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1.
Bioorg Med Chem ; 6(5): 509-22, 1998 May.
Article in English | MEDLINE | ID: mdl-9629465

ABSTRACT

Calpain I, an intracellular cysteine protease, has been implicated in the neurodegeneration following an episode of cerebral ischemia. In this paper, we report on a series of peptidomimetic ketomethylene and carbamethylene inhibitors of recombinant human calpain I (rh calpain I). Our study reveals that the -NHCO-moiety (possible hydrogen-bonding site) at the P2-P3 region of a potent tripeptide or a dipeptide inhibitor of calpain I is not a strict requirement for enzyme recognition. Compounds 7d ((R)-2-isobutyl-4-oxo-4-(9-xanthenyl)butanoic acid ((S)-1-formyl-3-methyl)butyl amide), 31 ((R)-2-isobutyl-4-(2-sulfonylnaphthyl)butyric acid ((S)1-formyl-3-methyl)butyl amide) and 34 ((R)-2-isobutyl-4-(2-sulfoxylnaphthyl)butyric acid ((S)-1-formyl-3-methyl)butyl amide) which exhibited good activity in the enzyme assay, also inhibited calpain I in a human cell line.


Subject(s)
Calpain/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Dipeptides/chemistry , Oligopeptides/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacology , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Humans , Magnetic Resonance Spectroscopy , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Protein Conformation , Recombinant Proteins/antagonists & inhibitors , Tumor Cells, Cultured
2.
J Med Chem ; 40(12): 1863-9, 1997 Jun 06.
Article in English | MEDLINE | ID: mdl-9191963

ABSTRACT

A series of 3,9 disubstituted [(alkylthio)methyl]- and (alkoxymethyl)-K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to > 500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C1 protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons.


Subject(s)
Carbazoles/chemistry , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Neurons/drug effects , Neurons/physiology , Animals , Apoptosis/drug effects , Chick Embryo , Choline O-Acetyltransferase/metabolism , Enzyme Inhibitors/pharmacology , Female , Humans , Indole Alkaloids , Motor Neurons/drug effects , Motor Neurons/physiology , Nerve Degeneration/drug effects , Nerve Growth Factors/antagonists & inhibitors , Prosencephalon/embryology , Prosencephalon/enzymology , Protein Kinase C/antagonists & inhibitors , Proto-Oncogene Proteins , Rats , Receptor Protein-Tyrosine Kinases , Receptor, trkA , Receptors, Nerve Growth Factor , Spinal Cord/embryology , Spinal Cord/enzymology , Substantia Innominata/cytology
4.
Eur J Pharmacol ; 139(3): 273-9, 1987 Jul 23.
Article in English | MEDLINE | ID: mdl-2822433

ABSTRACT

The benzophenone chromophore has been incorporated into a synthetic amino acid (p-benzoyl-L-phenylalanine; L-Bpa) to produce a chemically stable photoaffinity probe. L-Bpa was found to retain the photochemical reactivity of benzophenone. To test the utility of this synthetic amino acid as a photo-reactive probe for receptors, a tetrapeptide analog of morphiceptin was made as a model peptide in which the C-terminal prolinamide was replaced by L-Bpa amide. The affinity of the mu opioid receptor for this peptide is comparable to that for the parent compound, morphiceptin. Irradiation of the peptide-receptor complex reduced the subsequent binding of [3H]naloxone and virtually eliminated that of [3H]Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO). Binding studies with [3H]naloxone indicated that both the affinity and the capacity were reduced. Competition studies with [3H]D-Ala2-D-Leu5-enkephalin (DADLE) and naloxone indicated selective inactivation of a mu type opioid receptor.


Subject(s)
Endorphins/pharmacology , Phenylalanine/analogs & derivatives , Receptors, Opioid/radiation effects , Affinity Labels , Animals , Brain/metabolism , Chemical Phenomena , Chemistry , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/metabolism , Enkephalin, Leucine-2-Alanine , Guinea Pigs , In Vitro Techniques , Light , Naloxone/metabolism , Rats , Rats, Inbred Strains , Receptors, Opioid/metabolism , Receptors, Opioid, mu
5.
J Biol Chem ; 261(23): 10695-700, 1986 Aug 15.
Article in English | MEDLINE | ID: mdl-3733726

ABSTRACT

A new photoreactive amino acid analog, p-benzoyl-L-phenylalanine, is described. Convenient methods for the preparation of this amino acid and its subsequent incorporation into synthetic peptides by the solid-phase technique are outlined. To illustrate its utility, p-benzoyl-L-phenylalanine was substituted in place of tryptophan in a 17-residue calmodulin-binding peptide. The substitution did not measurably affect the affinity of this peptide for calmodulin. When this peptide was photolyzed at 350 nm in a 1:1 molar ratio with calmodulin in the presence of 500 microM CaCl2, 70% of the calmodulin was derivatized. The specificity of the reaction was investigated by photolysis in the absence of CaCl2 where little binding occurs; under these conditions little or no photolabeling occurred.


