Replacement of phe(8) in substance P by tyr (Tyr(8)-SP) alters the conformation of the peptide in DMSO, water, and lipid bilayers.

The conformation of [Tyr(8)]SP (Y8SP) in dimethylsulfoxide (DMSO), water, and dipalmitoyl phosphatidylcholine (DPPC) bilayers has been investigated by two-dimensional nmr and molecular dynamics simulations. Molecular modeling of the conformation of Y8SP by incorporating nuclear Overhauser effects as distance restraints shows wide differences in its conformation in the three media. In DMSO, the main structural features are gamma-bends along with a nonspecific bend around Gln(6)-Phe(7)-Tyr(8). The random coil structure seen in water is transformed into a beta-turn around the segment Gln(5)-Gln(6)-Phe(7)-Tyr(8) when Y8SP is incorporated into DPPC bilayers. The lower biological activity of Y8SP compared to the native peptide (SP) has been attributed to the absence of any helix like structure at the central residues, a feature shown to be an important prerequisite for SP and SP agonists to bind to the neurokinin 1 tachykinin receptor.     

Testing Equality of Means and Simultaneous Confidence Intervals in Repeated Measures with Missing Data

In this paper, repeated measures with intraclass correlation model is considered when the observations are missing at random. An exact test for the equality of the mean components and simultaneous confidence intervals (Scheffé and Bonferroni inequality types) are given for linear contrasts of the mean components when the missing observations are of a monotone type. When the missing observations are not of the monotone type, the maximum likelihood estimates are obtained numerically by iterative methods given in Srivastava and Carter (1986). These estimators are then used to obtain asymptotic tests and confidence intervals for the equality of mean components and linear contrasts, respectively. An example is given to illustrate the method.     

Withanolide A series steroidal lactones from Eucalyptus globulus bark

A new steroidal lactone of the Withanolide A series has been isolated from the supercritical fluid extract of Eucalyptus globulus L. (bark) as a major component (I) along with a known structurally similar steroidal lactone as minor component (II). The structural identification of the new lactone was accomplished by different spectroscopic techniques viz. ¹H and ¹³C NMR, etc. The relative stereochemistry was unequivocally determined from the X-ray crystallography.     

Diaryloxy methano phenanthrenes: a new class of antituberculosis agents

A new series of diaryloxy methano phenanthrenes were prepared through tertiary-aminoalkylations of [(methoxy-phenyl)-phenanthren-9-yl-methyl]-phenols obtained from Friedel-Crafts alkylations on (methoxy-phenyl)-phenanthren-9-yl-methanols. These series of compounds were evaluated against Mycobacterium tuberculosis H37Rv and showed the desired activity in the range of 6.25 microg/mL in vitro. One of the compound 12j protects the mice from the challenge of M. tuberculosis in vivo, as 30% of the mice were survived at treatment of 50 mg/kg body weight.     

Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II

Strong CD4(+) and CD8(+) T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4(+) and CD8(+) T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p24 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8(+) T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.     

Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine

The marine sponge metabolite hymenialdisine is a potent inhibitor of a variety of kinases including MEK-1, GSK-3 beta, and CK1. In addition, hymenialdisine and debromohymenialdisine exhibit inhibition of the G(2) cell cycle checkpoint at micromolar concentrations. We report herein the potent inhibition of cell cycle kinase Chk2 by the indolic-hymenialdisine indoloazepine 1 (IC(50)=8 nM).     

Synthesis and cytotoxic activity of 3-O-acyl/3-hydrazine /2-bromo/20,29-dibromo betulinic acid derivatives

A series of 3-O-acyl, 3-hydrazine, 2-bromo, and 20,29-dibromo betulinic acid derivatives (1-27) have been synthesized and screened for in vitro cytotoxic activity on human cancer cell lines MOLT-4, JurkatE6.1, CEM.CM3, BRISTOL8, U937, DU145, PA-1, A549, and L132. A number of compounds have shown ED(50)<1 microg/mL against the cancer cell lines tested and have shown better cytotoxicity than betulinic acid. Compounds 13, 19, 20, 23, and 27 were the best derivatives and were selected as lead molecules for further development. The structure-activity relationship has been described.