Comparative inhibition of tetrameric carbonyl reductase activity in pig heart cytosol by alkyl 4-pyridyl ketones.

CONTEXT AND OBJECTIVE: The present study is to elucidate the comparative inhibition of tetrameric carbonyl reductase (TCBR) activity by alkyl 4-pyridyl ketones, and to characterize its substrate-binding domain. MATERIALS AND METHODS: The inhibitory effects of alkyl 4-pyridyl ketones on the stereoselective reduction of 4-benzoylpyridine (4-BP) catalyzed by TCBR were examined in the cytosolic fraction of pig heart. RESULTS: Of alkyl 4-pyridyl ketones, 4-hexanoylpyridine, which has a straight-chain alkyl group of five carbon atoms, inhibited most potently TCBR activity and was a competitive inhibitor. Furthermore, cyclohexyl pentyl ketone, which is substituted by cyclohexyl group instead of phenyl group of hexanophenone, had much lower ability to be reduced than hexanophenone. DISCUSSION AND CONCLUSION: These results suggest that in addition to a hydrophobic cleft corresponding to a straight-chain alkyl group of five carbon atoms, a hydrophobic pocket with affinity for an aromatic group is located in the substrate-binding domain of TCBR.

Formation mechanism of triketo cage compounds from reaction of phencyclone with benzoquinones: cascade reaction of intermolecular [4+2]π and intramolecular [2+2]π cycloadditions.

The [4+2]π cycloadduct (3aa) of phencyclone (1a) and benzoquinone (2a) readily transformed into the corresponding [2+2]π cycloadduct (4aa) during purification. The structure of the triketo cage compound was determined by single crystal X-ray analysis. The structure-reactivity relationships are discussed based on the PM6-calculated energy profiles for the whole photocycloaddition of the [4+2]π cycloadducts of some cyclopentadienones and benzoquinones.

A new diterpenoid from the leaves of Clerodendron trichotomum.

A new diterpenoid was isolated from the leaves of Clerodendron trichotomumThunb. (Verbenaceae) along with one each of a known diterpenoid, phenylethanoid glycoside, and sterol and two known flavonoids. Their chemical structures were characterized on the basis of spectroscopic data and X-ray analysis. In addition, their antioxidant activities were evaluated using four different analyses.

Formation mechanism of furfuryl sulfides from o-furfuryl dithiocarbonates: density functional theory study for aromatic [3,3]-sigmatropic rearrangement.

Density functional theory (DFT) calculations at the B3LYP/6-31G(d) and B3LYP/6-31G+(d) levels demonstrated that O-furfuryl S-alkyl dithiocarbonate (1) undergoes aromatic [3,3]-sigmatropic rearrangement to the energetically unfavorable S-(2-methylene-2,3-dihydrofuran-3-yl) S-alkyl dithiocarbonate (2'), which then rearranges to furfuryl alkyl sulfide (3) with COS extrusion to regain the aromaticity lost in the first step.

New formation mechanism of allylic trithiocarbonates from sodium O-(2-Alkenyl) dithiocarbonates via sequential pericyclic reactions: Density functional theory study.

Density functional theory (DFT) calculations at the B3LYP/6-31G(d) level demonstrated that sodium O-(3-phenylallyl) dithiocarbonate undergoes [3,3]-sigmatropic rearrangement to sodium S-(1-phenylallyl) dithiocarbonate, which then isomerizes to the more thermodynamically stable sodium S-(3-phenylallyl) dithiocarbonate. The calculations also showed that sodium 2-alkenyl trithiocarbonates and their esters are more labile towards the allylic rearrangement.

Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein.

The inhibitory effects of flavonoids on the human cytochrome P450 1A2 (CYP1A2) were examined. Among flavonoids tested, galangin, kaempferol, chrysin, and apigenin were potent inhibitors. Although apigenin belonging to flavones and genistein belonging to isoflavones are similar in the chemical structures, the inhibitory potencies for CYP1A2 were distinguished markedly between these two flavonoids. In computer-docking simulation, apigenin interacted with the same mode of cocrystallized alpha-naphthoflavone in the active site of CYP1A2, and then the B ring of apigenin was placed close to the heme iron of the enzyme with a single orientation. In contrast, the docked genistein conformation showed two different binding modes, and the A ring of genistein was oriented to the heme iron of CYP1A2. Furthermore, the binding free energy of apigenin was lower than that of genistein. These results demonstrate a possible mechanism that causes the differential inhibitory potencies of apigenin and genistein for CYP1A2.

Crystallographic evidence for cyclopropane ring formation in isotwistenes obtained by thermal cascade reactions of cyclopentadienone with acyclic conjugated dienes.

The molecular structure of the double Diels-Alder (DDA) adduct derived from three-step thermal cascade reactions of 2,5-bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone with ethyl sorbate is elucidated by single crystal X-ray analysis. The structural features and the reaction mechanism of the adduct are discussed on the basis of density functional theory (DFT) calculation results.

A new homostilbene and two new homoisoflavones from the bulbs of Scilla scilloides.

A new homostilbene, named scillabene A (2), and two new homoisoflavones, named scillavones A (3) and B (4), were isolated from the bulbs of Scilla scilloides DRUCE (Liliaceae) along with 13 known compounds comprising a homostilbene, seven homoisoflavones, a xanthone, a lignan, and three nortriterpenes. The structures of 2-4 were characterized as 3,5,4'-trihydroxy-3'-methoxy-4-methyl-trans-stilbene, (3R)-5,7,2'-trihydroxy-3',4'-dimethoxyspiro{2H-1-benzopyran-7'-bicyclo[4,2,0]octa[1,3,5]-trien}-4-one and (3S)-3-(3,4-dihydroxybenzyl)-5-hydroxy-6,7-dimethoxychroman-4-one, respectively, on the basis of spectroscopic data and X-ray crystallographic analysis.

