Biomedical subjects
Publications and source records attributed to Hiroko Sano.
Indole- and indoline-type basic COX-1-selective competitive inhibitors, 5-amino-1-(3,5-dimethylbenzoyl)-1H-indole (1) and 5-amino-1-(3,5-dimethylphenyl)-2,3-dihydro-1H-indole (2), were found to possess anti-angiogenic activity estimated as a tube formation-inhibition using human umbilical vein endothelial cells (HUVECs).
In most organisms, primordial germ cells (PGCs) arise far from the region where somatic gonadal precursors (SGPs) are specified. Although PGCs in general originate as a single cluster of cells, the somatic parts of the gonad form on each site of the embryo. Thus, to reach the gonad, PGCs not only migrate from their site of origin but also split into two groups. Taking advantage of high-resolution real-time imaging, we show that in Drosophila melanogaster PGCs are polarized and migrate directionally toward the SGPs, avoiding the midline. Unexpectedly, neither PGC attractants synthesized in the SGPs nor known midline repellents for axon guidance were required to sort PGCs bilaterally. Repellent activity provided by wunen (wun) and wunen-2 (wun-2) expressed in the central nervous system, however, is essential in this migration process and controls PGC survival. Our results suggest that expression of wun/wun-2 repellents along the migratory paths provides faithful control over the sorting of PGCs into two gonads and eliminates PGCs left in the middle of the embryo.
5-Hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33: 10), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent anti-angiogenic activity in a human umbilical vein endothelial cell (HUVEC) assay. Thalidomide (1) and its metabolite, 5-hydroxythalidomide (5-HT: 2), which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, as well as IMiDs (immunomodulatory derivatives of thalidomide: 3 and 5), also showed weak or moderate activity in the same assay.
A series of substituted indoline and indole derivatives with cyclooxygenase (COX)-inhibitory activity was prepared during our structural development studies based on thalidomide as a multi-template lead compound. Structure-activity relationship studies indicated that the nature of the substituent introduced at the benzene ring of the indoline (indole) backbone, and the length and type of the linking group between the nitrogen atom of indoline (indole) and the N-substituent are important for the activity. This study has led to the identification of COX-1-selective inhibitors, and these should be useful not only as pharmacological tools to investigate the physiology and pathophysiology of COX, but also as sophisticated leads for the development of novel drugs to treat COX-associated diseases, such as inflammatory diseases, and cancer.
Thalidomide shows moderate inhibitory activity toward neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), but not toward endothelial NOS (eNOS). Structural development studies of thalidomide yielded novel phenylhomophthalimide-type NOS inhibitors with enhanced activity and different subtype selectivity.
Novel vitamin D(3) analogs having a lactam structure in their side chains, 1 alpha,25-dihydroxyvitamin D(3)-26,23-lactams (DLAMs), were designed based on the principle of regulation of the folding of helix-12 in the vitamin D nuclear receptor (VDR). The new analogs were synthesized via 1,3-dipolar cycloaddition reaction and subsequent reduction of the isoxazolidine as key steps. Among the analogs, (23S,25S)-DLAM-01 (4a) and (23S,25S)-DLAM-1P (5a) bind strongly to VDR. Moreover, these analogs were found to inhibit the differentiation of HL-60 cells induced by 1 alpha,25-dihydroxyvitamin D(3).
Several N-substituted phenylphthalimide and phenylhomophthalimide derivatives with cyclooxygenase (COX)-inhibitory activity were prepared during structural development studies based on thalidomide as a lead compound. Substituent effects on the subtype selectivity were investigated.
Thalidomide has been found to exhibit weak nitric oxide synthase (NOS)-inhibitory activity. Structural development studies of thalidomide showed that some N-2,6-dimethylphenylhomophthalimide analogs possess NOS-inhibiting activity.
The vasa gene (vas) is essential for germline development in Drosophila melanogaster. Zygotic vas is expressed in pole cells earlier than any other pole cell-expressing genes thus far identified, and VAS protein is continuously present in germline cells throughout development. Here, we report the identification of a regulatory region that directs germline-specific vas expression. A genomic fragment containing the vas locus was linked to enhanced green fluorescent protein (egfp)-vas fusion gene, and the resulting gene was introduced into fly genome. Developmental vas expression was assessed by monitoring the expression of EGFP-VAS in these transformants. The spatio-temporal expression pattern of EGFP-VAS is essentially identical to that of endogenous VAS throughout germline development. By dissecting the vas promoter, we identified a 40-bp regulatory element, which is necessary and sufficient for germline-specific expression during oogenesis. This region interacts specifically with ovarian protein(s). Furthermore, this region is also required for vas expression in pole cells during embryogenesis. These results suggest that a similar mechanism regulates vas expression both in oogenesis and embryogenesis.