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Protection conferred by pneumococcal polysaccharide conjugate vaccines (PCVs) is associated with PCV-induced antibodies against vaccine-covered serotypes that exhibit functional opsonophagocytic activity (OPA). Structural similarity between capsular polysaccharides of closely related serotypes may result in induction of cross-reactive antibodies with or without a cross-functional activity against a serotype not covered by a PCV, with the former providing an additional protective clinical benefit. Serotypes 15B, 15A, and 15C, in the serogroup 15, are among the most prevalent Streptococcus pneumoniae serotypes associated with invasive pneumococcal disease following the implementation of a 13-valent PCV; in addition, 15B contributes significantly to acute otitis media. Serological discrimination between closely related serotypes such as 15B and 15C is complicated; here, we implemented an algorithm to quickly differentiate 15B from its closely related serotypes 15C and 15A directly from whole-genome sequencing data. In addition, molecular dynamics simulations of serotypes 15A, 15B, and 15C polysaccharides demonstrated that while 15B and 15C polysaccharides assume rigid branched conformation, 15A polysaccharide assumes a flexible linear conformation. A serotype 15B conjugate, included in a 20-valent PCV (PCV20), induced cross-functional OPA serum antibody responses against the structurally similar serotype 15C but not against serotype 15A, both not included in PCV20. In PCV20-vaccinated adults (18-49 years), robust OPA antibody titers were detected against both serotypes 15B (the geometric mean titer [GMT] of 19,334) and 15C (GMTs of 1692 and 2747 for strains PFE344340 and PFE1160, respectively), but were negligible against serotype 15A (GMTs of 10 and 30 for strains PFE593551 and PFE647449, respectively). Cross-functional 15B/C responses were also confirmed using sera from a larger group of older adults (60-64 years)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Ingrid Scully, Li Hao, Allison Thompson, Seema Gangolli, Charles Tan, David Cooper, Wendy Watson, Paul Liberator, Michael Pride, Kathrin Jansen and Annaliesa Anderson are all employees of Pfizer and as such may hold stock and stock options. A. Krishna Prasad was an employee of Pfizer at the time the work was conducted but has since left the company. Michelle M. Kuttel reports a relationship with Pfizer Inc that includes: funding grants. Neil Ravenscroft reports a relationship with Pfizer Inc that includes: funding grants.]., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recently, we identified a novel cinnamate analog, ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) as a potent inhibitor of cell adhesion molecules (CAMs), such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. However, its mechanism of action has not been elucidated so far. Since, nuclear factor-kappa B (NF-κB) is the major transcription factor involved in the regulation of ICAM-1, VCAM-1 and E-selectin expression, we determined the status of NF-κB activation in ETMTC treated human endothelial cells. Here, we demonstrate that ETMTC inhibits TNF-α-induced nuclear translocation and activation of NF-κB by inhibiting phosphorylation and degradation of IκBα. The inhibition of IκBα phosphorylation and degradation by ETMTC was found to be due to its ability to inhibit IκB kinase activity. In addition, oxidative stress is known to regulate NF-κB activation through TNF-α signaling cascade, therefore, we examined the effect of ETMTC on TNF-α-induced reactive oxygen species generation. We observed that ETMTC significantly inhibits TNF-α-induced reactive oxygen species generation in endothelial cells. To further elucidate the anti-oxidant potential of ETMTC, we examined its effect on induction of anti-oxidant genes viz. glutamate-cysteine ligase, modifier subunit (GCLM), heme oxygenase-1 (HO1) and NAD (P)H:quinone oxidoreductase 1 (NQO1) in human bronchial epithelial cells. Interestingly, ETMTC significantly induces the anti-oxidant genes viz. GCLM, HO1 and NQO1 by activating nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Thus, ETMTC could be useful towards developing potent anti-inflammatory molecules., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Airway epithelial injury is the hallmark of various respiratory diseases and therapeutic targeting of epithelial injury could be an effective strategy for controlling these diseases. We recently reported that a novel cinnamate, ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) derived from Piper longum derivative, was most potent among various cinnamate derivatives in inhibiting inflammatory cell adhesion molecules (CAMs). In this study, we investigated the effects of ETMTC on the features of allergic asthma and epithelial injury in a murine model. ETMTC treatment to ovalbumin sensitized and challenged mice during ovalbumin challenge reduced airway hyperresponsiveness, and airway inflammation. This attenuation of asthma features was associated with the reduction in the expressions of various CAMs, NF-κB activation, Th2 cytokines, eotaxin and 8-isoprostane that were estimated in lung homogenates. Further, it increased activities of mitochondrial complexes I and IV in lung mitochondria and reduced cytochrome c and caspase 9 activities in lung cytosol. In addition, it reduced the levels of oxidative DNA damage marker in bronchoalveolar lavage fluid and DNA fragmentation of bronchial epithelia in lung sections. Further, ETMTC not only increased the levels of 15-(S)-hydroxyeicosatetraenoic acid, suppressor of airway remodeling, but also inhibited goblet cell metaplasia and sub-epithelial fibrosis. These results demonstrate that ETMTC reduces epithelial injury and mitochondrial dysfunction associated with allergic asthma and thus ETMTC could be useful to develop efficient therapeutic molecule against asthma., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A series of peracetylated O-aryl α,β-d-ribofuranosides have been synthesized and an efficient biocatalytic methodology has been developed for the separation of their anomers which was otherwise almost impossible by column chromatographic or other techniques. The incubation of 2,3,5-tri-O-acetyl-1-O-aryl-α,β-d-ribofuranoside with Lipozyme® TL IM immobilized on silica led to the selective deacetylation of only one acetoxy group, viz the C-5'-O-acetoxy group of the α-anomer over the other acetoxy groups derived from the two secondary hydroxyl groups present in the molecule and also over three acetoxy groups (derived from one primary and two secondary hydroxyls of the β-anomer). This methodology led to the easy synthesis of both, α- and β-anomers of O-aryl d-ribofuranosides. All the arylribofuranosides were screened for inhibition of Src kinase. 1-O-(3-Methoxyphenyl)-β-d-ribofuranoside exhibited the highest activity for inhibition of Src kinase (IC(50)=95.0μM)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Regio- and enantioselective synthesis of (S)-(+)-3-arylamino-1-chloropropan-2-ols has been achieved by the epoxide ring opening of (±)-epichlorohydrin with different aromatic amines in the presence of Candida rugosa lipase. Activities of seven model (S)-(+)-3-arylamino-1-chloropropan-2-ols, out of 10 compounds synthesized, have been evaluated for the inhibition of tumor necrosis factor-α TNF-α) induced expression of intercellular adhesion molecule-1 (ICAM-1), which is one of the factors responsible for the modulation of inflammation in biological systems; (S)-(+)-1-chloro-3-(2'-chlorophenylamino)-propan-2-ol has been found to exhibit highest activity, that is, 86% inhibition of TNF-α induced expression of ICAM-1 at a concentration of 40 μg/ml., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Calreticulin Transacetylase (CRTAase) catalyzes the transfer of acetyl groups from polyphenolic acetates (PAs) to the receptor proteins and modulates their biological activities. CRTAase was conveniently assayed by the irreversible inhibition of cytosolic glutathione S-transferase (GST) by the model acetoxycoumarin, 7,8-diacetoxy-4-methylcoumarin (DAMC). We have studied earlier, the influence of acetoxy groups on the benzenoid ring, the effect of reduction of double bond at C-3 and C-4 position, the effect of methyl/phenyl group at C-4, and the influence of position of carbonyl group with respect to oxygen heteroatom in the benzopyran nucleus, for the catalytic activity of CRTAase. In this communication, we have extended our previous work; wherein we studied the influence of an alkyl group (ethyl, hexyl and decyl) at the C-3 position of the acetoxy coumarins on the CRTAase activity. The substitution at C-3 position of coumarin nucleus resulted in the reduction of CRTAase activity and related effects. Accordingly the formation of NO in platelets by C-3 alkyl substituted acetoxy coumarins was found to be much less compared to the unsubstituted analogs. In addition the alkyl substitution at C-3 position exhibited the tendency to form radicals other than NO.

