NMR structural characterization of cecropin A(1-8) - magainin 2(1-12) and cecropin A (1-8) - melittin (1-12) hybrid peptides.

In order to elucidate the structure-antibiotic activity relationships of the peptides, the three-dimensional structures of two hybrid peptides, CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) in trifluoroethanol-containing aqueous solution were investigated by NMR spectroscopy. Both CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) have strong antibacterial activity but only CA(1-8) - ME(1-12) has hemolytic activity against human erythrocytes. CA(1-8) - MA(1-12) has a hydrophobic 310-helix of only two turns combined with one short helix in the N-terminus with a flexible hinge section in between. CA(1-8) - MA(1-12) has a severely bent structure in the middle of the peptide. These structural features as well as the low hydrophobicity of CA(1-8) - MA(1-12) seem to be crucial for the selective lysis against the membrane of prokaryotic cells. CA(1-8) - ME(1-12) has an alpha-helical structure of about three turns in the melittin domain and a flexible structure with one turn in the cecropin domain connected with a flexible hinge section in between, and these might be the structural features required for membrane disruption against prokaryotic and eukaryotic cells. The central hinge region (Gly9-Ile10-Gly11) in an amphipathic antibacterial peptide is considered to play an important role in providing the conformational flexibility required for ion channel formation of the C-terminal hydrophobic alpha-helix on cell membrane.     

1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea: A novel cyclophilin A allosteric activator

Cyclophilin A (CypA) plays an important role in many physiology processes and its overexpression has been involved in many diseases including immune disease, viral infection, neuro-degenerative disease, and cancer. However, the actual role of CypA in the diseases is still far from clear, and a complete understanding of CypA is necessary in order to direct more specific and effective therapeutic strategies. Based on the screening of our in-house library through the isomer-specific proteolysis method, we find a CypA activator (1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea), compound 1a, which can increase CypA’s PPIase activity and give allosteric behavior. The binding affinity of compound 1a to CypA has been confirmed by Fortebio’s Octet RED system and the increased phosphorylation of ERK in H446 cells is observed by treatment with both compound 1a and CsA. In order to further evaluate the binding mode between the activator and CypA, the allosteric binding site and allosteric mechanism of CypA are investigated by molecular dynamics (MD) simulations in combination with mutagenesis experiments. The results show that the allosteric binding site of CypA is 7 Å away from its catalytic site and is composed of Cys52, His70, His54, Lys151, Thr152 and Lys155. Compound 1a binds to the allosteric site of CypA, stabilizing the active conformation of catalytic residues, and finally promotes the catalytic efficiency of CypA. We believe our finding of the CypA allosteric activator will be used as an effective chemical tool for further studies of CypA mechanisms in diseases.     

Four great coccidioidomycologists: William Ophuls (1871-1933), Myrnie Gifford (1892-1966), and Charles Edward Smith (1904-1967) and William A. Winn (1903-1967)

The careers of William Ophuls (1871-1933), Myrnie Gifford (1892-1966), Charles Edward Smith (1904-1967) and William A. Winn (1903-1967) are briefly reviewed, with emphasis on their contributions to knowledge of Coccidioides and coccidioidomycosis. All were students with broad interests, and all were quite willing to suggest new concepts and classifications to replace those of their predecessors.     

Epacris crassifolia R. Br. (Epacridaceae) - A Reappraisal

Epacris crassifolia R. Br.s. lat.,as represented in collectionsat G, BM, HO, NSW, MEL, CBG and CAN, has been redefined as threeseparate species. The common lax, prostrate form includes twosubspecies,E. crassifoliassp.crassifoliaR. Br.stat. nov. andE.crassifoliassp.macrofloraCrowden et Menaduessp. nov.separatedon floral morphology.E. pinoideaCrowden et Menaduesp. nov.andE.lithophilaCrowden et Menaduesp. nov.are erect and woody, beingdistinguished on leaf and floral characters. Epacridaceae; Epacris crassifolia ; Epacris lithophila; Epacris pinoidea; new species     

Stage specific embryonic carbohydrate surface antigens of primordial germ cells in mouse embryos: FAL (S.S.E.A.-1) and globoside (S.S.E.A.-3)

Immunodetections of carbohydrate surface antigens were carried out for SSEA-1 and SSEA-3. Using alkaline phosphatase for the detection of primordial germ cells these surface antigens were detected at the cell membrane and the cytoplasm of the germ cells at E 10.     

A convenient synthesis of a novel nucleoside analogue: 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone

The nucleoside analogue 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone (5) was prepared from the corresponding 4-methyl pyrimidinone nucleoside by means of the Vilsmeier reaction. The unprotected nucleoside can be phosphorylated directly with phosphorus oxychloride in triethyl phosphate.     

Formation of (4R)- and (4S)-4-hydroxyochratoxin A and 10-hydroxyochratoxin A from Ochratoxin A by rabbit liver microsomes.

Three metabolites were formed from ochratoxin A in the presence of rabbit liver microsomal fractions and NADPH. They were isolated by extraction, thin-layer chromatography, and high-pressure liquid chromatography. Two of them were identified as (4R)- and (4S)-4-hydroxyochratoxin A. It is suggested on the basis of mass and nuclear magnetic resonance spectroscopy that the third metabolite is 10-hydroxyochratoxin A. The formation of the metabolites was inhibited by carbon monoxide and metyrapone and was stimulated when microsomes from phenobarbital-treated animals were used. The results suggest that cytochrome P-450 catalyzes the formation of these metabolites.     

Methylenecyclopropane analogues of nucleosides: synthesis, absolute configuration, and enantioselectivity of antiviral effect of (R)-(-)- and (S)-(+)-synadenol.

Synthesis, absolute configuration and antiviral activity of enantiomeric antiviral agents (R)-(-)- and (S)-(+)-synadenol (2 and 3a) are described.     

3,5-Bis(Phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones: A Novel Group of Cytotoxic Agents

A series of novel 3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones 3 have been synthesized which displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. In contrast, the related N-arylmaleamic acids 4 possessed little or no cytotoxicity in these four screens. Molecular modeling revealed certain interplanar and bond angles and interatomic distances which were perceived to contribute to the observed bioactivity as well as providing suggestions for future structural modifications of the piperidones 3. Evaluation of representative compounds in series 3 and 4 on the activity of human N-myristoyltransferase revealed that, at the maximum concentration utilized, namely 250?μM, only weak inhibiting properties were displayed by some of the compounds in series 4. Various members of series 3 and 4 were well tolerated in mice.