Biomimetic Synthesis of Chaxine and its Related Compounds.

The highly oxidized natural products chaxine B and BB have been synthesized from ergosterol in eight steps according to a route inspired by their proposed biosynthesis; key steps were an oxidative cascade from a furan intermediate to an enol ester using m-chloroperbenzoic acids (MCPBA), followed by diastereoselective epoxidation and acyloxy migration. This concise synthesis resulted in the revision of the structures of chaxine B and its naturally occurring analogs and syntheses of the unnatural analogues of these natural products for biological investigations.

Identification of an Asexual Reproduction Inducer of Phytopathogenic and Toxigenic Fusarium.

Asexual and sexual reproduction are the most important biological events in the life cycle of phytopathogenic and toxigenic Fusarium and are responsible for disease epidemics. However, the signaling molecules which induce the asexual reproduction of Fusarium are unknown. Herein we describe the structure elucidation, including the absolute configuration, of Fusarium asexual reproduction inducer (FARI), a new sesquiterpene derivative, by spectroscopic analysis, total synthesis, and conidium-inducing assays of synthetic isomers. We have also uncovered the universality of FARI among Fusarium species. Moreover, a mechanism-of-action study suggested that the Gpmk1 and LaeA signaling pathways are required for conidium formation induced by FARI; conversely, the Mgv1 of mitogen-activated protein kinase is not involved in conidium formation. FARI exhibited conidium-inducing activity at an extremely low dose and high stereoselectivity, which may suggest the presence of a stereospecific target.

Combined Effects of Amino Acids in Garlic and Buna-Shimeji (Hypsizygus marmoreus) on Suppression of CCl4-Induced Hepatic Injury in Rats.

The combination of the garlic-derived amino acid, S-allyl-l-cysteine sulfoxide (ACSO), and ornithine or arginine on CCl4-induced hepatic injury was examined. After investigating the effectiveness of the mixture of ACSO and ornithine or arginine in preventing hepatic injury in vivo, an extract rich in ACSO and ornithine was prepared by converting arginine in garlic to ornithine by arginase from Hypsizygus marmoreus (buna-shimeji), after screening the productivity of ornithine among 12 kinds of mushrooms. Co-administration of ACSO with ornithine or arginine suppressed the increase in aspartate transaminase, alanine transaminase, and thiobarbituric acid reactive substance, and the decrease in glutathione S-transferase and cytochrome p450 2E1 activities after CCl4 injection more effectively than a single administration of ACSO. All extracts prepared from garlic and buna-shimeji with low and high contents of ACSO and arginine or ornithine significantly suppressed CCl4-induced hepatic injury in rats. Considering that ACSO is tasteless, odourless, and enhances taste, and ornithine has a flat or sweet taste and masks bitterness, the extract rich in ACSO and ornithine from garlic and buna-shimeji could be considered a potential antioxidant food material that can be added to many kinds of food to prevent hepatic injury.

Visualization of AMPA receptors in living human brain with positron emission tomography.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

Biomimetic Synthesis and Structural Revision of Chaxine B and Its Analogues.

Chaxine B and its analogues were synthesized from ergosterol in eight steps on the basis of our proposed biosynthetic pathway, which includes a highly site-selective and regioselective Baeyer-Villiger oxidation as the key step. This synthesis enabled the revision of the structures of chaxine B and its analogues.