A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC(50) figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 microM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in various inflammatory and immune diseases. The molecules that block these interactions have been targeted as potential therapeutic targets for acute and chronic inflammatory diseases. In an effort to develop potent cell adhesion molecule inhibitors, a series of chromone derivatives bearing alkoxycarbonylvinyl unit at the C-3 position, that is, the chromones 8a-d and 9a-d, were designed and synthesized, and evaluated for their ICAM-1 inhibitory activity on human endothelial cells as well as their effect on NADPH-catalyzed rat microsomal lipid peroxidation. A structure-activity relationship was established and we found that length of the alkyl moiety of the chromone-3-yl-acrylate is important for this activity. Further, we found that incorporation of unsaturation in the alcohol moiety increases the potential of the compound for the inhibition of TNF-alpha induced expression of ICAM-1 and also for the inhibition of lipid peroxidation. Out of the screened compounds, the most potent compound ethyl trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylate (8a) was taken for further study. We have found that compound 8a also significantly inhibited the TNF-alpha induced expression of VCAM-1 and E-selectin, which play key roles in various inflammatory diseases. This inhibition was found to be concentration dependent. The functional consequences of inhibiting cell adhesion molecules were studied by performing cell-adhesion assay. We found that compound 8a significantly blocks the adhesion of neutrophils to endothelial monolayer. To elucidate the molecular mechanism of inhibition of cell adhesion molecules, we investigated the status of nuclear transcription factor-kappaB (NF-kappaB) and were able to establish that compound 8a significantly blocked the TNF-alpha induced activation of NF-kappaB.

