Total Synthesis and Structure–Activity Relationship Studies of the Cytotoxic Anhydrophytosphingosine Jaspine B (Pachastrissamine)

By utilizing an l-serine-derived bicyclic lactone as an advanced chiral building block, a short synthetic route to the cytotoxic marine natural product jaspine B has been developed. Targeting structure–activity relationship investigations, the synthetic route has also been utilized for the synthesis and cytotoxicity evaluation of strategically modified jaspine B analogues. In addition, a previously reported synthesis of the title natural product from our research has been reinvestigated to clarify the sterochemical assignment

A case of severe hypothyroidism presenting only with bleeding diathesis

Hypothyroidism can present with the variety of clinical features; however, bleeding manifestations as a sole presentation ofhypothyroidism is extremely rare. Hemostatic disorder may be a manifestation of several underlying etiology. Here, we reporta case of a 14 year old girl who initially presented with bleeding diathesis without any other symptoms suggestive of thyroiddysfunction but later on investigations was found to be suffering from severe hypothyroidism

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

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

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.This work was supported by NIH grant 1R01 AI50107

Reformatskii reaction on α-oxo ketene dithioacetals: synthesis of substituted and fused ethyl 2-hydroxy-6-(methylthio)benzoates, 6-(methylthio)pyran-2-ones, and 6-(methylthio)-2(1H)pyridone derivatives

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Polarized ketene dithioacetals 63 : stereoselective synthesis of α-ylidene-γ-butyrolactones

A facile method for highly stereoselective synthesis of α-arylidene (4a-4d,4f-4h and 4j) and α-ethylidene (4e,4i)-γ-butyrolactones has been developed by acid catalyzed lactonization of the corresponding α-ylidene-γ, δ-unsaturated esters 3a-aj . The required esters 3a-3j were obtained by regioselective reduction of the corresponding α-oxo- α-allyl (or substituted allyl) ketene dithioacetals 1a-1j with sodium borohydride and subsequent boron-trifluoride etherate catalyzed methanolysis of the resultant carbinol acetals 2a-j . Treatment of α-acetylketene dithioacetals 1e and 1i with methylmagnesium iodide afforded the carbinol acetals 5b and 5c respectively which under above sequence of reactions yielded the corresponding α-isopropylidene-γ-butyrolactones 7a and 7b in good yields

Interaction of Lucifer yellow with cetyltrimethyl ammonium bromide micelles and the consequent suppression of its non-radiative processes

The interaction of the fluorophore Lucifer yellow with micelles has been monitored using steady state and time resolved fluorescence techniques. Contrary to the popular belief that the fluorophore is too polar to associate with the stern layer or hydrophobic core of micelles, we have observed that it binds with the micelles of the positively charged surfactant cetyl trimethyl ammonium bromide and that such interaction causes an decrease in the rates of its non-radiative processes. This phenomenon cannot be explained solely in the light of a reduced polarity, as we have demonstrated that the photophysics of Lucifer yellow is complex and intramolecular charge transfer does not seem to be the only excited state process that is operative.© Elsevie

Polarised ketene dithioacetals. Part 32. Studies on base-catalysed rearrangements of 2-bis(methylthio)methyleneindan-1-one, 2-bis(methylthio)methylene-1-tetralone, and 3-bis(methylthio)methylene-2,3-dihydro-1-benzothiopyran-4-one

The ketene dithioacetal (7) derived from indan-1-one gave a dimeric product (8) on treatment with sodium hydride in dimethylformamide under nitrogen. The dithioacetal (15) derived from 1-tetralone on prolonged treatment with sodium hydride under identical conditions yielded the corresponding methyl β-oxodithioester (16) and the S-methyl β-oxothioester (17). Under similar conditions, the dithioacetal (28) derived from 2,3-dihydro-1-benzothiopyran-4-one gave the expected rearranged product (29) formed by a 1,3-methylthio shift. The structural assignments of the products (8), (16), (17), and (29) and the probable mechanism for the formation of (8), (16), and (17) are described