Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content.

Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives.

To develop a novel series of CDK8/19 dual inhibitors, we employed structure-based drug design using docking models based on a library compound, 4,5-dihydroimidazolo[3',4':3,4]benzo[1,2-d]isothiazole 16 bound to CDK8. We designed various [5,6,5]-fused tricyclic scaffolds bearing a carboxamide group to maintain predicted interactions with the backbone CO and NH of Ala100 in the CDK8 kinase hinge region. We found that 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivative 29a showed particularly potent enzymatic inhibitory activity in both CDK8/19 (CDK8 IC: 0.

Total synthesis of diaporthichalasin by using the intramolecular Diels-Alder reaction of an α,β-unsaturated γ-hydroxylactam in aqueous media.

The first total synthesis of diaporthichalasin has been successfully achieved and complete structure elucidation, including the absolute configuration, was also accomplished. The intramolecular Diels-Alder (IMDA) reaction between the diene side chain on the decalin skeleton and α,β-unsaturated γ-hydroxy-γ-lactam in aqueous media was effectively employed as the key step. From this synthetic study, we found that α,β-unsaturated γ-hydroxy-γ-lactam is an essential precursor for the construction of the diaporthichalasin-type pentacyclic skeleton.