ABSTRACT
Genetic relationships among Carica papaya cultivars, breeding lines, unimproved germplasm, and related species were established using amplified fragment length polymorphism (AFLP) markers. Seventy-one papaya accessions and related species were analyzed with nine EcoRI-MseI primer combinations. A total of 186 informative AFLP markers was generated and analyzed. Cluster analysis suggested limited genetic variation in papaya, with an average genetic similarity among 63 papaya accessions of 0.880. Genetic diversity among cultivars derived from the same or similar gene pools was smaller, such as Hawaiian Solo hermaphrodite cultivars and Australian dioecious cultivars with genetic similarity at 0.921 and 0.912, respectively. The results indicated that self-pollinated hermaphrodite cultivars were as variable as open-pollinated dioecious cultivars. Genetic diversity between C. papaya and six other Carica species was also evaluated. Carica papaya shared the least genetic similarity with these species, with an average genetic similarity of 0.432; the average genetic similarity among the six other species was 0.729. The results from AFLP markers provided detailed estimates of the genetic variation within and among papaya cultivars, and supported the notion that C. papaya diverged from the rest of Carica species early in the evolution of this genus.
Subject(s)
Carica/genetics , Genetic Variation , Genetic Markers , Nucleic Acid Amplification Techniques , Phylogeny , Polymorphism, Genetic , Sequence Analysis, DNAABSTRACT
To identify new orally active inhibitors, further modification of 1 (ONO-6818) was performed. Peptidic derivatives 4b, 4c and 4n showed more potent inhibitory activity than nonpeptidic derivatives 3a-c. As a result, a series of peptidic inhibitors, 4a-s and 5a-v, were discovered. Among these N-aryl derivatives 5a-g, 5i, 5m and 5o-v showed oral activity. Their oral activity showed good correlation with their metabolic stability. Compounds 5h and 5j-l, which were extremely metabolically unstable in hamster plasma, did not show oral activity. Oral activity was considered to be determined by a combination of at least two factors: oral absorption and metabolic stability.
Subject(s)
Leukocyte Elastase/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Administration, Oral , Animals , Cricetinae , Drug Design , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Hydrolysis , Leukocyte Elastase/metabolism , Oxadiazoles/chemistry , Oxadiazoles/metabolism , Peptides/chemical synthesis , Peptides/metabolism , Pyrimidinones/chemistry , Pyrimidinones/metabolismABSTRACT
5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Leukocyte Elastase/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Cricetinae , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hemorrhage/drug therapy , Humans , Hydrolysis , Lung Diseases/drug therapy , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipSubject(s)
Enzyme Inhibitors/chemical synthesis , Leukocyte Elastase/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Pyrimidinones/chemical synthesis , Administration, Oral , Animals , Crystallography, X-Ray , Dogs , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Photon-ion merged-beam apparatus using a compact ECR ion source and a high-brilliance light source has been designed for the study of photoabsorption processes of multiply charged ions. Photoion spectroscopy will be performed along isoelectronic, isonuclear and isoionic sequences. The main features of this apparatus are described.
ABSTRACT
To develop a model of chronic experimental asthma in guinea pigs, the animal was forced to inhale the mist of a low dose of ovalbumin (OA) adsorbed on fine Al(OH)3 for sensitization once every 4 weeks. The animal was challenged by inhalation with the mist of OA on day 14 after the respective sensitizations. Either the first or the second antigen challenge markedly induced an early asthmatic response (EAR), whereas there was hardly any late asthmatic response (LAR). At the 3rd challenge, LAR also emerged with some severity. These dual responses were consistently observed until the 10th challenge. On the other hand, repeated inhalation/challenge, once every 2 weeks, with OA alone at the same dose tended to lead to the desensitization of the EAR. In addition, LAR was hardly observed throughout the experiments. In both groups, gamma 1 and IgE levels in the serum were elevated by the repetitive antigen inhalations, yet no obvious relationship between these antibody levels and the intensity of either EAR or LAR was recognized. The present results indicate that the asthmatic model with reproducible EAR and LAR developed in this study appears to be very beneficial for the investigation of bronchial asthma and for the assessment of anti-asthma drugs.
