the reaction of MDT with I2 was carried out in water, the reaction produced a monocation having I-5(-), indicating the reactivity of MDT toward I2 is very similar to that of the most commonly used antithyroid drug methimazole (MMI). In contrast to MMI, MDT and DMETT, the triazine-based compound MTDT acts as a weak donor toward iodine. (C)2010 Elsevier Ltd. All rights reserved.

5-(4-Chlorophenyl)-3-(2,4-dimethylthiazol-5-yl)-1,2,4-triazolo[3,4-a]isoquinoline

In the title molecule, C21H15ClN4S, the triazoloisoquinoline ring system is approximately planar, with an r.m.s. deviation of 0.054 (2) angstrom and a maximum deviation of 0.098 (2) angstrom from the mean plane for the triazole ring C atom that is bonded to the thiazole ring. The thiazole and benzene rings are twisted by 66.36 (7) and 56.32 (7)degrees respectively, with respect to the mean plane of the triazoloisoquinoline ring system. In the crystal structure, molecules are linked by intermolecular C-H center dot center dot center dot N interactions along the a axis. The molecular conformation is stabilized by a weak intramolecular pi-pi interaction involving the thiazole and benzene rings, with a centroid-centroid distance of 3.6546 (11) angstrom . In addition, two other intermolecular pi-pi stacking interactions are observed, between the triazole and benzene rings and between the dihydropyridine and benzene rings [centroid-centroid distances = 3.6489 (11) and 3.5967 (10) angstrom, respectively].

Folding a Polymer via Two-Point Interaction with an External Folding Agent: Use of H-Bonding and Charge-Transfer Interactions

A polymer containing electron-rich aromatic donors (1,5-dialkoxynaphthalene (DAN)) was coerced into a folded state by an external folding agent that contained an electron-deficient aromatic acceptor (pyromellitic diimide (PM)) unit. The donor-containing polymer was designed to carry a tertiary amine moiety in the linking segment, which served as an H-bonding site for reinforcing the interaction with the acceptor containing folding agent that also bore a carboxylic acid group. The H-bonding interaction of the carboxylic acid and the tertiary amine brings the PDI unit between two adjacent DAN units along the polymer backbone to induce charge-transfer (C-T) interactions, and this in turn causes the polymer chain to form a pleated structure. Evidence for the formation of such a pleated structure was obtained from NMR titration studies and also by monitoring the C-T band in their UV-visible spectra. By varying the length of the segment that links the PDI acceptor to the carboxylic acid group, we showed that the most effective folding agent was the one that had a single carbon spacer, as evident from the highest value of the association constant. Control experiments with propionic acid clearly demonstrated the importance of the additional C-T interactions for venerating the folded structures. Further, solution viscosity measurements in the presence of varying amounts of the folding agent revealed a gradual stiffening of the chain in the case of the PDI carrying carboxylic acid, whereas no such affect was seen in the case of simple propionic acid. These observations were supported by D FT calculations of the interactions of a dimeric model of the polymer with the various folding agents; here too the stability of the complex was seen to be highest in the case of the single carbon spacer.

Synthesis and identification of a new class of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent antileukemic agents

Benzothiazoles are multitarget agents with broad spectrum of biological activity. Among the antitumor agents discovered in recent years, the identification of various 2-(4-aminophenyl) benzothiazoles as potent and selective antitumor drugs against different cancer cell lines has stimulated remarkable interest. Some of the benzothiazoles are known to induce cell cycle arrest, activation of caspases and interaction with DNA molecule. Based on these interesting properties of benzothiazoles and to obtain new biologically active agents, a series of novel 4,5,6,7-tetrahydrobenzo[d]thiazole derivatives 5(a-i) were synthesized and evaluated for their efficacy as antileukemic agents in human leukemia cells (K562 and Reh). The chemical structures of the synthesized compounds were confirmed by H-1 NMR, LCMS and IR analysis. The cytotoxicity of these compounds were determined using trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Results showed that, these compounds mediate a significant cytotoxic response to cancer cell lines tested. We found that the compounds having electron withdrawing groups at different positions of the phenyl ring of the thiourea moiety displayed significant cytotoxic effect with IC50 value less than 60 mu M. To rationalize the role of electron withdrawing group in the induction of cytotoxicity, we have chosen molecule 5g (IC50 similar to 15 mu M) which is having chloro substitution at ortho and para positions. Flow cytometric analysis of annexin V-FITC/ propidium iodide (PI) double staining and DNA fragmentation suggest that 5g can induce apoptosis.

