Biomedical subjects
Publications and source records attributed to Tomomi Noguchi.
4,7-Difluoro-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione [4,7FPP-33 (14)] has a potent tubulin-polymerization-inhibiting activity comparable with those of the known tubulin-polymerization inhibitors rhizoxin and colchicine. The structure-activity relationship for fluorine substitution was elucidated.
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).
Mono- and dihydroxylated metabolites of thalidomide were efficiently prepared and characterized, and their inhibitory activity on tumor necrosis factor (TNF)-alpha production in the human monocytic leukemia cell line THP-1 was evaluated. 5,N-Dihydroxythalidomide was a much more potent TNF-alpha production inhibitor than thalidomide.
Various analogs of known immunomodulatory derivatives of thalidomide (1) (IMiDs: 3, 5) were synthesized, focusing on cell-differentiation-inducing, cyclooxygenase-inhibitory and anti-angiogenesis activities. Among the prepared compounds, NIDO-33 (14) showed cell differentiation-inducing activity on HL-60 cells and anti-angiogenic activity on human umbilical vein endothelial cells (HUVEC). AIDO-00 (7) also showed anti-angiogenic activity. NIDO-11 (8) showed an enhancing effect on all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation, and AIDO-30 (13) exhibited cyclooxygenase (COX)-inhibitory activity.
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.
5-Hydroxy- and 4-amino-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33 and 4APP-33, respectively) have been shown to possess cell differentiation-inducing activity toward human leukemia cell line HL-60.
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.
2-(2,6-Diisopropylphenyl)-5-hydroxy-1H-isoindole-1,3-dione (5HPP-33), which was obtained during our previous structural development studies on thalidomide, was revealed to possess potent tubulin-polymerization-inhibiting activity, comparable to that of the known tubulin-polymerization inhibitors, rhizoxin and colchicine. A major metabolite of thalidomide, 5-hydroxythalidomide, which possesses a hydroxyl group at the position corresponding to that of 5HPP-33, also showed moderate inhibitory activity.
Thalidomide (Thal: 1) and its two metabolites, 5-hydroxythalidomide (5-HT: 2) and N-hydroxythalidomide (N-HT: 3), showed an enhancing effect on all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation. 5-HT and N-HT showed tubulin polymerization-inhibiting activity, but thalidomide did not.
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.
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 showed cyclooxygenase (COX)-1/2 inhibitory activity with a potency comparable to that of aspirin. Structural development studies of thalidomide resulted in potent COX-1/2 inhibitors, and COX-1-selective and COX-2-selective inhibitors.