Hidefumi Makabe

Anti-inflammatory sesquiterpenes from Curcuma zedoaria

From the methanolic extract of the rhizome of Curcuma zedoaria, we isolated anti-inflammatory sesquiterpene furanodiene (1) and furanodienone (2) along with new sesquiterpene compound 3 and known eight sesquiterpenes, zederone (4), curzerenone (5), curzeone (6), germacrone (7), 13-hydroxygermacrone (8), dehydrocurdione (9), curcumenone (10), and zedoaronediol (11). Their structures were elucidated on the basis of spectroscopic data. The anti-inflammatory effect of isolated components on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation of mouse ears were examined. Compounds 1 and 2 suppressed the TPA-induced inflammation of mouse ears by 75% and 53%, respectively, at a dose of 1.0 µmol. Their activities are comparable to that of indomethacin, the normally used anti-inflammatory agent.

Catalytic generation and trapping of acylmetals containing Ni and Cu with enolates

Abstract Carbonylative cyclization of iodoarenes and iodoalkenes containing a proximal enolate precursor can selectively provide either cyclic ketones or lactones in the presence of Ni or Cu catalysts via trapping of putative acylmetal derivatives with C - or O -enolates, respectively; the ring size and regioselectivity of the reaction may be predicted based on two generalizations derived from the recently developed corresponding Pd-catalyzed reaction.

Dynamic function of the spacer region of acetogenins in the inhibition of bovine mitochondrial NADH-ubiquinone oxidoreductase (complex I).

Studies of the action mechanism of acetogenins, the most potent and structurally unique inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase), are valuable in characterizing the inhibitor binding site in this enzyme. Our previous study deepened our understanding of the dynamic function of the spacer region of bis-THF acetogenins [Abe, M., et al. (2005) Biochemistry 44, 14898-14906] but, at the same time, posed new important questions. First, while the two toxophores (i.e., the hydroxylated THF and the gamma-lactone rings) span a distance shorter than that of the extended 13 carbon atoms [-(CH 2) 13-], what is the apparent optimal length of the spacer for the inhibition of 13 carbon atoms? In other words, what is the functional role of the additional methylene groups? Second, why was the inhibitory potency of the mono-THF derivative, but not the bis-THF derivative, drastically reduced by hardening the spacer covering 10 carbon atoms into a rodlike shape [-CH 2-(C identical withC) 4-CH 2-]? This study was designed not only to answer these questions but also to further disclose the dynamic functions of the spacer. We here synthesized systematically designed acetogenins, including mono- and bis-THF derivatives, and evaluated their inhibitory effects on bovine complex I. With regard to the first question, we demonstrated that the additional methylenes enhance the hydrophobicity of the spacer region, which may be thermodynamically advantageous for bringing the polar gamma-lactone ring into the membrane-embedded segment of complex I. With regard to the second question, we observed that a decrease in the flexibility of the spacer region is more adverse to the action of the mono-THF series than that of the bis-THF series. As a cause of this difference, we suggest that for bis-THF derivatives, one of the two THF rings, being adjacent to the spacer, is capable of working as a pseudospacer to overcome the remarkable decrease in the conformational freedom and/or the length of the spacer. Moreover, using photoresponsive acetogenins that undergo drastic and reversible conformational changes with alternating UV-vis irradiation, we provided further evidence that the spacer region is free from steric congestion arising from the putative binding site probably because there is no receptor wall for the spacer region.

Anti-inflammatory Cyathane Diterpenoids from Sarcodon scabrosus

Four novel diterpenoids were isolated from the fruiting bodies of Sarcodon scabrosus (Fr.) Karst. (Boraginaceae) together with neosarcodonin A. One of the novel compounds was elucidated to be a cyathane diterpenoid, namely neosarcodonin O, by its spectral data. The others were characterized as 19-O-linoleoyl, 19-O-oleoyl and 19-O-stearoyl derivatives of sarcodonin A, after comparison with the authentic samples synthetically prepared from sarcodonin A. These compounds, together with the five 19-O-acyl derivatives synthesized from sarcodonin A, each exhibited inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation on mouse ears by topical application.

AN EFFICIENT SYNTHESIS OF PROCYANIDINS USING EQUIMOLAR CONDENSATION OF CATECHIN AND/OR EPICATECHIN CATALYZED BY YTTERBIUM TRIFLATE

Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensation of equimolar amount of catechin derivatives catalyzed by Yb(OTf) 3 . The coupled products were successfully converted to procyanidins B1, B2, B3, and B4, respectively. Procyanidins Bl, B2, B3, and B4 could be used as standard compounds for identifying the polyphenols in natural source.

Myrsinoic Acid E, an Anti-inflammatory Compound from Myrsine seguinii

The methanolic extract of Myrsine seguinii yielded the novel anti-inflammatory compound, myrsinoic acid E (1), whose structure was elucidated to be 3,5-digeranyl-4-hydroxy benzoic acid. We synthesized 1- and its 3,5-diprenyl (2) and 3,5-difarnesyl analogues (3). Compounds 1-3 suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation of mouse ears by 59%, 14%, and 69% at a dose of 1.4 μmol.

Synthesis of annonaceous acetogenins from muricatacin.

Synthetic studies of annonaceous acetogenins starting from (−)-muricatacin (1a) or (+)-muricatacin are described, involving (−)-muricatacin (1a), mono-THF acetogenin, solamin (2), reticulatacin (3), (15R, 16R, 19S, 20S)-cis-solamin (4a) and (15S, 16S, 19R, 20R)-cis-solamin (4b), non-adjacent bis-THF acetogenin, 4-deoxygigantecin (5), and epoxide-bearing acetogenin, (15S, 16R, 19S, 20R)-diepomuricanin (6a).

Total synthesis of (15S, 16R, 19S, 20R, 34S)-diepomuricanin☆

An eleven-step reaction sequence starting from enantiomerically pure (−)-muricatacin (6) afforded the key intermediate 12, which was then converted to (15S, 16R, 19S, 20R, 34S)-diepomuricanin (1) via introduction of an acetylene unit and a coupling reaction with iodo lactone synthon 15.

Winners of CASMI2013: Automated Tools and Challenge Data.

CASMI (Critical Assessment of Small Molecule Identification) is a contest in which participants identify the molecular formula and chemical structure of challenging molecules using blind mass spectra as the challenge data. Seven research teams participated in CASMI2013. The winner of CASMI2013 was the team of Andrew Newsome and Dejan Nikolic, the University of Illinois at Chicago, IL, USA. The team identified 15 among 16 challenge molecules by manually interpreting the challenge data and by searching in-house and public mass spectral databases, and chemical substance and literature databases. MAGMa was selected as the best automated tool of CASMI2013. In some challenges, most of the automated tools successfully identified the challenge molecules, independent of the compound class and magnitude of the molecular mass. In these challenge data, all of the isotope peaks and the product ions essential for the identification were observed within the expected mass accuracy. In the other challenges, most of the automated tools failed, or identified solution candidates together with many false-positive candidates. We then analyzed these challenge data based on the quality of the mass spectra, the dissociation mechanisms, and the compound class and elemental composition of the challenge molecules.

Synthesis of pyranicin and its inhibitory action with bovine heart mitochondrial complex I.

Total synthesis of pyranicin was achieved using Cl2Pd(CH3CN)2-catalyzed diastereoselective cyclization of the allylic ester as the key step. The inhibitory activity of this compound for mitochondrial NADH-ubiquinone oxidoreductase (complex I) was slightly poorer than that of ordinary mono-THF acetogenins such as cis-solamin.