Elucidation of the mechanism of interaction of sheep spleen galectin-1 with splenocytes and its role in cell-matrix adhesion

The binding of a 14 kDa beta-galactoside animal lectin to splenocytes has been studied in detail. The binding data show that there are two classes of binding sites on the cells for the lectin: a high-affinity site with a K-a ranging from 1.1 x 10(6) to 5.1 x 10(5) M-1 and a low affinity binding site with a K-a ranging from 7.7 x 10(4) to 3.4 x 10(4) M-1 The number of receptors per cell for the high- and low-affinity sites is 9 +/- 3 x 10(6) and 2.5 +/- 0.5 x 10(6) respectively. The temperature dependence of the K value yielded the thermodynamic parameters. The energetics of this interaction shows that, although this interaction is essentially enthalpically driven (Delta H - 21 kJ lambda mol(-1)) for the high-affinity sites, there is a very favorable entropy contribution to the free energy of this interaction (-T Delta S - 17.5 Jmol(-1)), suggesting that hydrophobic interaction may also be playing a role in this interaction. Lactose brought about a 20% inhibition of this interaction, whereas the glycoprotein asialofetuin brought about a 75 % inhibition, suggesting that complex carbohydrate structures are involved in the binding of galectin-1 to splenocytes, Galectin-1 also mediated the binding and adhesion of splenocytes to the extracellular matrix glycoprotein laminin, suggesting a role for it in cell-matrix interactions. Copyright (C) 2000 John Wiley & Sons, Ltd.

Effect of interaction of macrocracks on the stress intensity factor in a beam

Beams with a central edge crack, as well as other noncentral vertical and inclined edge cracks distributed symmetrically, subjected to three-point as well as four-point bending, are analysed using the finite element technique. Values of stress intensity factor K1 at the central crack tip for a crack-to-beam depth ratio Image equal to 0.5, are calculated for various cracked-beam configurations, using the compliance calibration technique as well as method of strain energy release rate. These are compared with the value of K1 for the case of a beam with central edge crack alone. Results of the present parametric study are used to specify the range of values pertaining to basic parameters such as crack-to-beam depth ratios, geometry and position with respect to central edge crack, of other macrocracks for which interaction exists. Accordingly, the macrocracks are classified as either interacting or noninteracting types. Hence for noninteracting types of cracks, analytical expressions available for the determination of K1 in the case of beam with a central edge crack alone, are applicable.

Interaction of 3-hydroxybenzoate-6-hydroxylase with cibacron blue

Cibacron blue is a potent inhibitor of 3-HBA-6-hydroxylase at a concentration < 1 mu M. Kinetic analyses revealed that at a concentration below 0.5 mu M the dye behaves as an uncompetitive inhibitor with respect to 3-HBA and competes with NADH for the same site on the enzyme. The alteration of the near-UV CD spectrum and quenching of the emission fluorescence of the enzyme by cibacron blue indicates a significant alteration in the environment of aromatic amino acid residues due to a stacking interaction and subtle conformatiodnal changes in the enzyme. The concentration-dependent quenching of the intrinsic fluorescence of the enzyme by cibacron blue was employed to determine the binding parameters such as association constant (K-a) and stoichiometry (r) for the enzyme-dye complex.

