Apurba Datta

Structure−Activity Relationships in Toll-like Receptor-2 Agonistic Diacylthioglycerol Lipopeptides

The N-termini of bacterial lipoproteins are acylated with a (S)-(2,3-bisacyloxypropyl)cysteinyl residue. Lipopeptides derived from lipoproteins activate innate immune responses by engaging Toll-like receptor 2 (TLR2) and are highly immunostimulatory and yet without apparent toxicity in animal models. The lipopeptides may therefore be useful as potential immunotherapeutic agents. Previous structure-activity relationships in such lipopeptides have largely been obtained using murine cells, and it is now clear that significant species-specific differences exist between human and murine TLR responses. We have examined in detail the role of the highly conserved Cys residue as well as the geometry and stereochemistry of the Cys-Ser dipeptide unit. (R)-Diacylthioglycerol analogues are maximally active in reporter gene assays using human TLR2. The Cys-Ser dipeptide unit represents the minimal part-structure, but its stereochemistry was found not to be a critical determinant of activity. The thioether bridge between the diacyl and dipeptide units is crucial, and replacement by an oxoether bridge results in a dramatic decrease in activity.

Stereoselective total synthesis of (−)-deoxoprosophylline

Abstract An efficient synthesis of the prosopis alkaloid (−)-deoxoprosophylline has been developed, utilizing the easily available amino acid l -serine as a chiral pool starting material.

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

ABSTRACT A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8 or C9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.

Stereoselective synthesis of (−)-N-Boc-statine and (−)-N-Boc-Norstatine☆

Abstract An efficient synthesis of optically pure N-Boc-statine ( 9 ) and N-Boc-norstatine ( 11 ) has been developed via a syn selective Grignard reaction of N-Boc-leucinal with allyl- or vinylmagnesium bromide.

STUDIES TOWARDS THE TOTAL SYNTHESES OF SOLANDELACTONES : STEREOSELECTIVE SYNTHESIS OF THE CYCLOPROPANE : LACTONE SEGMENT

Abstract A concise stereoselective route to the right hand fragment of solandelactones have been developed, where initial synthesis of the key bifunctional cyclopropane intermediate 2 was followed by construction of the eight-membered lactone ring in good overall yield.

Stereoselective synthesis of the antifungal antibiotic (+)-preussin

Abstract A concise total synthesis of enantiopure (+)-preussin (1) from L-phenylalanine (3) is described. The key steps involve i) syn-selective formation of the 1, 2-amino alcohol fragment2, via chelation controlled addition of allylmagnesium bromide toN-Boc-phenylalaninal, and ii) L-selectride® mediated stereoselective reduction of the ketone8 to the alcohol derivative9 with the required stereochemistry for final cyclization. A concise total synthesis of natural (+) preussin has been developed starting from readily available L-phenylalanine. Download : Download full-size image

Selective C-2 and C-4 deacylation and acylation of taxol: The first synthesis of a C-4 substituted taxol analogue

Hydrolytic procedures for selective 2-debenzoylation and 2,4-dideacylation of 2′-O-tert-butyldimethylsilyl-7-O-(triethylsilyl)taxol are reported. The first synthesis and biological evaluation of a 4-substituted analogue, 4-deacetyl-4-isobutanoyltaxol, is presented. The chemistry described in this letter is suitable for the facile synthesis of taxol congeners modified at C-2 and/or C-4.

Stereoselective total synthesis of (+)-azimic acid

Abstract An efficient synthesis of enantiopure (+)-azimic acid has been developed, utilizing easily available amino acid L-alanine as a chiral pool starting material.

Bound To Shock: Protection from Lethal Endotoxemic Shock by a Novel, Nontoxic, Alkylpolyamine Lipopolysaccharide Sequestrant

ABSTRACT Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N1,mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.

Stereoselective synthesis of (2S, 3R)-N-Boc-3-hydroxyglutamic acid☆

Abstract An efficient method has been developed for the stereoselective synthesis of the title compound, a non-proteinogenic amino acid of structural and biological importance.