Efficient and scalable synthesis of thiazole fused benzazepine as a D2 partial agonist

The development of an efficient and scalable synthetic route to prepare the selective D2 partial agonist (1) is described here. Regioselective nitration of tetrahydrobenzazepine 2, followed by reductive amination, hydrogenation, and oxidative cyclization afforded 1 in good yield, without the need of column chromatography.     

The absolute configuration of the glutarimide antibiotics streptimiodone and 9-methylstreptimidone.

Chemical and spectroscopic studies have established the absolute configuration of the glutarimide antibiotics streptimidone and 9-methylstreptimidone, which can now be represented as the (2R,5S,6E)-structures 14 and 15 , respectively.     

Evodiamine functions as an agonist for the vanilloid receptor TRPV1

Evodiamine, a quinozole alkaloid constituent of Evodia rutaecarpa, has been reported previously to induce several responses comparable to capsaicin in animal systems. Here, we characterize evodiamine as an agonist for rat TRPV1 expressed heterologously in CHO cells. Evodiamine bound to rat TRPV1 with a Ki of 5.95 +/- 0.87 microM, as measured by inhibition of [3H] RTX binding (capsaicin, Ki = 1.8 +/- 0.3 microM). Evodiamine was a full agonist for induction of 45Ca2+ uptake, with an EC50 of 856 +/- 43 nM (capsaicin, EC50 = 45 +/- 4 nM) and was competitively antagonized by capsazepine, as revealed by a Schild plot. The pattern of cellular response, as determined by calcium imaging, was similar to that with capsaicin and yielded an EC(50) of 1.03 +/- 0.21 [micro sign]M. Molecular modeling suggested a consistent pattern of overlap between evodiamine and TRPV1 agonists. We conclude that evodiamine represents a novel class of agonists for rat TRPV1, albeit 3-19-fold less potent than capsaicin, and thus represents a new potential class of lead molecules for drug development.     

Synthesis and absolute configuration of natural 8-hydroxyl-9-angeloyloxythymol

8-Hydroxyl-9-angeloyloxythymol, isolated from Eupatorium fortuneri Turcz, was synthesized for the first time. The synthesis was achieved through a seven-step route, using m-cresol as the starting material and Sharpless asymmetric dihydroxylation to install the quaternary stereogenic center. The enantio-enriched synthetic sample showed spectroscopic data consistent with those of the natural product and thus confirmed the gross structure assigned previously. By comparing the sign for optical rotations of the synthetic and the natural samples, the absolute configuration for the natural product was also assigned.     

Lifetimes of partial charge transfer exciplexes of 9-cyanophenanthrene and 9-cyanoanthracene

The fluorescence decays of several exciplexes with partial charge transfer have been investigated in solvents of various polarity. The measured lifetimes are found to be in reasonable agreement with the activation enthalpy and entropy of exciplex decay obtained earlier from the temperature dependence of the exciplex emission quantum yields. For exciplexes with 9-cyanophenanthrene substantial contribution of the higher local excited state into the exciplex electronic structure is found and borrowed intensity effect enhances the exciplex emission rate constants.     

Resolvent technique and Padé approximants in configuration interaction calculations

A perturbation approach based on resolvent technique and Padé approximants is proposed. The eigenvalue of interest is part of a solution of two nonlinear algebraic equations. The nonlinear equations are arrived at by considering two different expression of the expectation value of the resolvent of an outer projection of the Hamiltonian. The first expression is based on the spectral resolution of the resolvent, and the second one is obtained by a power series expansion analogous to that applied in the derivation of the energy expression in the Brillouin–Wigner perturbation theory. The truncated power series is extrapolated by Padé approximants of type II. The method is tested on a CI calculation of the energy of the lowest ¹Σ state of the B₂ molecule.     

Crystal structure and configuration revision of 9-hydroxy-7,8-dehydro-sarcotrocheliol and sarcotrocheliol

Herein, we report the isolation and stereo-structure of rare pyrane-based cembranoid diterpenes, 9-hydroxy-7,8-dehydro-sarcotrocheliol (1) and sarcotrocheliol (2), from Sarcophyton trocheliophorum collected from Red Sea. Absolute configurations of both compounds were revised based on single crystal X-ray analyses.     

Monosaccharides as internal probes for the determination of the absolute configuration of 2-butanol

D-Glucose, D-mannose and L-rhamnose were reacted with a racemic mixture of 2-butanol, and the resulting alpha-glycosides were analyzed by 1H NMR with COSY and NOESY experiments. Conformational analysis of alpha-glycosidic bonds performed with molecular modeling and appropriate heteronuclear long-range coupling measurements and combined with analysis of dipolar couplings observed in NOESY spectra allowed the assignment of absolute configuration in the aglycones of elucidated alpha-glycosides.     