A spectroscopic study of the interaction of isoflavones with human serum albumin

Genistein and daidzein, the major isoflavones present in soybeans, possess a wide spectrum of physiological and pharmacological functions. The binding of genistein to human serum albumin (HSA) has been investigated by equilibrium dialysis, fluorescence measurements, CD and molecular visualization. One mole of genistein is bound per mole of HSA with a binding constant of 1.5 +/- 0.2 X 10(5) m(-1). Binding of genistein to HSA precludes the attachment of daidzein. The ability of HSA to bind genistein is found to be lost when the tryptophan residue of albumin is modified with N-bromosuccinimide. At 27 degrees C (pH 7.4), van't Hoff's enthalpy, entropy and free energy changes that accompany the binding are found to be -13.16 kcal.mol(-1), -21 cal.mol(-1)K(-1) and -6.86 kcal.mol(-1), respectively. Temperature and ionic strength dependence and competitive binding measurements of genistein with HSA in the presence of fatty acids and 8-anilino-1-naphthalene sulfonic acid have suggested the involvement of both hydrophobic and ionic interactions in the genistein-HSA binding. Binding measurements of genistein with BSA and HSA, and those in the presence of warfarin and 2,3,5-tri-iodobenzoic acid and Forster energy transfer measurements have been used for deducing the binding pocket on HSA. Fluorescence anisotropy measurements of daidzein bound and then displaced with warfarin, 2,3,5-tri-iodobenzoic acid or diazepam confirm the binding of daidzein and genistein to subdomain IIA of HSA. The ability of HSA to form ternery complexes with other neutral molecules such as warfarin, which also binds within the subdomain IIA pocket, increases our understanding of the binding dynamics of exogenous drugs to HSA.

Interaction between the Z-type DNA duplex and 1,3-propanediamine:crystal structure of d(CACGTG)(2) at 1.2 angstrom resolution

The crystal structure of a hexamer duplex d(CACGTG)(2) has been determined and refined to an R-factor of 18.3% using X-ray data up to 1.2 angstrom resolution. The sequence crystallizes as a left-handed Z-form double helix with Watson-Crick base pairing. There is one hexamer duplex, a spermine molecule, 71 water molecules, and an unexpected diamine (Z-5, 1,3-propanediamine, C3H10N2)) in the asymmetric unit. This is the high-resolution non-disordered structure of a Z-DNA hexamer containing two AT base pairs in the interior of a duplex with no modifications such as bromination or methylation on cytosine bases. This structure does not possess multivalent cations such as cobalt hexaammine that are known to stabilize Z-DNA. The overall duplex structure and its crystal interactions are similar to those of the pure-spermine form of the d(CGCGCG)(2) structure. The spine of hydration in the minor groove is intact except in the vicinity of the T5A8 base pair. The binding of the Z-5 molecule in the minor grove of the d(CACGTG)(2) duplex appears to have a profound effect in conferring stability to a Z-DNA conformation via electrostatic complementarity and hydrogen bonding interactions. The successive base stacking geometry in d(CACGTG)(2) is similar to the corresponding steps in d(CG)(3). These results suggest that specific polyamines such as Z-5 could serve as powerful inducers of Z-type conformation in unmodified DNA sequences with AT base pairs. This structure provides a molecular basis for stabilizing AT base pairs incorporated into an alternating d(CG) sequence.

Spectroscopic, microscopic and first rheological investigations in charge-transfer interaction induced organogels