Ten 4-aryl-1,4-dihydropyridine and three 4-aryl-1,2,3,4-tetrahydropyrimidin-2-one derivatives have been synthesized and examined for their activity against pathogenic strains of Aspergillus fumigatus and Candida albicans. Although none of the three compounds belonging to pyrimidin-2-one series showed any activity against two pathogens, two of the compounds of the dihydropyridine series, that is, diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarboxylate and dimethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarboxylate, exhibited significant activity against A. fumigatus in disc diffusion, microbroth dilution and percent spore germination inhibition assays. The most active diethyl dihydropyridine derivative exhibited a MIC value of 2.92 microg/disc in disc diffusion and 15.62 microg/ml in microbroth dilution assays. The MIC(90) value of the most active compound by percent germination inhibition assay was found to be 15.62 microg/ml. The diethyl dicarboxylate derivative of dihydropyridine also exhibited appreciable activity against C. albicans. The in vitro toxicity of the most active diethyl dihydropyridine derivative was evaluated using haemolytic assay, in which the compound was found to be non-toxic to human erythrocytes even at a concentration of 625 microg/ml. The standard drug amphotericin B exhibited 100% lysis of erythrocytes at a concentration almost 16 times less than the safer concentration of the most active dihydropyridine derivative.

Benzoyl cyanide in the ionic liquid 1-methoxyethyl-3-methylimidazolium methanesulfonate has been employed as a 'green' alternative and mild reaction condition protocol to conventional pyridine-benzoyl chloride system for efficient and selective benzoylation of nucleosides (of both the ribo- and deoxyribo-series) at ambient temperatures. The use of benzoyl cyanide-ionic liquid combination has been successfully extended for highly efficient benzoylation of phenols, aromatic amines, benzyl alcohol, aliphatic diols, 3-aminophenol and 2-aminobenzylalcohol, which indicates the versatility of this benzoylating system.

