Skin- and airway-deliverable TRPA1 inhibitor.

This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists.

Concise total synthesis of (-)-berkelic acid regioselective spiroacetal/pyran formation.

We successfully developed (1) scalable synthesis of the triol segment and (2) regio- and stereoselective synthesis of the tetracyclic skeleton by tandem spiroacetal/pyran formation from a simpler alkyne precursor, resulting in the achievement of concise total synthesis of (-)-berkelic acid.

Concise Total Synthesis and Biological Evaluation of Pargamicin A and its Diastereomer, Piperazic Acid-containing Cyclopeptides.

We have accomplished the total synthesis, structure determination, and biological evaluation of pargamicin A and one of its diastereomers. Two key tripeptide segments were synthesized using a linear peptide elongation process that includes the direct coupling of a poorly nucleophilic piperazic acid derivative. The resulting tripeptides were coupled using triphosgene/collidine at ambient temperature leading to a precursor for the final cyclization step.

Concise total synthesis and structure revision of metacridamides A and B.

Concise total synthesis of metacridamides A and B was accomplished through repetitive vinylogous Mukaiyama aldol reactions and ynamide-mediated macrolactonization. Spectral data of both synthetic products were identical to those of the natural products, resulting in the revision of the absolute configuration of the C-9 position to be .

Total Synthesis of Aplysiasecosterols A and B, Two Marine 9,11-Secosteroids.

The total synthesis of aplysiasecosterols A and B has been accomplished. Key features of the synthesis include the Suzuki-Miyaura coupling of each AB-ring segment and common D-ring segment. The AB-ring segment of aplysiasecosterol B was synthesized by Shi asymmetric epoxidation as a key reaction.

Isolation and Synthesis of Azuriaplysins A and B, Bromoditerpenes with an α-Methylene Carbonyl from the Sea Hare .

New bromoditerpenes having an α-methylene carbonyl structure, azuriaplysins A () and B (), were isolated from the sea hare . Their relative stereostructures were determined based on one- and two-dimensional NMR spectroscopic analysis. In addition, the absolute stereostructures were determined by the total synthesis of both enantiomers of azuriaplysins A () and B (), the key points of which were bromocyclization of farnesol and optical resolution of a key intermediate.

Structure Revision of Trichomide D by Total Synthesis.

A structure revision of trichomide D has been achieved by its total synthesis. The sterically hindered peptide sequence was successfully prepared using not only a conventional amidation with EDCI but also coupling with an Fmoc-protected amino acid chloride derivative. The cyclization precursor was synthesized by coupling of a tetrapeptide with an acylproline derivative and subsequent removal of silyl groups at the N- and C-termini.

Total Synthesis of a PPAP, Nemorosonol, Using a Tandem Michael Addition-Intramolecular Aldol Reaction.

A strategy for constructing a tricyclo[4.3.1.

Structure-activity relationship studies on an antitumor marine macrolide using aplyronine a-swinholide A hybrid.

An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and biologically evaluated. This hybrid induced protein-protein interactions between two major cytoskeletal proteins actin and tubulin in the same manner as aplyronine A, and exhibited potent cytotoxicity and actin-depolymerizing activity. The importance of the methoxy group in the ,,-trimethylserine ester was clarified by the structure-activity relationship studies of the amino acid moiety by using the hybrid analogs.

The C29-C34 parts of antitumor macrolide aplyronine A serve as versatile actin-affinity tags.

Anticancer drug development inspired by natural products based on protein-protein interactions (PPI) is a promising strategy. We developed structurally-simplified C29-C34 side-chain analogs of aplyronine A (ApA), an antitumor marine macrolide. Among them, the analog possessing the C23 acyloxy group, the C29 ,-dimethyl-L-alanine ester and the C34 -methyl enamide showed potent actin-depolymerizing activity.

Feasibility of application of an absorbable topical collagen hemostat sheet (INTEGRAN) for prevention of postoperative recurrence of pneumothorax in youths.

Background: Staple-line coverage is an effective method for prevention of postoperative recurrence of pneumothorax. However, the recurrence rate in young patients is still unsatisfactory using this method. Moreover, there is no consensus about the optimal material for use in this technique.

A dynein-associated photoreceptor protein prevents ciliary acclimation to blue light.

Light-responsive regulation of ciliary motility is known to be conducted through modulation of dyneins, but the mechanism is not fully understood. Here, we report a novel subunit of the two-headed f/I1 inner arm dynein, named DYBLUP, in animal spermatozoa and a unicellular green alga. This subunit contains a BLUF (sensors of blue light using FAD) domain that appears to directly modulate dynein activity in response to light.

Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death.

α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor.