Subject(s)
Affinity Labels/pharmacology , Calmodulin/metabolism , Phenylalanine/analogs & derivatives , Animals , Cattle , Chromatography, High Pressure Liquid , Indicators and Reagents , Kinetics , Male , Peptide Fragments/analysis , Phenylalanine/chemical synthesis , Phenylalanine/pharmacology , Photolysis , Structure-Activity Relationship , Testis/metabolism
6.
Plant Physiol ; 77(2): 403-6, 1985 Feb.
Article in English | MEDLINE | ID: mdl-16664066

ABSTRACT

Several aryl-carbamoyl dipeptide alcohols increased the uptake of nitrate and ammonium ions into corn root segments by up to 50% and 90%, respectively. The most effective one was N-carbobenzoxy-l-prolyl-l-valinol. Foliar application of this compound to underfertilized corn plants caused an increase in the rate of plant growth in the greenhouse and provided modest (6-10%) corn yield increases in field tests in Delaware.

7.
J Med Chem ; 21(12): 1188-94, 1978 Dec.
Article in English | MEDLINE | ID: mdl-214558

ABSTRACT

Attempts to design an agent which would release cytotoxic nitrogen mustards within collagenase-producing tumors led to the synthesis of Cbz-L-Pro-L-Leu-Gly-L-Pro-Gly-NHC6H4N(CH2CH2Cl)2 (10). 10 was cleaved in vitro by bacterial and tumor-associated collagenase as expected at the peptide bond joining L-leucine and glycine to give Gly-L-Pro-Gly-NHC6H4N(CH2CH2Cl)2 which was over six times more toxic, on a molar basis, than 10. In vivo tests of 10 against well-advanced Sarcoma-180 gave disappointing results. The lack of specific antitumor activity may be accounted for by the presence of competing cleavage reactions by collagenases in certain normal tissues.


Subject(s)
Antineoplastic Agents/chemical synthesis , Microbial Collagenase/metabolism , Nitrogen Mustard Compounds/chemical synthesis , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Autoradiography , Female , Guinea Pigs , In Vitro Techniques , Mice , Nitrogen Mustard Compounds/metabolism , Nitrogen Mustard Compounds/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/metabolism , Oligopeptides/pharmacology , Rats , Sarcoma 180/drug therapy , Sarcoma 180/enzymology , Swine
8.
J Gen Virol ; 27(3): 329-42, 1975 Jun.
Article in English | MEDLINE | ID: mdl-167116

ABSTRACT

HeLa cells infected with radioactive poliovirus type 2 were disrupted with ultrasonic treatment, followed by addition of a non-ionic detergent. Two types of virus particles were found to sediment at 80 to 90% the rate of native virus. The first of these appeared to be a complex of native virus particles and membrane components, since treatment with 0-2% SDS released infectious native particles. The second was non-infectious and its sedimentation rate was not greatly altered by SDS. One hour after infection this non-infectious particle was the major product of cell-mediated eclipse. We have confirmed that 10 to 30 mg-g/ml S-7, a substituted thiopyrimidine, blocks infection of cells by poliovirus in a specific manner. Analysis of cells infected with radioactive poliovirus type 2 in the presence of S-7 showed that the virus particles remained as the complex which can be disrupted with SDS. In addition to blocking cell-mediated eclipse, S-7 stabilizes poliovirus against heat inactivation in vitro at the same concentrations which block infection. This action resembles the effect of 10-2 M-glutathione, which is also known to block cell-mediated eclipse of poliovirus.


Subject(s)
Poliovirus/analysis , Viral Proteins/analysis , Virus Replication , Adsorption , Carbon Radioisotopes , Carboxylic Acids/pharmacology , Centrifugation, Density Gradient , Electrophoresis, Polyacrylamide Gel , Encephalomyocarditis virus/growth & development , Glutathione/pharmacology , HeLa Cells , Hot Temperature , Humans , Peptides/analysis , Poliovirus/drug effects , Poliovirus/growth & development , Pyrimidines/pharmacology , Rhinovirus/growth & development , Sodium Dodecyl Sulfate/pharmacology , Sonication , Sulfides/pharmacology , Virus Replication/drug effects
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