RESUMO
Passive membrane permeability and an active transport process are key determinants for penetrating the blood-brain barrier. P-glycoprotein (P-gp), a well-known transporter, serves as the primary gatekeeper, having broad substrate specificity. A strategy to increase passive permeability and impair P-gp recognition is intramolecular hydrogen bonding (IMHB). 3 is a potent brain penetrant BACE1 inhibitor with high permeability and low P-gp recognition, although slight modifications to its tail amide group significantly affect P-gp efflux. We hypothesized that the difference in the propensity to form IMHB could impact P-gp recognition. Single-bond rotation at the tail group enables both IMHB forming and unforming conformations. We developed a quantum-mechanics-based method to predict IMHB formation ratios (IMHBRs). In a given data set, IMHBRs accounted for the corresponding temperature coefficients measured in NMR experiments, correlating with P-gp efflux ratios. Furthermore, the method was applied in hNK2 receptor antagonists, demonstrating that the IMHBR could be applied to other drug targets involving IMHB.
RESUMO
A novel lipopeptide antibiotic, stalobacin I (1), was discovered from a culture broth of an unidentified Gram-negative bacterium. Stalobacin I (1) had a unique chemical architecture composed of an upper and a lower half peptide sequence, which were linked via a hemiaminal methylene moiety. The sequence of 1 contained an unusual amino acid, carnosadine, 3,4-dihydroxyariginine, 3-hydroxyisoleucine, and 3-hydroxyaspartic acid, and a novel cyclopropyl fatty acid. The antibacterial activity of 1 against a broad range of drug-resistant Gram-positive bacteria was much stronger than those of "last resort" antibiotics such as vancomycin, linezolid, and telavancin (MIC 0.004-0.016 µg/mL). Furthermore, compound 1 induced a characteristic morphological change in Gram-positive and Gram-negative strains by inflating the bacterial cell body. The absolute configuration of a cyclopropyl amino acid, carnosadine, was determined by the synthetic study of its stereoisomers, which was an essential component for the strong activity of 1.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Lipopeptídeos/química , Aminoglicosídeos/farmacologia , Antibacterianos/química , Avaliação Pré-Clínica de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Lipoglicopeptídeos/farmacologia , Lipopeptídeos/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Alchivemycin A, a novel polycyclic polyketide, was isolated from the culture extract of a plant-derived actinomycete Streptomyces sp. The structure and relative configuration were elucidated by spectroscopic analysis and X-ray crystallography, and the absolute configuration was determined by a (1)H NMR anisotropy method using MPA ester derivatization. The new compound contains an unprecedented heterocyclic ring system, 2H-tetrahydro-4,6-dioxo-1,2-oxazine. Alchivemycin A showed potent antimicrobial activity against Micrococcus luteus and inhibitory effects on tumor cell invasion.