Our earlier observations led to the identification of a microsomal enzyme termed as acetoxy drug: protein transacetylase (TAase) catalyzing the transfer of acetyl groups from acetylated polyphenols to the receptor proteins. TAase was conveniently assayed by the irreversible inhibition of cytosolic glutathione S-transferase (GST) by the model acetoxycoumarin, 7,8-diacetoxy-4-methylcoumarin (1). The specificities of the acetoxy group on the benzenoid ring and position of the pyran carbonyl group of the coumarin with respect to oxygen heteroatom for the catalytic activity of TAase were also reported earlier. In this communication, we have demonstrated that the acetoxy coumarins and acetoxy dihydrocoumarins having a methyl group instead of a phenyl ring at the C-4, when used as the substrates, resulted in enhancement of TAase activity, while the saturation of double bond at C-3 and C-4 position had no effect on TAase activity. A comparison of the optimized structures of 1 and 7,8-diacetoxy-4-phenylcoumarin (2) suggested that the observed influence may be due to out of plane configuration of the phenyl ring at C-4. Further, the TAase-catalyzed activation of NADPH cytochrome c reductase and inhibition of aflatoxin B1 (AFB1)-DNA binding by acetoxy 4-phenylcoumarins and dihydrocoumarins were significantly lower as compared to those caused by acetoxy 4-methylcoumarins.

Different coumarin/thiocoumarin derivatives, that is, 7-hydroxy-4-methylcoumarin, 7,8-dihydroxy-4-methylcoumarin, 7-acetoxy-4-methylcoumarin, 7,8-diacetoxy-4-methylcoumarin, 7-hydroxy-4-methylthiocoumarin, 7,8-dihydroxy-4-methylthiocoumarin, 7-acetoxy-4-methylthiocoumarin and 7,8-diacetoxy-4-methylthiocoumarin were synthesized and evaluated for their effects on TNF-alpha induced expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells and on NADPH-catalyzed rat liver microsomal lipid peroxidation with a view to identify modulators for expression of cell adhesion molecules and to establish structure-activity relationship. We found that dihydroxy and diacetoxy derivatives of thiocoumarin were more potent in comparison to the corresponding coumarin derivatives in inhibiting TNF-alpha-induced expression of ICAM-1. However, coumarin derivatives were found to be more potent in comparison to the corresponding thiocoumarins in inhibiting microsomal lipid peroxidation. We have also tested the intermediate compounds 7,8-dibenzyloxy-4-methylcoumarin and 7,8-dibenzyloxy-4-methylthiocoumarin for their inhibitory activity on TNF-alpha-induced ICMA-1 expression. We found that dibenzyloxy-4-methylthiocoumarin is better than dibenzyloxy-4-methylcoumarin. The mechanisms underlying the observed activities of coumarins and thiocoumarins have been discussed with reference to their structures. Such structure-function relationship studies may help in developing molecules with better anti-inflammatory and anti-oxidant activities.

Cell adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1) and E-selectin, play important roles in the recruitment of leukocytes to the site of inflammation. Blocking the expression of these molecules or preventing their interaction with the receptors has been shown to be important in controlling various inflammatory diseases. These cell adhesion molecules are induced on endothelial cells by various proinflammatory cytokines like IL-1beta and TNF-alpha and also by bacterial LPS. We demonstrate here that 1,4-Dihydroxyxanthone (1,4 DHX) inhibits the expression of cell adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin, on endothelial cells in a concentration and time dependent manner. The inhibition by 1,4 DHX is reversible. On further analysis, our results also show that 1,4 DHX inhibits the adhesion of peripheral neutrophils to the endothelial cell monolayers. 1,4 DHX, therefore, could be used as a novel target for controlling various pathological conditions associated with upregulation of endothelial leukocyte adhesion molecules.

