Petasin activates AMP-activated protein kinase and modulates glucose metabolism.

Petasin (1), a natural product found in plants of the genus Petasites, has beneficial medicinal effects, such as antimigraine and antiallergy activities. However, whether or not 1 modulates metabolic diseases is unknown. In this study, the effects of 1 on AMP-activated protein kinase (AMPK), which is considered a pharmacological target for treating metabolic diseases, are described. It was found that an extract of Petasites japonicus produces an increase in the phosphorylation of AMPK in vitro, and the main active compound 1 was isolated. When this compound was administered orally to mice, activation of AMPK in the liver, skeletal muscle, and adipose tissue was observed. Moreover, pretreatment with 1 enhanced glucose tolerance following the administration of a glucose solution to normal mice. The mechanism by which 1 activates AMPK was subsequently investigated, and an increased intracellular AMP/ATP ratio in the cultured cells treated with 1 occurred. In addition, treatment with petasin inhibited mitochondrial respiratory chain complex I. Taken together, the present results indicated that 1 modulates glucose metabolism and activates AMPK through the inhibition of mitochondrial respiration. The preclinical data suggested that petasin (1) could be useful for the treatment of metabolic diseases in humans.

Efficient preparation of Fmoc-aminoacyl-N-ethylcysteine unit, a key device for the synthesis of peptide thioesters.

The synthesis of Fmoc-aminoacyl-N-ethyl-S-triphenylmethylcysteine, an N- to S-acyl migratory device for the preparation of peptide thioesters by Fmoc-SPPS (solid-phase peptide synthesis) is described. Condensation of Fmoc-aminoacyl pentafluorophenyl ester and N-ethyl-S-triphenylmethylcysteine was efficiently performed in the presence of HOOBt (3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine) in DMF. A small amount of diastereomer yielded during the reaction was easily separated by HPLC purification and the highly pure devices were obtained for most of the proteinogenic amino acids.

Evaluation of a Novel Boron-Containing α-D-Mannopyranoside for BNCT.

Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as 10B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient 10B concentration within tumors. To address the issue of 10B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that 10B-MMT1242 is a candidate for further clinical BNCT studies.