1,2-Dihydro-3,1-benzoxazin-4-one and 4H-1,2-dihydro-pyrido-[2,3-d]- [1,3]-oxazin-4-one derivatives as potential prodrugs. Part I: Synthesis.
Explore the source record for details and available documents.
Niflumic Acid↗
Biomedical subjects
J B Chen
Publications and source records attributed to J B Chen.
1,2-Dihydro-3,1-benzoxazin-4-one and 4-H-1,2-dihydro-pyrido-[2,3-d]-[1,3]-oxazin-4-one derivatives as potential prodrugs. Part II: Hydrolysis.
The kinetics of the spontaneous hydrolysis of the potential prodrugs 1a-1f, 2a-2g, and 3a-3e in methanol-buffer mixtures (3:7) at various pH-values was studied and a simple analytical uv-spectroscopic method was developed. The results show that most of the new potential prodrugs were very quickly reconverted to their parent drugs under these conditions. All of the potential prodrugs are very sensitive between pH 4.0 and 8.0, with half lives less than 50 min at 20 degrees C, except for compounds 1f, 2f, and 3d. Compounds 1b and 1c are so sensitive that they reconverted to their parent drug during the mixing of the stock solution and the buffer-methanol-mixture.
Hydrolysis↗
1,2-Dihydro-3,1-benzoxazin-4-one and 4H-1,2-dihydro-pyrido-[2,3-d]- [1,3]-oxazin-4-one derivatives as potential prodrugs. Part III: Permeability through excised human skin in vitro.
The percutaneous permeation characteristics of 6 potential prodrugs 2-7 in comparison with their parent drug mefenamic acid (1) in vitro using excised human skin were studied. The results show that all potential prodrugs tested were at least 2.0 times as effective as mefenamic acid; compounds 2 and 7 permeated almost 5 times as quickly as mefenamic acid through excised human skin. The relations between the permeation behaviour, the RM values and the melting points were interpreted.
Humans↗
Structure-activity relationship of quinazolinedione inhibitors of calcium-independent phosphodiesterase.
A series of quinazolinediones and azaquinazolinediones is described which possess potent inhibitory activity toward the calcium-independent phosphodiesterase enzyme (CaIPDE). In vivo testing showed that this in vitro activity translates to animal models predictive of chronic diseases such as depression and inflammation. These results support the hypothesis that inhibition of CaIPDE may lead to useful activity in such chronic diseases.
Animals↗
Open-lung biopsy in patients with pulmonary infiltrate.
The application of open-lung biopsy to a patient with diffuse pulmonary infiltrate is dependent on whether it affords to a specific information and leads to a change in therapy. To evaluate the impact of open-lung biopsy on diagnosis and treatment of diffuse pulmonary infiltrates, we conducted a retrospective review of 37 patients undergoing this procedure during a 8-year period. There were 26 males and 11 females, at an average age of 53 years (ranging from 3 months to 79 years). Diagnostic yield was 97.2%, and biopsy yielded a specific diagnosis in 25(67.6%) patients and a change in therapy in 19 (51.4%) patients. Complications developed in 4 (11%) patients and the rate was higher under local anesthesia (3/4). Seven patients died, but no one was related to biopsy procedure. A specific diagnosis was obtained in 4 (50%) of the 8 immunocompromised patients, and a change in therapy occurred in 2 (25%) of these patients after biopsy, but these findings could not affect the survival rates. A specific diagnosis was obtained in 21 (72.4%) of the 29 nonimmunocompromised patients and a change in therapy occurred in 17 (58.6%) patients in this group. Five (83%) of 6 patients, who lacked definite tissue diagnosis by transbronchial biopsy, achieved confirmed diagnosis by open-lung biopsy. Open-lung biopsy in patients with a diffuse pulmonary infiltrate is an accurate diagnostic tool and frequently leads to a change in treatment. The procedure can be performed with acceptable morbidity and mortality in nonimmunocompromised patients, but should be used conservatively in immunocompromised patients.
Adult↗
Improved developmental potential of rabbit oocytes fertilized by sperm microinjection into the perivitelline space enlarged by hypertonic media.
The objectives of the present study were: 1) to develop a simple and more efficient technique for sperm microinjection than is currently available, using the rabbit as a model, and 2) to evaluate the development of rabbit oocytes fertilized by single or multiple sperm microinjection. Hyperosmotic sucrose in phosphate-buffered saline (SPBS) was employed to dehydrate oocytes to increase the perivitelline space for sperm microinjection and prevent possible injury to the vitellus. In the first experiment, 58% (n = 29) oocytes treated with 0.5 M SPBS developed to morulae following multiple sperm microinjection compared, respectively, to 47% (n = 34) and 60% (n = 15) for control IVF with or without sucrose exposure (P greater than 0.05). Blastocyst development from microinjected oocytes, however, was much lower (P less than 0.05) than that of controls (14% vs. 42% and 40%, respectively). Sham operation by puncturing the zona pellucida of the sucrose-treated oocytes with the microinjection pipette did not increase parthenogenesis (P greater than 0.05). In Experiment 2 a smaller-size injection pipette and shorter sucrose exposure time after sperm microinjection resulted in 41% (n = 42) of the oocytes developing into blastocysts for the microinjection group, whereas only 21% (n = 24) developed to blastocysts in the control IVF group (P less than 0.05). When relatively older oocytes (17 hr post ovulation injection) were used to test if microinjection could reduce the time to fertilization and cleavage (Expt. 3), an average of 27% (n = 63) blastocysts resulted from microinjection vs. 0% (n = 28) for the control IVF group.
