Kenichiro Shimokawa

Biological activity, structural features, and synthetic studies of (-)-ternatin, a potent fat-accumulation inhibitor of 3T3-L1 adipocytes.

A series of studies, including preliminary screening, isolation, structure determination, synthesis, and biological evaluation, of (-)-ternatin (1) are described. A highly N-methylated cyclic heptapeptide isolated from the mushroom Coriolus versicolor, 1 shows an inhibitory effect on fat accumulation by 3T3-L1 murine adipocytes (EC50 = 0.02 microg mL(-1)). Detailed analysis of 1D and 2D NMR spectra, as well as amino acid analysis, suggested four stereoisomers as candidates for 1. For the complete structural elucidation of 1, chemical syntheses were carried out by solid-phase peptide synthesis. By comparing the spectroscopic data for the natural product with the data for the synthetic stereoisomers, the structure of 1 was confirmed to be cyclo[D-allo-Ile1-L-(NMe)Ala2-L-(NMe)Leu3-L-Leu4-L-(NMe)Ala5-D-(NMe)Ala6-(2R,3R)-3-hydroxy-Leu7].

Asymmetric synthesis via heteroconjugate addition: valinol template as oxazolidine heteroolefin vs acetylenic nucleophiles

Abstract Abstract The diastereoselective CC bond forming reaction via heteroconjugate addition strategy was expanded for asymmetric synthesis. A valinol derivative was employed as chiral template to induce chelation control in the heteroconjugate addition of alkyls and alkynyls.

(-)-Ternatin inhibits adipogenesis and lipid metabolism in 3T3-L1 cells.

(-)-Ternatin, a highly N-methylated cyclic peptide, inhibits fat accumulation in 3T3-L1 cells and reduces fat mass in mice. However, the mechanism for its anti-adipogenic effect has remained unknown. To examine the mechanism used by (-)-ternatin to inhibit adipocyte differentiation, we examined the effects of (-)-ternatin and [l-Ala(4)]ternatin, an inactive analog of (-)-ternatin, on the expression of adipocyte markers and lipogenic enzymes. We found that (-)-ternatin potently reduced mRNA expression of several adipocyte markers in a dose-dependent manner, whereas [l-Ala(4)]ternatin showed no effects. At the immediate early phase, (-)-ternatin, but not [l-Ala(4)]ternatin, reduced the expression of Srebp1c, Fas, Acc2 and C/EBP-alpha while showing no effects on C/EBP-beta and C/EBP-delta. These results suggest that (-)-ternatin affects the mid-to late differentiation stages of adipocytes. Consistent with the decreased expression of lipogenic enzymes, (-)-ternatin potently inhibited triglyceride synthesis. Intriguingly, (-)-ternatin also inhibited triglyceride synthesis in rat primary hepatocytes, suggesting that the potential action sites for (-)-ternatin are shared by adipocytes and liver. Although the target molecule of (-)-ternatin remains unknown, our data suggest that (-)-ternatin and its potential target might provide a new therapeutic approach to metabolic disorders.

Synthesis and inhibitory effect on fat accumulation of (−)-ternatin derivatives modified in the β-OH-D-Leu7 moiety

An efficient synthesis of (-)-ternatin derivatives directed toward their SAR at the beta-OH-D-Leu(7) moiety and their biological activities against 3T3-L1 murine adipocytes are described.

Whole Structure−Activity Relationships of the Fat-Accumulation Inhibitor (−)-Ternatin: Recognition of the Importance of Each Amino Acid Residue

A series of Ala and Aoc analogues of (-)-ternatin were prepared, and their bioactivities were assessed by a fat-accumulation inhibition assay using 3T3-L1 adipocytes, which led to the discovery of key structure-activity relationships (SAR).

Importance of the backbone conformation of (−)-ternatin in its fat-accumulation inhibitory activity against 3T3-L1 adipocytes

Key relationships between the intramolecular H-bond-derived backbone conformation and the bioactivity of the novel fat-accumulation inhibitor (-)-ternatin are examined by analyses of the NMR spectroscopic data and CD spectra of designed analogues. The results reveal that the beta-turn structure of (-)-ternatin is responsible for its potent fat-accumulation inhibitory effect against 3T3-L1 murine adipocytes.

Design, synthesis, and biological evaluation of biotin-labeled (-)-ternatin, a potent fat-accumulation inhibitor against 3T3-L1 adipocytes.

The design, synthesis, and biological activity of biotin-labeled (-)-ternatin are reported. Chemical modification, that is, biotinylation, was conducted using Click chemistry at the 6-position (NMe-D-ProGly moiety), which was a plausible location selected on the basis of our SAR studies. The compound displayed sufficient fat-accumulation inhibitory effect against 3T3-L1 adipocytes for further bio-organic studies.

Methodology for stereochemical control in bioactive natural product synthesis - new methods toward enediyne antitumor antibiotics

ABSTRACT Acetylenic compounds are of great interests in the development of the synthetic methodologies directed toward enediyne antitumor antibiotics. This paper discusses on the new asymmetric synthesis via heteroconjugate addition methodology by utilizing acetylide carbanions as the nucleophiles. On the other hand, silyl acetylenes can be nucleophiles under acidic condition and the products are quite useful as the precursor of heteroolefins. Most of the reactions undergo in highly stereoselective.

Structure-based hybridization of the bioactive natural products rhizonin A and ternatin leading to a selective fat-accumulation inhibitor against 3T3-L1 adipocytes

Based on the structural similarity between the naturally occurring cyclic heptapeptides rhizonin A and ternatin, two novel analogues were designed. The synthetic analogues were assessed with regard to their fat-accumulation inhibitory effect against 3T3-L1 adipocytes, and this led to the discovery of a potent and selective fat-accumulation inhibitor compared to the parent compound rhizonin A.