Invasion is the hallmark of malignant tumors, and is responsible for the bad prognosis of the untreated cancer patients. The search for anti-invasive treatments led us to screen compounds of different classes for their effect in an assay for invasion. Thirty-nine new compounds synthesized in the present study along with 56 already reported compounds belonging mainly to the classes of lactones, pyrazoles, isoxazoles, coumarins, desoxybenzoins, aromatic ketones, chalcones, chromans, isoflavanones have been tested against organotypic confronting cultures of invasive human MCF-7/6 mammary carcinoma cells with embryonic chick heart fragments in vitro. Three of them (a pyrazole derivative, an isoxazolylcoumarin and a prenylated desoxybenzoin) inhibited invasion at concentrations as low as 1 microM; instead of occupying and replacing the heart tissue within 8 days, the MCF-7/6 cells grew around the heart fragments and left it intact, when treated with these compounds. At the anti-invasive concentration of 1 microM, the three compounds did not affect the growth of the MCF-7/6 cells, as shown in the sulforhodamine B assay. Aggregate formation on agar was not stimulated by any of the three anti-invasive compounds, making an effect on the E-cadherin/catenin complex improbable. This is an invasion suppressor that can be activated in MCF-7/6 cells by a number of other molecules. Our data indicate that some polyphenolic and heterocyclic compounds are anti-invasive without being cytotoxic for the cancer cells.

The quantitative structure-activity relationship (QSAR) studies conducted by us earlier revealed the cardinal role of the pyran ring carbonyl group in the acetoxy polyphenolic compounds for the acetoxy polyphenol:protein transacetylase (TAase) activity. Hence, an attempt was made to examine whether such substrate analogues of benzopyran acetates which lack in the pyran ring carbonyl group, such as 7-acetoxy-2,3-dihydro-2,2-dimethylbenzopyran (BPA), cetachin pentaacetate (CPA) and hematoxylin pentaacetate (HPA) could inhibit the 7,8-diacetoxy-4-methylcoumarin (DAMC):protein (glutathione-S-transferase) transacetylase activity. These compounds were indeed found to remarkably inhibit the TAase activity in a concentration dependent manner and exerted their inhibitory action very rapidly. Further BPA, CPA and HPA were found to abolish the TAase mediated activation of NADPH cytochrome C reductase as well as the inhibition of liver microsome catalyzed aflatoxin B(1) (AFB(1))-DNA binding by DAMC very effectively. These results strongly suggest that the acetoxybenzopyrans merit as potent inhibitors of TAase.

Eleven (+/-)-5/6/7-acetoxy-4-aryl-3,4-dihydrocoumarins have been synthesised in two steps starting from the coupling of cinnamic acid/substituted cinnamic acid with appropriate phenols, followed by acetylation in 50-83% overall yields. All hydroxy- and acetoxycoumarins were unambiguously identified on the basis of their spectral data. Candida antarctica lipase-catalysed deacetylation of these racemic acetoxydihydrocoumarins in dioxane occurred with moderate enantioselectivity. This is one of the rare examples of resolution using phenolic ester moiety as a remote handle for chiral recognition by a lipase.

The evidences for the possible enzymatic transfer of acetyl groups (catalyzed by a transacetylase localized in microsomes) from an acetylated compound (acetoxy-4-methylcoumarins) to enzyme proteins leading to profound modulation of their catalytic activities was cited in our earlier publications in this series. The investigations on the specificity for transacetylase (TA) with respect to the number and positions of acetoxy groups on the benzenoid ring of coumarin molecule revealed that acetoxy groups in proximity to the oxygen heteroatom (at C-7 and C-8 positions) demonstrate a high degree of specificity to TA. These studies were extended to the action of TA on acetates of other polyphenols, such as flavonoids and catechin with a view to establish the importance of pyran carbonyl group for the catalytic activity. The absolute requirement of the carbonyl group in the pyran ring of the substrate for TA to function was established by the observation that TA activity was hardly discernible when catechin pentacetate and 7-acetoxy-3,4-dihydro-2,2-dimethylbenzopyran (both lacking pyran ring carbonyl group) were used as the substrates. Further, the TA activity with flavonoid acetates was remarkably lower than that with acetoxycoumarins, thus suggesting the specificity for pyran carbonyl group in proximity to the oxygen heteroatom. The biochemical properties of flavonoid acetates, such as irreversible activation of NADPH cytochrome C reductase and microsome-catalyzed aflatoxin B(1) binding to DNA in vitro were found to be in tune with their specificity to TA.