Animals↗
Preparation and partial characterization of old yeast cells.
Age-synchronized populations of the binding yeast Saccharomyces cerevisiae were prepared by a combination of growth-synchronization methods and cell separation by rate-zonal sedimentation in density gradients. The procedure allowed the bulk preparation of cells of any desired age up to at least 20 generations with minimum yields of 10(8) cells per preparation, starting with 6 X 10(9) 0-generation cells. The purity of the preparations was greater than 90%, with an accuracy of +/- 2 generations. The procedure itself had no detrimental effects on the cells, as indicated by a number of physiological parameters. Cell viability and resistance to sonication remained essentially unchanged during aging. In contrast, cell size and generation time increased, providing biomarkers for the aging process. The procedure described here should help establish yeast as a useful model system for studies of cellular aging at the molecular level.
Cell Division↗
Prolongation of the yeast life span by the v-Ha-RAS oncogene.
The budding yeast Saccharomyces cerevisiae has a finite life span that is defined by the number of times the cell divides. The patterns of expression of certain genes change in a specific manner during the life span, implying that at least some of the manifestations of the ageing process are subject to gene regulation. It has now been determined that the controlled expression of the RAS oncogene in yeast increases the longevity of this organism, indicating that, conversely, a defined alteration in the activity of a single gene can extend this organism's life span. The results suggest that there is a balance between life-span extension and growth arrest when RAS is expressed. Inasmuch as the homologues of RAS in yeast function to integrate cell metabolism with the cell cycle, these studies raise the possibility that this integrative function may also apply to the co-ordination of successive cell cycles during the life span.
Gene Expression Regulation, Fungal↗
Specific alterations in transcript prevalence during the yeast life span.
The budding yeast Saccharomyces cerevisiae has a finite life span, limited by the number of generations the cell can undergo. Yeast cells display a variety of changes as they age. In order to determine whether age-associated changes occur in the prevalence of specific mRNAs, a differential hybridization screen has been used to identify yeast genes that are preferentially expressed in either young or in old cells. In this screen, a yeast genomic DNA library was probed with cDNA prepared to the poly(A)+ mRNA of young and old cells. Six clones representing distinct genes that showed differential patterns of expression throughout the life span were isolated, as determined by genomic blot and RNA dot blot analyses. On the basis of their expression patterns five of the genes were classified as young- and one as old-specific. These genes were all derived from the nuclear genome. Analysis of the expression during the cell cycle of two of these genes, one young cell-specific and the other old-cell-specific, revealed that it was not growth state-dependent. These results suggest that aging in yeast is accompanied by defined alterations in the levels of certain gene transcripts.
Cell Cycle↗
Replication control and cellular life span.
Cell proliferation involves both control of progress through the current cell cycle and coordination of successive cell cycles. We have focused our attention on the events that trigger traversal of the G1/S boundary of the cell cycle. A protein kinase activity was found in preparations of the DNA-replicative complex from the budding yeast Saccharomyces cerevisiae. The activity phosphorylated only a few of the proteins present in the replicative fraction, and it displayed a marked preference for a 48-kDa polypeptide. Most importantly, the protein kinase activity was heat-sensitive in replicative fractions from cdc7 cells, a mutant that arrests at the G1/S boundary at restrictive temperature. The results suggest that phosphorylation of components of the replication machinery may play a role in control of initiation of DNA replication during the cell cycle. We have also begun an analysis of cellular aging in yeast, as a means of addressing the problem of coordination of successive cell cycles. Yeast cells have a finite life span defined by reproductive capacity. With age, the generation time of yeast cells lengthened. The cell cycle of the daughter cell was under the control of the mother. This control was transient, and the daughter cell began dividing at the rate characteristic of its own age within three divisions of its birth. This suggests that the senescent phenotype, as manifested by lengthened generation time, is a dominant feature in yeast cells, and that it is determined by a diffusible cytoplasmic molecule(s) that undergoes turnover in young cells. In a search for this putative senescence factor(s), we are cloning genes that differentially expressed during the yeast life span. Several such genes have been isolated and partially characterized. Our goals are to determine whether the expression of one or more of these genes is casually associated with cell longevity. We propose the Cell Spiral model to describe the relationship between the cell cycle and cellular aging.
Cell Cycle↗