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Biomedical subjects

K Burgess

Publications and source records attributed to K Burgess.

53 records · Page 3Linked to original sources
PubMed1994

Evaluation of "norpeptides" as potential inhibitors of HIV-proteases.

Peptide mimics of substrates for HIV-proteases were prepared. These "norpeptides" are identical to a fragment of the HIV-polyprotein except that a crucial scissile bond was deleted, and an alpha,beta-disubstituted amino acid spans the P1 and P1 site. Thus all four stereoisomers of Leu psi[]Ala (i.e. H2NCH(CH2iPr)CH(Me)CO2H, 1) were incorporated into Ac-Ala-Arg-Val-Leu psi[]Ala-Glu-Ala-NH2 (all other residues being L-amino acids), and tested with respect to inhibition of HIV-1 and HIV-2 proteases.

Amino Acid Sequence↗
PubMed1993

Subcutaneous injection of an analog of neuropeptide FF precipitates morphine abstinence syndrome.

Neuropeptide FF (NPFF) has been shown to exert various antiopiate actions, including precipitation of opiate abstinence syndrome by third ventricle injection in morphine dependent rats. In the present study, dansyl-Pro-Gln-Arg-Phe-amide, a lipophilic analog of NPFF, was injected into morphine dependent rats and appropriate sham controls at a dose of 9 mg/kg s.c. Comparison groups were injected with ethanol/water vehicle alone. The NPFF analog precipitated a vigorous opiate abstinence syndrome in morphine dependent rats, but not in sham controls.

Amino Acid Sequence↗
PubMed1987

Q fever inflammatory pseudotumor of the lung.

A 36-year-old man presented with malaise, myalgia, fever, and weight loss. Liver function tests were moderately abnormal and chest x-ray film revealed an irregular mass in the right lower lobe. Bronchoscopy with cytology was not helpful. Serology revealed markedly elevated titers to Q fever. The mass was presumed to represent the presence of a Q fever pseudotumor. The patient responded to therapy with resolution of symptoms and chest x-ray film and decrease in titers to Q fever.

Adult↗
PubMed1977

Quinine-induced agranulocytosis: toxic effect of quinine bisulphate on bone marrow cultures in vitro.

In a case of quinine-induced agranulocytosis marrow culture studies confirmed the inhibitory effect on the patient's cells of equivalent therapeutic plasma concentrations of quinine. Similar concentrations had no effect on normal marrow cells. Quinidine, the stereoisomer of quinine, had no effect on either cells from the patient or normal cells. The results encourage the use of in-vitro bone marrow cultures for identifying drugs responsible for agranulocytosis.

Agranulocytosis↗
PubMedDate not supplied

Enhanced antiopiate activity in peptidomimetics of FMRFamide containing Z-2,3-methanomethionine.

FMRFa is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. The current study determined the antiopiate potency of FMRFa and two conformationally constrained peptidomimetics of FMRFa containing stereoisomers of Z-2,3-methanomethionine. Morphine abstinence signs were observed after varying doses (0.25-25.0 micrograms) of these substances were injected into the third ventricle of morphine-dependent rats. Although both peptidomimetics were far more potent than FMRFa itself, they bound with lower affinity than FMRFa to rat spinal cord receptors for the mammalian FMRFa-like peptide, NPFF.

Amino Acid Sequence↗
PubMedDate not supplied

A rigid linker-scaffold for solid-phase synthesis of dimeric pharmacophores.

Bifunctional linker-scaffolds (compounds 1-3) were designed to meet several criteria for solid-phase syntheses of bivalent ligands. They have two amine-functionalized arms that can be differentially protected. Elaboration of these arms could give ligand-pharmacophore dimers wherein the two active components are held reasonably rigidly at around 10 A separation. Their bifunctional design also enables reactions of libraries with libraries to amplify diversity in a truly combinatorial fashion. Molecules 1-3 are also designed so that cleavage of the linker liberates the scaffold entity into solution under conditions that create only byproducts that should not interfere with biological assays. Thus they contain 2-nitrobenzene sulfonamide components that cleave in the presence of good nucleophiles. In the event, the linker-scaffolds 1-3 were prepared (Schemes 1 and 2). The N-benzyl system 2 was shown to have good stability to the types of conditions that might be used to functionalize the scaffold arms and to be sufficiently labile to the cleavage nucleophile (vide infra). The nucleophiles generally used to cleave nitrobenzene sulfonamides either generate undesirable byproducts (thiophenol or alkane thiols) or proved to be insufficiently reactive for the required solid-phase transformations (n-propylamine). However, sodium sulfide was investigated as a new alternative and shown to be a highly reactive cleavage agent that gives only volatile byproducts and sodium hydroxide. It is suggested that sodium sulfide is a highly desirable nucleophile for cleavage of 2-nitrobenzene sulfonamides, in general. The linker-scaffolds 1-3 were used to prepare a small library of bivalent ligands targeted to a protein receptor having charged cavities separated by approximately 10 A. These systems were made from guanidine, pyridinium, carboxylic acid, and sulfonic acid constituents (Tables 1 and 2).

