Kosuke Dodo

Novel small molecule nonpeptide aminopeptidase n inhibitors with a cyclic imide skeleton.

A novel series of small molecule nonpeptide aminopeptidase N (APN) inhibitors with a N-phenylphthalimide or N-phenylhomophthalimide skeleton were prepared. Evaluation of their protease inhibitory activities revealed that (i) some N-phenylphthalimide analogs are potent APN inhibitors, but they are also inhibitors of another protease, dipeptidylpeptidase IV (DPP-IV), and (ii) some N-phenylhomophthalimide analogs, including 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22), are potent and specific inhibitors of APN without DPP-IV-inhibitory activity. The structure-activity relationship studies of N-phenylphthalimides and N-phenylhomophthalimides are reviewed. PIQ-22 showed potent tumor-cell invasion-inhibitory activity.

Synthesis of the novel analogues of dysidiolide and their structure-activity relationship.

The novel analogues of natural cdc25A inhibitor dysidiolide were synthesized. To investigate the structure-activity relationship, the inhibitory activity to enzyme and cell cycle was examined.

Co-existence of α-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development

Liver X receptors (LXR), which were originally reported as oxysterol-activated nuclear receptors, were recently found to recognize glucose as a physiological ligand. On this basis, we have already developed novel LXR antagonists based upon alpha-glucosidase inhibitors derived from thalidomide. Here, to clarify the relationship between alpha-glucosidase inhibition and LXR modulation, we investigate the alpha-glucosidase-inhibitory activity of typical LXR ligands and the LXR-modulating activity of typical alpha-glucosidase inhibitors. Although there were some exceptions, co-existence of LXR-regulatory and alpha-glucosidase-inhibitory activities seemed to be rather general among the examined compounds. The LXR ligands were found to be non-competitive alpha-glucosidase inhibitors, suggesting that it might be possible to separate the two activities. To test this idea, we focused on riccardin C, a naturally occurring LXR ligand, which we found here to be a potent alpha-glucosidase inhibitor as well. Structural development of riccardin C afforded novel LXR antagonists lacking alpha-glucosidase-inhibitory activity, 19c and 19f, and a LXRalpha-selective antagonist, 22.

Antiproliferative and apoptosis-inducing activities of alkyl gallate and gallamide derivatives related to (-)-epigallocatechin gallate.

Green tea and (-)-epigallocatechin gallate (EGCG: one of the main components of green tea) are reported to have cancer-preventive activity in humans. A previous SAR study of EGCG and derivatives indicated that a galloyl group is essential for the activity. To test this hypothesis, we synthesized various alkyl gallate and gallamide derivatives and evaluated their antiproliferative effects on human leukemia HL-60 cells. Dodecyl 3,4,5-trihydroxybenzoate (6c) showed the most potent activity, being more potent than EGCG. To clarify the molecular mechanism of the antiproliferative action, we investigated the effects of 6c on various factors. Compound 6c was found to induce apoptosis mediated by endoplasmic reticulum (ER)-stress-related caspase-12. Upregulation of gadd-153, an ER-stress marker protein, was also observed. These results indicate that 6c induced apoptosis via the ER-stress-related pathway.

Synthesis of a novel class of cdc25A inhibitors from Vitamin D3

We have developed a novel class of cdc25A inhibitors by drastic modification of the hydrophobic and hydrophilic substructures of dysidiolide. The unsaturated derivative 3b strongly inhibited cdc25A (IC50 = 7.7 microM) and caused GI arrest of HL60 cells.

Concise asymmetric synthesis of dysidiolide

The cdc25A protein phosphatase inhibitor dysidiolide (1) has been synthesized via intermolecular Diels–Alder reaction of the triene 4 with crotonaldehyde and construction of a quaternary carbon center by methylation of the exocyclic enolate.

Unnatural enantiomer of chaetocin shows strong apoptosis-inducing activity through caspase-8/caspase-3 activation.

Chaetocin, a natural product isolated from Chaetomium species fungi, was reported to have various biological activities, including antitumor and antifungal activities. Recently, we reported the first total synthesis of chaetocin and its derivatives. Here, we examined the cell-death-inducing activity of these compounds in human leukemia HL-60 cells. The unnatural enantiomer of chaetocin (ent-chaetocin) was more potent than chaetocin, and was found to induce apoptosis through the caspase-8/caspase-3 activation pathway.

Development of selective inhibitors of necrosis

Oxidative stress-induced necrosis plays an important role in ischemia-reperfusion injury, such as stroke and heart attack. Here, we describe the development of selective inhibitors of necrosis, MS-1 and IM-54, as potential cardioprotective agents and biological tools for investigating the molecular mechanisms of cell death. By means of chemical modifications of kinase inhibitor BM I, its affinity for various kinases was successfully removed and a potent and selective inhibitor of necrosis, IM-54, was obtained. IM-54 inhibits necrosis induced by oxidative stress, but not apoptosis induced by anticancer drugs.

Retinobenzaldehydes as proper-trafficking inducers of folding-defective P23H rhodopsin mutant responsible for retinitis pigmentosa.

The Retinitis pigmentosa (RP)-causing mutant of rhodopsin, P23H rhodopsin, is folding-defective and unable to traffic beyond the endoplasmic reticulum (ER). This ER retention, and in some cases aggregation, are proposed to result in ER-stress and eventually cell death. The endogenous rhodopsin ligand 11-cis-retinal and its isomer 9-cis-retinal have been shown to act as pharmacological chaperones, promoting proper folding and trafficking of the P23H rhodopsin. In spite of this promising effect, the development of retinals and related polyenealdehydes as pharmacological agents has been hampered by their undesirable properties, which include chemical instability, photolability, and potential retinoidal actions. Here, we report the design and synthesis of a class of more stable nonpolyene-type rhodopsin ligands, structurally distinct from, and with lower toxicity than, retinals. A structure-activity relationship study was conducted using cell-surface expression assay to quantify folding/trafficking efficiency of P23H rhodopsin.