ABSTRACT
A collection of natural peptides, simplified analogs of natural peptides, de novo amphipathic peptides and de novo amphipathic peptides composed of 50-80% alpha,alpha-dialkylated glycines (alpha,alpha-Dags) were synthesized on solid-phase resin as the C-terminus amides using N-alpha-fluorenylmethyloxycarbonyl protection. The synthesis of the peptides rich in alpha,alpha-Dags used acid fluoride coupling methods. The peptides show antimicrobial activity against Escherichia coli and Staphylococcus aureus but no direct antimicrobial activity against Brucella abortus at 100 microm in vitro. However, in vivo treatment with several of these peptides results in significant reductions of B. abortus in chronically infected immune BALB/c mice relative to infected control animals. The chronically infected mice were susceptible to peptide toxicity at much lower peptide doses than control animals. The highest nonlethal dose for infected mice was only 25 microg for melittin, whereas 500 microg doses were nonlethal for many of the other peptides. Several of the alpha,alpha-Dag-rich peptides selectively destroy B. abortus-infected murine macrophages in vitro. Thus, these peptides apparently reduce the bacterial load in vivo by destroying a portion of the infected macrophages and exposing the sequestered bacteria to the immune response in the mice.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Brucella abortus/drug effects , Peptides/chemistry , Peptides/pharmacology , Amino Acid Sequence , Animals , Anti-Bacterial Agents/chemical synthesis , Biochemistry/methods , Brucellosis/drug therapy , Brucellosis/microbiology , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Escherichia coli/drug effects , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/microbiology , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Molecular Sequence Data , Peptides/chemical synthesis , Staphylococcus aureus/drug effects , Trypsin/chemistryABSTRACT
Efficient and general procedures have been developed for the solid-phase preparation of substituted benzothiazoles (1), 3, 4-dihydro-1,4-benzothiazines (2), 3,4-dihydro-1,4-benzothiazine-1, 1-dioxides (3), 3,4-dihydro-3-oxo-1,4-benzothiazines (4), and 3, 4-dihydro-3-oxo-1,4-benzothiazine-1,1-dioxides (5). All five classes of compounds were prepared from a common intermediate, resin-bound 2-amino-4-carboxythiophenol, in a minimal number of steps. This intermediate was generated by (i) coupling 4-fluoro-3-nitrobenzoic acid onto Wang resin, or onto an amino acid bound to the resin, (ii) substitution of the aryl fluoride with a protected thiol, (iii) reduction of the nitro group, and (iv) removal of sulfur protection. Reaction with the appropriate substrates and reagents to effect cyclization gave the substituted core structures, which were modified further to introduce additional point(s) of diversity. Following cleavages from the solid support, the compounds were obtained in high initial purities and good isolated yields after purification.
Subject(s)
Aniline Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Magnetic Resonance Spectroscopy , Mass SpectrometryABSTRACT
Cyclohexanespiro-5'-hydantoin monohydrate, C8H12N2O2.H2O, has a chair-shaped cyclohexane ring with endocyclic torsion-angle magnitudes in the range 54.4 (2)-56.3 (2) degrees. All potential hydrogen-bond donors are involved in intermolecular hydrogen bonding, with lengths in the range 2.760 (2)-2.908 (2) A. In its indolyl adduct, 2-(3-indolyl)cyclohexanespiro-5'-hydantoin monohydrate, C16H17N3O2.H2O, the cyclohexane moiety adopts a chair conformation with the indolyl substituent in an equatorial position. The N-H portion of the hydantoin ring is cis to indolyl, while the C=O of the hydantoin is trans. Endocyclic torsion-angle magnitudes of the cyclohexane ring are in the range 54.2 (2)-56.7 (2) degrees. All potential hydrogen-bond donors are involved in intermolecular hydrogen bonds, with lengths 2.828 (2)-3.187 (2) A.
Subject(s)
Indoles/chemistry , Spiro Compounds/chemistry , Crystallography, X-Ray , Molecular Conformation , Molecular StructureABSTRACT
In the title compound, C19H15NO2S, the benz[f]indole ring system is essentially planar, with maximum and mean deviations for the 13 ring atoms of 0.051 (2) and 0.023 (4) A. The N atom lies 0.199 (1) A out of the plane of the three atoms bonded to it. The phenyl group forms a dihedral angle of 82.83 (5) degrees with the benz[f]indole plane. The S--N distance is 1.646 (1) A and the S = O distances average 1.426 (1) A.
