Binding of high-mannose-type oligosaccharides and synthetic oligomannose clusters to human antibody 2G12: implications for HIV-1 vaccine design

Human antibody 2G12 broadly neutralizes human immunodeficiency virus type 1 (HIV-1) isolates and shows protective activity against viral challenge in animal models. Previous mutational analysis suggested that 2G12 recognized a novel cluster of high-mannose type oligosaccharides on HIV-1 gp120. To explore the carbohydrate antigen for HIV-1 vaccine design, we have studied the binding of 2G12 to an array of HIV-1 high-mannose type oligosaccharides by competitive ELISAs and found that Man9GlcNAc is 210- and 74-fold more effective than Man5GlcNAc and Man6GlcNAc in binding to 2G12. The results establish that the larger high-mannose oligosaccharide on HIV-1 is the favorable subunit for 2G12 recognition. To mimic the putative epitope of 2G12, we have created scaffold-based multivalent Man9 clusters and found that the galactose-scaffolded bi-, tri-, and tetra-valent Man9 clusters are 7-, 22-, and 73-fold more effective in binding to 2G12 than the monomeric Man9GlcNAc2Asn. The experimental data shed light on further structural optimization of epitope mimics for developing a carbohydrate-based HIV-1 vaccine.     

Pyrrole studies part 41. Reactivity of 3,4-diformyl-2,5-dimethylpyrrole with diaminoalkanes. An unusual formation of 2-azafulvenes

3,4-Diformyl-2,5-dimethylpyrrole (1) reacts with ,ω-diamino-alkanes, NH₂(CH₂)_nNH₂t' to form either the potentially tautomeric 2:2 macrocyclic adduct (7a) (8), when N = 2, or the potentially tautomeric 1:1 bicyclic adduct (18) (19), when N = 4, 5, 6, and 12. ¹H and ¹³C N.m.r. spectral data indicate that the 2-azafulvene structures predominate for both types of cycloadducts. Only polymeric material was obtained when N = 3.     

Heterocyclic inflammation inhibitors

Non steroidal anti-inflammatory drugs are the most widely used medicines for relief of pain. These drugs have some side effects, particularly toxicity in the gastrointestinal tract and kidneys. Various approaches have been used for obtaining safer anti-inflammatory drugs. In this review we have summarized the recent developments in the following areas; (i) mode of action of NSAIDs (ii) Role of COX-1 & COX-2 in inflammation, (iii) Different approaches used to improve gastric tolerance i.e. chemical manipulation, formulation & co-administration, development of non specific (COX-1 & COX-2 inhibitors) and specific (COX-2 inhibitors) inflammation inhibitors, and development of inflammation inhibitors having a mode of action other than COX-1 & COX-2 inhibition. We have also focused on the safety of COX-2 inhibitors and the synthesis of heterocyclic compounds and their role as inflammation inhibitors.     

Fe-exchanged montmorillonite K10--the first heterogeneous catalyst for acylation of sulfonamides with carboxylic acid anhydrides

Fe-exchanged montmorillonite K10 catalyzes a highly efficient reaction between sterically and electronically diverse sulfonamides and carboxylic acid anhydrides to furnish N-acylsulfonamides in excellent yield and high selectivity. The catalyst can also be reused several times.     

Stereodivergent total asymmetric synthesis of polyhydroxylated pyrrolidines via tandem allylic epoxidation and intramolecular cyclization reactions

Epoxidation of the allylic alcohols 10 and 11 using the VO(acac)₂/t-BuOOH system followed by an intramolecular 5-exo cyclization of the resulting δ-epoxycarbamates 12, 13, 18, and 19 has been shown to provide a general and efficient solution for the asymmetric synthesis of polyhydroxy pyrrolidines. The requisite vicinal amino alcohol functionality was enantio-/regio-selectively installed by the Os-catalyzed asymmetric aminohydroxylation reaction of the designed achiral olefin 6.     