This article describes two-component charge-transfer interaction mediated organogels (CT-gels) derived from anthracene carboxamides obtained from 2-amino 2-hydroxymethyl-1,3-propanediol (TRIS), and 2,3-dialkoxyanthracenes as donors, with 2,4,7-trinitrofluorenone (TNF) as the common acceptor. We demonstrate the versatility of TNF as an electron acceptor in the formation of these gels. The effect of subtle changes in the donor structure on the gelation ability has been investigated by varying the alkyl chain length in the dialkoxyanthracene donors, and by varying the position of the TRIS substituent in the anthracene carboxamide donors. Distinct differences have been observed in the nature of the CT-gels based on these two kinds of anthracene donors. It has been reported in the literature that 2,3-dialkoxyanthracenes form gels on their own in various aliphatic hydrocarbons and alcohols for linear alkyl chains bearing at least 6mcarbon atoms (C-6). In the present study, it is shown that themCT-complex of these molecules with TNF is able to gel many alcoholic and a few hydrocarbon solvents. Also, in the presence of TNF, the 2,3-dialkoxyanthracenes (C-4-C-5) which were non-gelators on their own at ambient temperatures, form CT-gels in a number of alcohols. The other series of gelators discussed, the anthracene carboxamides, require the mandatory presence of TNF to form gels. This donor-acceptor complex forms gels in various aliphatic alcohols. Interestingly, the formation of these CT-gels requires rapid cooling in most of the cases. Thermal stability studies with both types of CT-gels indicate an optimum stoichiometry of 1 : 1 between the donor and the acceptor. Dynamic rheological experiments reveal these gels as viscoelastic soft materials, with the mechanical strength of these gels depending on the amount of TNF present. This provides a means to tune the strength of the gel by varying the doping concentration of the acceptor.

Hormones andCuscuta development: interaction of cytokinin and indole-3-acetic acid in the growth and curvature of subapical stem segments

Cuscuta stem (vines) exhibits two modes of growth—longitudinal elongation forming free-hanging vines, or coiling growth to twine around the host. The elongation zone of free-hanging vine extended up to 160 mm from the stem apex and in vivo growth rate (during 8 h of growth) was maximal in the 20-to-40-mm region. While gibberellic acid (GA3) or fusicoccin (FC) could maintain (GA3) or enhance (FC) the growth rate of apical (10 or 25 mm) segments, indole-3-acetic acid (IAA) (10 mgrM) induced growth only in subapical (5–160 mm) segments. In vitro growth rate induced by IAA (10 mgrM) was similar to the in vivo growth rate up to 40 mm. Thereafter, up to 100 mm, IAA induced growth rate exceeded in vivo growth. p ]Subapical segments (sim13 mm) from 5- to 40-mm regions responded to a cytokinin (BA, Z, or iP) or to low IAA (0.1 mgrM) with curved growth, whereas the segments grew straight in the presence of high IAA (10 mgrM). Curvature (measured as the angle subtended at the center of the circle of which the segment formed an arc) induced by BA and low (0.1 mgrM) IAA was greater than either added separately. Besides, segments induced to curve in BA + low-IAA solution could be made to straighten out by transferring to a solution containing high IAA (10 mgrM) with or without BA. Thus in vivo patterns of straight and coiling growth could be mimicked reversibly in vitro by adjusting the relative concentrations of cytokinin and auxin; low auxin and cytokinin induced coiling growth, whereas high auxin and cytokinin induced straight growth. p ]Beyond 40 mm, BA had no growth-promoting or curvative-inducing effect.Cuscuta vine segments thus showed sequential sensitivity to applied hormones, the apical region (0–25 mm) to GA3, the subapical (5–40 mm) region to BA and IAA and the region beyond (40–160 mm) to IAA alone.

Stabilization of the bio-membrane by small molecules: interaction of trehalose with the phospholipid bilayer

Anhydrobiotic organisms undergo periods of acute dehydration during their life cycle. It is of interest to understand how the biomembrane remains intact through such stress. A disaccharide, trehalose, which is metabolised during anhydrobiosis is found to prevent disruption of model membrane systems. Molecular modelling techniques are used to investigate the possible mode of interaction of trehalose with a model monolayer. The objective is to maximise hydrogen bonding between the two systems. A phospholipid matrix consisting of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) is chosen to represent the monolayer. The crystal structure of DMPC reveals that there are two distinct conformers designated as A and B. An expansion of the monolayer, coplanar with its surface, results in the trehalose molecule being accommodated in a pocket formed by four B conformers. One glucose ring of the sugar rests on the hydrophobic patch provided by the choline methyls of an A conformer. Five hydrogen bonds are formed involving the phosphate oxygens of three of the surrounding B conformers. The model will be discussed with reference to relevant experimental data on the interaction.