Diganta Sarma

A novel green protocol for ligand free Suzuki–Miyaura cross-coupling reactions in WEB at room temperature

A highly efficient green protocol for palladium acetate-catalysed ligand-free Suzuki–Miyaura cross-coupling reactions in neat ‘water extract of banana (WEB)’ was developed. This method offers a mild, efficient and highly economical alternative to the existing protocols since the reaction proceeds in WEB at room temperature in air at very short reaction times (5–90 min) under ‘ligand/external base/external promoter/organic medium’ free conditions.

Significance of interactions of BACE1–Arg235 with its ligands and design of BACE1 inhibitors with P2 pyridine scaffold

Recently, we reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Because these inhibitors contained some natural amino acids, we would need to improve their enzymatic stability in vivo and permeability across the blood-brain barrier, so that they become practically useful. Subsequently, non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold, 2,6-pyridenedicarboxylic, chelidamic or chelidonic moiety, at the P(2) position were reported. These inhibitors were designed based on the conformer of docked inhibitor in BACE1. In this study, we discuss the role and significance of interactions between Arg235 of BACE1 and its inhibitor in BACE1 inhibitory mechanism. Moreover, we designed more potent small-sized BACE1 inhibitors with a 2,6-pyridinedicarboxylic scaffold at the P(2) position, that were optimized for the interactions with Arg235 of BACE1.

Protein Targets of Thioacetamide Metabolites in Rat Hepatocytes

Thioacetamide (TA) has long been known as a hepatotoxicant whose bioactivation requires S-oxidation to thioacetamide S-oxide (TASO) and then to the very reactive S,S-dioxide (TASO2). The latter can tautomerize to form acylating species capable of covalently modifying cellular nucleophiles including phosphatidylethanolamine (PE) lipids and protein lysine side chains. Isolated hepatocytes efficiently oxidize TA to TASO but experience little covalent binding or cytotoxicity because TA is a very potent inhibitor of the oxidation of TASO to TASO2. However, hepatocytes treated with TASO show extensive covalent binding to both lipids and proteins accompanied by extensive cytotoxicity. In this work, we treated rat hepatocytes with [(14)C]-TASO and submitted the mitochondrial, microsomal, and cytosolic fractions to 2DGE, which revealed a total of 321 radioactive protein spots. To facilitate the identification of target proteins and adducted peptides, we also treated cells with a mixture of TASO/[(13)C2D3]-TASO. Using a combination of 1DGE- and 2DGE-based proteomic approaches, we identified 187 modified peptides (174 acetylated, 50 acetimidoylated, and 37 in both forms) from a total of 88 nonredundant target proteins. Among the latter, 57 are also known targets of at least one other hepatotoxin. The formation of both amide- and amidine-type adducts to protein lysine side chains is in contrast to the exclusive formation of amidine-type adducts with PE phospholipids. Thiobenzamide (TB) undergoes the same two-step oxidative bioactivation as TA, and it also gives rise to both amide and amidine adducts on protein lysine side chains but only amidine adducts to PE lipids. Despite their similarity in functional group chemical reactivity, only 38 of 62 known TB target proteins are found among the 88 known targets of TASO. The potential roles of protein modification by TASO in triggering cytotoxicity are discussed in terms of enzyme inhibition, protein folding, and chaperone function, and the emerging role of protein acetylation in intracellular signaling and the regulation of biochemical pathways.

New developments for the design, synthesis and biological evaluation of potent SARS-CoV 3CLpro inhibitors

Abstract A series of trifluoromethyl, benzothiazolyl or thiazolyl ketone-containing peptidic compounds as SARS-CoV 3CL protease inhibitors were developed and their potency was evaluated by in vitro protease inhibitory assays. Three candidates had encouraging results for the development of new anti-SARS compounds.

Magnetically recoverable chitosan-stabilised copper–iron oxide nanocomposite material as an efficient heterogeneous catalyst for azide–alkyne cycloaddition reactions

Chitosan-stabilised copper–iron oxide nanocomposite material is found to be a very efficient recyclable/reusable heterogeneous catalyst for azide–alkyne cycloaddition reaction under mild conditions. The as-synthesized nanocomposite material is magnetically recoverable and reusable for a minimum of four cycles without significant loss in its catalytic activity. The catalytic system is found to be highly useful for the regioselective synthesis of a wide range of 1,2,3-triazoles from various azides and alkynes.