Alkynes↗
PubMedDate not supplied

Facile macrocyclizations to beta-turn mimics with diverse structural, physical, and conformational properties.

On-resin S(N)Ar reactions were performed to prepare the macrocyclic beta-turn mimics 1a-n (Scheme 1 and Table 1). These reactions occurred more efficiently than completely analogous macrocyclization reactions that do not involve an iodinated aromatic electrophile. The synthesis was also modified to allow introduction of an alkyne via a solid-phase Sonogashira reaction (giving compound 2, Scheme 2) and an aryne via a solid-phase Suzuki reaction (giving compound 3, Scheme 2). Conformational analyses of three illustrative compounds, i.e., 1i, 2, and 3, were performed using a combination of NMR, circular dichroism, and computer-aided molecular simulation methods. Overall, the preferred conformations of all three molecules tended to be type-I-like beta-turns, but for compound 3 interaction of the electron cloud of the aryl substituent with the oxygen lone pairs seems to cause differences in the preferred orientation of the turn frameworks. This study illustrates how iodinated electrophiles can be used in solid-phase S(N)Ar reactions to increase the molecular and conformational diversity in a library.

Alkynes↗
PubMedDate not supplied

Solution- and solid-phase syntheses of substituted guanidinocarboxylic acids.

A library of guanidine-based compounds was produced to mimic the lead compound 1, which is a substance known to have intensely sweet-taste characteristics. Libraries of guanidinocarboxylic acids were therefore prepared via two synthetic methods. The solid-phase method involving trapping of solution-phase carbodiimides by supported amines was used to produce N,N'-dialkyl derivatives (Scheme 1). The second solid-phase method, featuring supported carbodiimides and solution-phase amines (Scheme 2), was devised to prepare N,N'-disubstituted and N,N',N'-trisubstituted guanidinocarboxylic acids. A small collection of guanadinoacetic acid dimers and trimers was also prepared, but this time via a solution-phase coupling of carbodiimides to a polyamine linker.

Amines↗
PubMedDate not supplied

Treatment of immune-mediated hemolytic anemia in dogs with cyclophosphamide.

A review of 60 cases of immune-mediated hemolytic anemia (IMHA) in the dog was performed in order to characterize the disease and to identify potential prognostic indicators. Dogs ranged in age from 1 to 13 years, with a mean age of 6.5 years. The 2 most commonly affected breeds were Cocker Spaniels and Labrador Retrievers. Fifty-two of the 60 dogs tested (87%) were autoagglutination positive and spherocytes were present in 45 (75%). Forty-one (89%) of 46 patients tested positive for the presence of immunoglobulin on the red blood cell surface (Coombs assay). The most common clinical signs at presentation were lethargy, weakness, pale mucous membranes, icterus, hemoglobinuria, and anorexia. PCV less than 25% was present in 59 (98%) dogs. At the time of presentation, 35 dogs (58%) had a nonregenerative anemia, whereas 25 patients (42%) had a regenerative response. Thrombocytopenia was seen in 41 (68%) dogs. Nine of 34 dogs (26%) had a prolonged prothrombin time, 19 of 34 (56%) had a prolonged activated partial thromboplastin clotting time, and 12 of 34 (35%) had abnormal fibrinogen concentrations. All dogs received prednisone at immunosuppressive doses (2.2-4.4 mg/kg PO as a single or divided dose every 24 hours) and cyclophosphamide as primary therapy. Forty-one dogs (63%) received cyclophosphamide at 50 mg/m2 q24h for 4 days, whereas 9 dogs (15%) received an initial high dose (200 mg/m2) followed by 3 days of a lower dose (50 mg/m2 q24h). No statistical difference in survival times was found for either protocol. Thirteen dogs were treated with azathioprine in addition to cyclophosphamide and prednisone. The median survival time of dogs that received all 3 drugs was 370 days as compared to 9 days for those dogs that were treated with cyclophosphamide and prednisone alone. Thirty-one (52%) dogs died from the disease, 13 (22%) dogs were alive, and 15 (25%) dogs were lost to follow-up. The median length of survival for all dogs was 21 days. Eight dogs that were discharged from the hospital suffered a relapse (PCV < 25%).

Anemia, Hemolytic, Autoimmune↗