Acyl-CoA dehydrogenase long chain (ACADL) is a target protein of stylissatin A, an anti-inflammatory cyclic heptapeptide.

Stylissatin A (SA) is a cyclic heptapeptide isolated from the marine sponge Stylissa massa. SA shows anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cells, but the detailed mechanism of action remains unclear.

Synthesis of 2-(2-Hydroxyethoxy)-3-hydroxysqualene and Characterization of Its Anti-Inflammatory Effects.

Squalene (SQ), a natural precursor of many steroids, can inhibit tumor progression and decrease serum cholesterol levels. However, it is difficult to discern the effect of highly active molecules in the treatment of diseases because not enough active compounds reach the site of pathology in crowded biosystems. Therefore, it is necessary to design artificial probes that work effectively within crowded systems.

N,N-Dimethylaminopyrene as a fluorescent affinity mass tag for ligand-binding mode analysis.

Elucidation of the binding mode of protein-ligand interactions provides insights for the design of new pharmacological tools and drug leads. Specific labeling of target proteins with chemical probes, in which the ligands are conjugated with reacting and detecting groups, can establish the binding positions of ligands. Label-assisted laser desorption/ionization mass spectrometry (LA-LDI MS) is a promising detection method to selectively detect labeled molecules.

Isolated unilateral absence of the pulmonary artery.

Isolated unilateral absence of the pulmonary artery (UAPA) is a rare malformation. It is associated with respiratory symptoms, such as dyspnea or hemoptysis. We suggest that surgical treatment should be positively considered in patients with UAPA who are severely symptomatic and who have no other cardiovascular or respiratory comorbidities.

Synthesis and Biological Activities of Aplyronine A Analogues toward the Development of Antitumor Protein-Protein Interaction Inducers between Actin and Tubulin: Conjugation of the C1-C9 Macrolactone Part and the C24-C34 Side Chain.

Aplyronine A (ApA) is an antitumor marine macrolide that induces an protein-protein interaction (PPI) between actin and tubulin. The C1-C9 macrolactone part including the C7 ,,-trimethylserine (TMSer) ester is important for its highly potent activities. To develop new antitumor PPI inducers, four aplyronine analogues were synthesized, which bear the C1-C9 macrolactone part with 0-2 TMSer ester(s) and the C24-C34 actin-binding side chain.

Toward the Synthesis of Yuzurimine-Type Alkaloids: Stereoselective Construction of the Heterocyclic Portions of Deoxyyuzurimine and Macrodaphnine.

The heterocyclic portions of yuzurimine-type alkaloids, such as deoxyyuzurimine and macrodaphnine, were synthesized by using a stereoselective hydroboration-oxidation reaction to install the C20 methyl group, the intramolecular Mitsunobu reaction to construct the E-ring portion, and the intramolecular S2 reaction to construct the F-ring portion as key steps.

Anti-inflammatory marine cyclic peptide stylissatin A and its derivatives inhibit differentiation of murine preadipocytes.

Stylissatin A, an anti-inflammatory cyclic heptapeptide, and its derivatives potently inhibited the differentiation of preadipocytes and reduced triglyceride accumulation in mature adipocytes, with little cytotoxicity. Our studies might contribute to the development of leads for new anti-inflammatory and anti-obesity agents.

Concise total syntheses of phelligridins A, C, and D.

We have established a concise and scalable synthetic pathway for phelligridins A (1), C (2) and D (3). The synthetic highlights were Suzuki-Miyaura coupling and aldol-type condensation of α-pyrone. Phelligridin A was synthesized in four steps, while phelligridins C and D were each synthesized in six steps.

Whole-genome resequencing to identify candidate genes for the QTL for oleic acid percentage in Japanese Black cattle.

In our previous study, we detected a QTL for the oleic acid percentage (C18:1) on BTA9 in Japanese Black cattle through a genome-wide association study (GWAS). In this study, we performed whole-genome resequencing on eight animals with higher and lower C18:1 to identify candidate polymorphisms for the QTL. A total of 39,658 polymorphisms were detected in the candidate region, which were narrowed to 1993 polymorphisms within 23 genes based on allele differences between the high and low C18:1 groups.

Specific protein-labeling and ligand-binding position analysis with amidopyrene probes as LDI MS tags.

To readily analyze the binding mode of protein-ligand interactions, we developed ligand-bound-type and ligand-dissociation-type probes having 6-amidopyrene (apy) as a detecting group. Matrix- and label-assisted laser desorption/ionization mass spectrometry (MALDI and LA-LDI MS) analyses and a covalent docking simulation using these probes precisely determined the binding position of the ligand biotin on the target protein avidin (RMSD = 0.786 and 0.