Ryuichi Shirai

Enantioselective Deprotonation by Chiral Lithium Amide Bases: Asymmetric Synthesis of Trimethylsilyl Enol Ethers from 4-Alkylcyclohexanones

Some reactions of bases of type (I), generated by action of BuLi on the corresponding amide, with cyclohexanones of type (II) are examined.

Asymmetric synthesis of antimitotic combretadioxolane with potent antitumor activity against multi-drug resistant cells.

The (S,S)-enantiomer of combretadioxolane (3), designed as a chirally preorganized derivative of combretastatin A-4, exhibited quite strong tubulin polymerization-inhibitory activity (IC50: 4-6 microM). (S,S)-3 is 20 times more potent than vincristine as an in vitro growth inhibitor (in terms of GI50) of the multi-drug-resistant (MDR) cell line PC-12, which produces P-glycoprotein.

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.

Evidence that 3′-phosphorylated polyphosphoinositides are generated at the nuclear surface: use of immunostaining technique with monoclonal antibodies specific for PI 3,4-P2

Phosphatidylinositol (PI) 3,4‐P2 is a phosphoinositide that has been shown to be important for signal transduction in growth factor stimulation. We have produced monoclonal antibodies specific for PI 3,4‐P2, which were able to detect PI 3,4‐P2 generated in 293T cells treated with H2O2, or in MKN45/BD110 cells expressing activated PI 3‐kinase in immunostaining. Prolonged treatment with 0.05% Tween 20 resulted in detection of staining not only at the plasma membrane, but also at the nuclear surface, indicating that 3′‐phosphorylated phosphoinositides can be generated and function in the nucleus.

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.

Specific detection of phosphatidylinositol 3,4,5-trisphosphate binding proteins by the PIP3 analogue beads: An application for rapid purification of the PIP3 binding proteins

Phosphatidylinositol (PI) 3-kinase is known as one of the key molecules involved in the various biological events such as vesicle trafficking, cytoskeletal rearrangements and cell survival. T clarify the molecular basis underlying these events, we have tried to identify the proteins that can interact with phosphatidylinositol 3,4,5-trisphosphate (PIP3), the lipid product of PI3-kinase. Using a new PIP3 analogue, PIP3-APB, we synthesized an affinity column for PIP3 binding proteins. This enabled us to purify and identify several PIP3 binding proteins such as Tec tyrosine kinase, Gap1m, and Akt, as the candidates for the downstream molecules of PI3-kinase. All of these proteins contain PH domains, possible binding sites for phospholipids. Studies with various deletion mutants of Tec or Gap1m revealed that their PH domains are indeed the binding sites for PIP3. These results demonstrate that this PIP3-analogue binds various PIP3 binding proteins with high specificity and may be useful to elucidate the downstream mechanisms of PI3-kinases-mediated signaling pathways.

Enantioselective deprotonation of the monoacetals of bicyclo[3.3.0]octan-3,7-dione. An approach to the asymmetric synthesis of chiral synthons for carbacyclins

Abstract Kinetic deprotonation of the monoacetals (4) of bicyclo[3.3.0]octan-3,7-dione by chiral lithium amides (5) in the presence of excess trimethylsilyl chloride afforded the corresponding silyl enol ethers (6), useful synthons for the synthesis of optically active carbacyclins, in up to 94% ee.

A mild and selective deprotection of p-methoxybenzyl (PMB) ether by magnesium bromide diethyl etherate-methyl sulfide

Abstract The magnesium bromide diethyl etherate (MgBr 2 ·OEt 2 )-methyl sulfide (Me 2 S) system is useful for the mild and chemo-selective deprotection of p -methoxybenzyl (PMB) ether in the presence of 1,3-diene, t -butyldimethylsilyl (TBDMS) ether, benzoate, benzyl ether and acetonide.

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.