Pd(OAc)2 and (DHQD)2PHAL as a simple, efficient and recyclable/reusable catalyst system for Suzuki–Miyaura cross-coupling reactions in H2O at room temperature

Suzuki–Miyaura cross-coupling reaction catalyzed by Pd(OAc)2–(DHQD)2PHAL is a very simple, mild and efficient protocol for the synthesis of biaryls/heterobiaryls in neat H2O at room temperature. The catalyst system is recyclable/reusable and can be employed in several consecutive runs without significant loss in catalytic activity.

(DHQD)2PHAL ligand-accelerated Cu-catalyzed azide–alkyne cycloaddition reactions in water at room temperature

Herein, we have described, a ‘Click Chemistry’ protocol for the rapid synthesis of 1,2,3-triazoles in water. (DHQD)2PHAL has been found to be an excellent accelerating ligand for the copper(I)-catalyzed azide–alkyne cycloaddition reaction under air. The procedure is simple, efficient, environmentally-friendly and the products were isolated in excellent yields with high purity.

Covalent modification of lipids and proteins in rat hepatocytes and in vitro by thioacetamide metabolites.

Thioacetamide (TA) is a well-known hepatotoxin in rats. Acute doses cause centrilobular necrosis and hyperbilirubinemia while chronic administration leads to biliary hyperplasia and cholangiocarcinoma. Its acute toxicity requires its oxidation to a stable S-oxide (TASO) that is oxidized further to a highly reactive S,S-dioxide (TASO(2)). To explore possible parallels among the metabolism, covalent binding, and toxicity of TA and thiobenzamide (TB), we exposed freshly isolated rat hepatocytes to [(14)C]-TASO or [(13)C(2)D(3)]-TASO. TLC analysis of the cellular lipids showed a single major spot of radioactivity that mass spectral analysis showed to consist of N-acetimidoyl PE lipids having the same side chain composition as the PE fraction from untreated cells; no carbons or hydrogens from TASO were incorporated into the fatty acyl chains. Many cellular proteins contained N-acetyl- or N-acetimidoyl lysine residues in a 3:1 ratio (details to be reported separately). We also oxidized TASO with hydrogen peroxide in the presence of dipalmitoyl phosphatidylenthanolamine (DPPE) or lysozyme. Lysozyme was covalently modified at five of its six lysine side chains; only acetamide-type adducts were formed. DPPE in liposomes also gave only amide-type adducts, even when the reaction was carried out in tetrahydrofuran with only 10% water added. The exclusive formation of N-acetimidoyl PE in hepatocytes means that the concentration or activity of water must be extremely low in the region where TASO(2) is formed, whereas at least some of the TASO(2) can hydrolyze to acetylsulfinic acid before it reacts with cellular proteins. The requirement for two sequential oxidations to produce a reactive metabolite is unusual, but it is even more unusual that a reactive metabolite would react with water to form a new compound that retains a high degree of chemical reactivity toward biological nucleophiles. The possible contribution of lipid modification to the hepatotoxicity of TA/TASO remains to be determined.

Structure–activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P2 position

We have previously reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. While these inhibitors exhibited potent activities in enzymatic and cellular assays (KMI-429 in particular inhibited Aβ production in vivo), these inhibitors contained some natural amino acids that seemed to be required to improve enzymatic stability in vivo and permeability across the blood-brain barrier, so as to be practical drug. Recently, we synthesized non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold at the P2 position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety.

‘On-water’ organic synthesis: a green, highly efficient, low cost and reusable catalyst system for biaryl synthesis under aerobic conditions at room temperature

A simple, greener, efficient, low cost and mild protocol has been developed for sucrose assisted palladium-catalyzed Suzuki reactions in water at room temperature under aerobic conditions. The results demonstrate that the sucrose played a crucial role making this protocol highly efficient. The PdCl2/sucrose/K2CO3/H2O system showed superb catalytic activity towards the Suzuki reaction of a wide range of aryl/heteroaryl halides with different substituted phenylboronic acids. This method offers an attractive alternative to the existing protocols since the reaction proceeds in aqueous media at room temperature with operational simplicity, shorter reaction time, cost-effectiveness and provides the products in high yields. The catalytic system is highly recyclable, allowing the reuse of the palladium catalyst in subsequent catalytic runs without significant loss of activity.