13C NMR as a general tool for the assignment of absolute configuration

(13)C NMR, alone or in combination with (1)H NMR, allows the assignment of the absolute configuration of chiral alcohols, amines, carboxylic acids, thiols, cyanohydrins, sec,sec-diols and sec,sec-aminoalcohols, derivatized with appropriate chiral auxiliaries. This extends the assignment possibilities of NMR to fully deuterated and to nonproton containing compounds.     

Structure reassignment and absolute configuration of 9-epi-presilphiperfolan-1-ol

Reevaluation of ¹³C NMR data in combination with X-ray diffraction and VCD studies led us to reassign the structure of (−)-epi-presilphiperfolan-1-ol (1), isolated from Anemia tomentosavar.anthriscifolia, to (−)-9-epi-presilphiperfolan-1-ol (2) and to establish its absolute configuration as 1S,4S,7R,8R,9S.     

Immunoaffinity column as sample cleanup method for determination of the beta-adrenergic agonist ractopamine and its metabolites

A monoclonal antibody-based immunoaffinity column (RAC-IAC) was developed as a cleanup method for the determination of ractopamine and ractopamine glucuronides. [14C]Ractopamine (5 microg) and [14C]ractopamine glucuronides (5 microg) were fortified into 10 mL cattle urine, and loaded onto an RAC-IAC (5 mg IgG/mL) column. The column was washed and the bound analytes were eluted. In the initial loading and washing, 22% of the radioactivity was washed off and the subsequent elution step recovered 78%. A blank column prepared from nonspecific IgG retained <10% of the radioactivity. The RAC-IACs were damaged by high methanol concentrations, preventing reuse. Elution of the analytes with 50mM glycine buffer, pH 2.8, prevented damage, and the columns could be reused at least 20 times with no change in performance. They were stored >3 months in phosphate-buffered saline with 0.02% sodium azide at 4 degrees C. The method was used with fortified cattle muscle, liver, and kidney samples with recoveries of 82.1+/-7.6, 87.8+/-1.9, and 92.5+/-0.4%, respectively (n = 3). Similar studies with sheep muscle, liver, and kidney samples gave recoveries of 91.8+/-0.2, 91.7+/-0.3, and 92.3+/-0.3, respectively (n = 3). Liver and kidney samples were diluted to prevent column plugging, but all of the eluants were suitable for liquid chromatography analysis. This IAC is a selective, efficient, and economical cleanup method in a variety of matrixes for ractopamine determination.     

Influence of the dipeptide linker configuration on the activity of PSMA ligands

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Spatial arrangement of rhodopsin in the disk membrane as studied by enzymatic labeling.

Abstract—Intact disks prepared from fresh bovine retinas were phosphorylated with γ-[³²P]-ATP and highly purified rhodopsin kinase. After regeneration. the visual pigment was cxtracted and purified on ECTEOLA-cellulose. The purified pigment contained [³²P]-radioactivity. When intact disks were frozen and thawed. the membrane was inverted and became capable of binding concanavalin A. The inversion process could be followed by measuring the entrapment by the disk of [³H]-inulin. the impermeable polysaccharide. When the inverted disks were incubated with UDP-[³H]-galactose and galactosyltransferase and rhodopsin was extracted and purified. [³H]-gahctose was incorporated into the pigment. From these results we conclude that rhodopsin is a transmembrane protein with its carbohydrate moiety on the internal (intradiscal) surface and its phosphorylation sites on the external (interdiscal) surface     

Lipid length and iso-branching of trehalose diesters influences Mincle agonist activity

We report on the efficient synthesis of linear trehalose diesters (TDEs) and iso-branched TDEs (maradolipids or iso-TDEs) and their ability to activate bone marrow-derived macrophages (BMDMs) as determined by cytokine (IL-1β, IL-12, IL-6, IL-10) and chemokine (MIP-2) production. Both classes of TDEs were found to activate BMDMs in a Mincle-dependent manner, with longer-chain (≥C18) lipids leading to a robust inflammatory response. On the whole, the iso-branched TDEs led to greater cytokine production and a faster immune response when compared to their linear counterparts. Moreover, C12-TDE and iso-C12-TDE elicited the production of MIP-2 by BMDMs, thereby providing the first example of TDEs with a chain length of ≤ C12 leading to a Mincle-dependent immune response and one that is less inflammatory in nature.