Total synthesis of diaporthichalasin by using the intramolecular Diels-Alder reaction of an α,ß-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,ß-unsaturated γ-hydroxy-γ-lactam in aqueous media was effectively employed as the key step. From this synthetic study, we found that α,ß-unsaturated γ-hydroxy-γ-lactam is an essential precursor for the construction of the diaporthichalasin-type pentacyclic skeleton. This important finding strongly suggests that this route is involved in the biosynthetic pathway for diaporthichalasin.

A novel convergent method for the synthesis of α-acyl-γ-hydroxylactams and its application in the total synthesis of PI-090 and 091.

A novel convergent method for the synthesis of α-acyl-γ-hydroxylactams utilizing the aldol reaction of N-Boc-protected γ-methoxylactams was developed. As the first application of this method for the synthesis of biologically active natural products, the total synthesis of platelet aggregation inhibitors PI-090 and PI-091 were also investigated and successfully achieved.

Discovery of a new type inhibitor of human glyoxalase I by myricetin-based 4-point pharmacophore.

The human glyoxalase I (hGLO I), which is a rate-limiting enzyme in the pathway for detoxification of apoptosis-inducible methylglyoxal (MG), has been expected as an attractive target for the development of new anti-cancer drugs. We have previously identified a natural compound myricetin as a substrate transition-state (Zn(2+)-bound MG-glutathione (GSH) hemithioacetal) mimetic inhibitor of hGLO I. Here, we constructed a hGLO I/inhibitor 4-point pharmacophore based on the binding mode of myricetin to hGLO I. Using this pharmacophore, in silico screening of chemical library was performed by docking study. Consequently, a new type of compound, which has a unique benzothiazole ring with a carboxyl group, named TLSC702, was found to inhibit hGLO I more effectively than S-p-bromobenzylglutathione (BBG), a well-known GSH analog inhibitor. The computational simulation of the binding mode indicates the contribution of Zn(2+)-chelating carboxyl group of TLSC702 to the hGLO I inhibitory activity. This implies an important scaffold-hopping of myricetin to TLSC702. Thus, TLSC702 may be a valuable seed compound for the generation of a new lead of anti-cancer pharmaceuticals targeting hGLO I.