Studies in oxidation-reduction reactions: Oxidation with chloramine-b indirect determinations

Chloramine-B has been used as an oxidizing agent in hydrochloric acid medium for the indirect volumetric estimations of hydrogen peroxide, lead dioxide, manganese dioxide, selenium dioxide, sodium formate, sodium sulphide, sodium metavanadate, potassium iodate and copper sulphate using iodine monochloride as a catalyst and pre-oxidiser. Chloroform is used as an indicator. It is coloured pink owing to the liberation of iodine during the titration and becomes light pale yellow at the end-point because of the formation of iodine monochloride.     

Sodium meta-vanadate as volumetric reagent : Iodine monochloride method (Indirect determinatios)

Sodium meta-vanadate has been used as an oxidizing agent in hydrochloric acid medium for the indirect volumetric determination of hydrogen peroxide, lead dioxide, manganese dioxide, selenium dioxide, potassium persulphate, copper sulphate, sodium formate and sodium sulphide using iodine monochloride as a catalyst, pre-oxidizer and an indicator. Chloroform is coloured pink owing to the liberation of iodine during the titration and becomes light pale yellow at the end-point owing to the formation of iodine monochloride.     

d-xylose transport by Candida succiphila and Kluyveromyces marxianus

The kinetics and regulation of d-xylose uptake were investigated in the efficient pentose fermentor Candida succiphila, and in Kluyveromyces marxianus, which assimilate but do not ferment pentose sugars. Active high-affinity (K _m ∼ 3.8 mM; V _max ∼ 15 nmol/[mg·min]) and putative facilitated diffusion low-affinity (K _m ∼ 140 mM; V _max ∼ 130 nmol/[mg·min]) transport activities were found in C. succiphila grown, respectively, on xylose or glucose. K. marxianus showed facilitated diffusion low-affinity (K _m ∼ 103 mM; V _max ∼ 190 nmol/[mg·min]) transport activity when grown on xylose under microaerobic conditions, and both a low-affinity and an active high-affinity (K _m ∼ 0.2 mM; V _max ∼ 10 nmol/[mg·min]) transport activity when grown on xylose under fully aerobic conditions.     

Probing metabolic alterations in breast cancer in response to molecular inhibitors with Raman spectroscopy and validated with mass spectrometry

Rapid and accurate response to targeted therapies is critical to differentiate tumors that are resistant to treatment early in the regimen. In this work, we demonstrate a rapid, noninvasive, and label-free approach to evaluate treatment response to molecular inhibitors in breast cancer (BC) cells with Raman spectroscopy (RS). Metabolic reprogramming in BC was probed with RS and multivariate analysis was applied to classify the cells into responsive or nonresponsive groups as a function of drug dosage, drug type, and cell type. Metabolites identified with RS were then validated with mass spectrometry (MS). We treated triple-negative BC cells with Trametinib, an inhibitor of the extracellular-signal-regulated kinase (ERK) pathway. Changes measured with both RS and MS corresponding to membrane phospholipids, amino acids, lipids and fatty acids indicated that these BC cells were responsive to treatment. Comparatively, minimal metabolic changes were observed post-treatment with Alpelisib, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, indicating treatment resistance. These findings were corroborated with cell viability assay and immunoblotting. We also showed estrogen receptor-positive MCF-7 cells were nonresponsive to Trametinib with minimal metabolic and viability changes. Our findings support that oncometabolites identified with RS will ultimately enable rapid drug screening in patients ensuring patients receive the most effective treatment at the earliest time point.

Rapid and accurate response to targeted therapies is critical to differentiate tumors that are resistant to treatment early in the regimen.     

Synthesis of 1-(5-phenyl-2H-tetrazol-2-ylacetyl)-4-substituted thiosemicarbazides as possible antiinflammatory agents

A series of 1-(5-phenyl-2H-tetrazol-2-ylacetyl)-4-substituted thiosemicarbazids were prepared as possible antiinflammatory agents. Their antiproteolytic activity was reported.