Xanthones bearing different functionalities, namely 1-hydroxyxanthone (1), 3-hydroxyxanthone (2), 1,4-dihydroxyxanthone (3), 2,6-dihydroxyxanthone (4), 1,2-diacetoxyxanthone (5), 2,6-diacetoxyxanthone (6), 3-methoxyxanthone (7), 1,3,7-trimethoxyxanthone (8) and 1,5-dihydroxy-6-methoxyxanthone (9) were synthesised and examined for their effect on nicotinamide adenine dinucleotide phosphate (NADPH)-catalysed liver microsomal lipid peroxidation and on tumour necrosis factor-alpha (TNF-alpha) induced expression of intercellular adhesion moledule-1 (ICAM-1) on endothelial cells, with a view to establish structure-activity relationship. Hydroxy- and acetoxyxanthones showed potent inhibitory effects on NADPH-catalysed lipid peroxidation and TNF-alpha induced expression of ICAM-1 on endothelial cells.

Capabilities of lipases from Candida antarctica, Candida rugosa and porcine pancreas have been evaluated for regioselective acetylation of 2-phenyl-4-(D-arabino-tetrahydroxybutyl)-2H-1,2,3-triazole, 2-phenyl-4-(D-arabino-O-1',2'-isopropylidene-3',4'-dihydroxybutyl)-2H-1,2,3-triazole and 2-phenyl-4-(D-threo-trihydroxypropyl)-2H-1,2,3-triazole, precursors for the synthesis of triazolylacyclonucleosides. C. antarctica lipase and porcine pancreatic lipase exhibited exclusive selectivity for the acetylation of primary hydroxyl group over secondary hydroxyl group(s) in all the three cases.

Five 2-phenyl-4-(D-arabino-4'-cycloamino-3'-hydroxy-O-1',2'-isopropylidene-butyl)-2H-1,2,3-triazoles, acyclonucleosides containing unnatural bases have been synthesised by opening of the epoxide ring of 2-phenyl-4-(D-arabino-3',4'-epoxy-O-1',2'-isopropylidenebutyl)-2H-1,2,3-triazole with the corresponding cyclic amines in 70-85% yields. The starting arabino-epoxytriazole was prepared in five steps starting from D-glucose in an overall yield of 15%. All the five triazolylacyclonucleosides were unambiguously identified on the basis of their spectral data. The structure of one of the intermediates, that is 2-phenyl-4-(D-arabino-1',2',3',4'-tetrahydroxybutyl)-2H-1,2,3-triazole was confirmed by its X-ray crystallographic studies. These acyclonucleosides were subjected to antiviral activity evaluation in CEM-SS cell-based anti HIV assay with the lymphocytropic virus strains HIV-1(IIIB) and HIV-1(RF).

The chemo- and enantioselective capabilities of porcine pancreatic lipase (PPL) in tetrahydrofuran, and Candida rugosa lipase (CRL) in diisopropyl ether have been investigated for the acetylation of racemic 2-alkyl/aryl-3-hydroxypropiophenones, which are important precursors in the synthesis of biologically active chromanones and isoflavanones. A highly chemoselective acetylation of primary hydroxy group in preference to phenolic hydroxy group leading to the formation of enantiomerically enriched monoacetates has been observed.

Fourteen novel C-prenylated and O-allylated 1,3-diarylpropenones (chalcones) were synthesized by Claisen-Schmidt condensation reaction of C-prenylated/O-allylated acetophenones with appropriate aldehydes; twelve of these model chalcones were screened in an assay based on the confrontation of invasive human MCF-7/6 mammary carcinoma cells with fragments of normal embryonic chick heart in vitro. Out of the twelve chalcones tested, three were found to exhibit potent anti-invasive activity. Some of these chalcones and their precursor acetophenones were also tested for inhibition of initiation of lipid peroxidation in rat liver microsomes; a prenylated acetophenone carrying two methoxy groups and two free phenolic hydroxy functions was found to be a potential antioxidant.

Background: Acute respiratory tract infection (ARI) is the major cause of morbidity and mortality in young children in developing countries. Information on viral aetiology in ARI in India is very limited., Objective: The aim of the study was to define the role of viruses in acute lower respiratory tract infections (ALRTI) in children in India using centrifugation enhanced cultures followed by indirect immunofluorescence (IIF)., Study Design: Nasopharyngeal aspirates (NPAs) were collected from children from September 1995 to April 1997, attending paediatric clinic of All India Institute of Medical Sciences (AIIMS) with symptoms of ALRTI. Virus isolation was done by centrifugation enhanced cultures using HEp-2, LLC-MK2 and MDCK cells. The viruses were identified at 24-48 h post inoculation by IIF staining using monoclonal antibodies to respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus and adenovirus., Results: Of 200 NPA samples, 89 (44.5%) were positive for one or more viral pathogens. RSV was detected in 34 (17%) of all ALRTI cases followed by influenza viruses in 29 (14.5%), PIVs in 23 (11.5%) and adenoviruses in three (1.5%). In 79 children with bronchiolitis, RSV was most frequently isolated (25%) pathogen, while in bronchopneumonia cases (101) the most common viral pathogen was influenza virus (17%). In eight cases (4%) of ALRTI dual infections were detected. In 100 NPA specimens IIF staining on direct cell smears was carried out and viruses were detected in only 17%. RSV and influenza virus infection peaked from September to December, where as PIV infections were more frequent from January to April., Conclusion: Respiratory viruses accounted for 44.5% of cases of ALRTI in India and the results of viral aetiology could be given in 24-48 h using centrifugation enhanced cultures. RSV was the most common viral agent associated with ALRTI in children under 5 years of age with greater association with bronchiolitis.

Porcine pancreatic lipase in tetrahydrofuran catalyses the deacetylation of 2,4-diacetoxyphenyl alkyl ketones in a highly regioselective fashion. The strategy of regioselective deacetylation of diacetoxyphenyl alkyl ketones has also resulted in the enantiomeric resolution of a racemic diacetoxyphenyl alkyl ketone, i.e. (+/-)-2,4-diacetoxyphenyl (1-ethyl)pentyl ketone, a precursor for the synthesis of an antifungal coumarin, 7-acetoxy-4-(1-ethyl)pentyl-3-phenyl-2H-1-benzopyran-2-one.

A facile synthesis of (Z)- and (E)-2-(5-arylpyrazol-3-yl)-3-(pyrrol-2-yl)acrylonitriles and (Z)-2-(1,3-diarylpyrazol-5-yl)-3-pyrrol-2-yl)acrylonitriles, and isomerisation of (Z)-2-(5-arylpyrazolyl)acrylonitriles to (E)-2-(5-arylpyrazolyl)acrylonitriles under basic conditions have been reported. (Z)-2-(1,3-Diarylpyrazolyl)acrylonitriles did not undergo isomerisation under the similar conditions. New compounds were identified on the basis of their spectral data (1H-, 13C-, 1H-1H COSY, NOESY, NOE, HMQC NMR, IR, UV and EI mass). The structures of one acrylonitrile and five of their precursor 6-arylpyran-2-ones and cyanomnethylpyrazoles were confirmed by X-ray crystallographic studies. Effects of pyrazolylacrylonitriles and their precursors on rat liver-microsomal lipid peroxidation were evaluated in vitro with a view to establish structure activity relationship and to identify a lead compound.

Highly chemo- and regioselective de-esterification has been observed in the deacetylation of peracetylated enolic forms of polyphenolic benzyl phenyl ketones by lipase from porcine pancreas (PPL) suspended in tetrahydrofuran (THF). The enzyme selectively deacetylates the enolic acetoxy over the phenolic acetoxy group(s) and continuation of the reaction resulted, in addition the regioselective deacetylation of acetoxy function para to the nuclear carbonyl group.

Regioselectivity has been observed in the deacetylation of peracetates of polyphenolic aromatic ketones by lipases from porcine pancreas (PPL) and Candida cyclindracea (CCL) suspended in organic solvents. The deacetylation of acetoxyl groups at positions para and meta to the carbonyl (ketonic) group is favoured over the one at the ortho position.