Bisabolane-type sesquiterpenes from the aerial parts of Lippia dulcis.

Six new bisabolane-type sesquiterpenes, peroxylippidulcines A-C (3-5), peroxyepilippidulcine B (6), and epilippidulcines B (7) and C (8), have been isolated from the aerial parts of Lippia dulcis, along with two known bisabolane-type sesquiterpenes, seven known flavonoids, and a known triterpenoid. The structures of 3-8 were characterized on the basis of NMR, MS, specific rotation, and X-ray crystallographic analysis data and chemical evidence.

Functional and structural effects of mutagenic replacement of Asn37 at subsite F on the lysozyme-catalyzed reaction.

To investigate the functional role of subsites E and F in lysozyme catalysis, Asn37 of hen egg-white lysozyme (HEL), which is postulated to participate in sugar residue binding at the right-sided subsite F through hydrogen bonding, was replaced by Ser or Gly by site-directed mutagenesis. The mutations of Asn37 neither significantly affected the binding constant for chitotriose nor the enzymatic activity toward the substrate glycol chitin. However, kinetic analysis with the substrate N-acetylglucosamine pentamer, (GlcNAc)(5), revealed that the conversion of Asn37 to Gly decreased the binding free energies for subsites E and F, while the conversion to Ser increased the substrate affinity at subsite F. It was further found that the rate constant of transglycosylation was reduced by these mutations. These results suggest that Asn37 is involved not only in substrate binding at subsite F but also in transglycosylation activity. No remarkable change in the tertiary structure except the side chain of the 37th residue was detected on X-ray analysis of the mutant proteins, indicating that the alterations in the enzymatic function between the wild type and mutant enzymes depend on limited structural change around the substitution site. It is thus speculated that the slight conformational difference in the side chain of position 37 may affect the substrate and acceptor binding at subsites E and F, leading to lower the efficiency of the transglycosylation activities of the mutant proteins.

Pericyclic reaction of ketenes with cascade reaction products of pyridine N-oxides and dipolarophiles. X-ray structures of the adducts and formation mechanism.

The structures of the adducts derived from the reactions of substituted ketenes with dihydropyridine derivatives have been clarified by single crystal X-ray analyses and the formation mechanism is discussed on the basis of the reaction-path calculations by semiempirical and density functional theory (DFT) molecular orbital methods.

Carboxylic acid clathrate hosts of Diels-Alder adducts of phencyclone and 2-alkenoic acids. Role of bidentate C-H ... O hydrogen bonds between the phenanthrene and carbonyl groups in host-host networks.

Carboxylic acid host compounds (3) having a phenanthrene-condensed bicyclo[2.2.1]hept-2-en-7-one skeleton have been synthesized by the [4 + 2]pi cycloaddition of phencyclone (1a) with 2-alkenoic acids (2) and their inclusion behavior was investigated. The endo [4 + 2]pi cycloadducts (3) enclathrated alcohols and ethers besides aromatics and ketones. The X-ray crystallographic analysis of the inclusion compound (3ac-dioxane) of the endo [4 + 2]pi cycloadduct (3ac) of phencyclone and trans 2-butenoic acid (2c) indicated that dioxanes are located at the opposite side of the bridged carbonyl of the bicyclo[2.2.1]hept-2-en-7-one moiety, in which the O-H...O and C-H...O hydrogen bonds play an important role in the inclusion complex formation. Similarly, a pair of 3-pentanone molecules were included in the endo [4 + 2] pi cycloadduct (3ae) of 1a and cinnamic acid (2e). In both cases, the hosts are linked by the edge-to-face interaction between the phenanthrene and phenyl rings and the "bidentate" C-H...O hydrogen bonds between the phenanthrene-ring hydrogens and the bridged carbonyl or the carboxylic carbonyl group. The endo [4 + 2] pi cycloadduct (3bl) of tetracyclone (1b) and acrylamide (2l) also showed a wide-range inclusion behavior, in which alcohols are included by making a hydrogen-bond loop with the amide groups. The inclusion behavior of the carboxylic acid Diels-Alder hosts is discussed on the basis of the single crystal X-ray analysis, thermal analysis and semiempirical molecular orbital calculation data.

Atropisomers of 1-(acyl or aroyl)-2-naphthylindolines. Isolation, X-ray crystal structure and conformational analysis.

A series of pairs of stable diastereomeric atropisomers caused by restricted rotation around the Csp3-Csp2 bond of [2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-(3- or 4-substituted phenyl)-methanone or [2-(2-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]-1-alkanone were isolated. The conformational analyses of the atropisomers were performed based on the X-ray crystallographic and (1)H-NMR spectral data. It became clear that rotation about the C2-naphthyl bond is restricted at room temperature, whereas the >NCO-Ar bond rotates freely.

Cascade reaction of imines with phenylsulfinylallene. X-ray structure of the product and its formation mechanism.

The structure of the product derived from the reaction of a dihydropyridine derivative with phenylsulfinylallene has been clarified by a single crystal X-ray analysis and the formation mechanism is discussed on the basis of the reaction-path calculations by semiempirical and ab initio molecular orbital methods.

Preparation and Stereochemistry of Dioxatetraazaperhydroanthracenes and -perylenes from the Reaction of 2-Hydrazinoethanols with Aldehydes and Glutaraldehyde.

Hydrazinoethanols 1 were reacted with aldehydes 2 and 6 and glutaraldehyde (14) in aqueous solution to give dioxatetraazaperhydroanthracenes 3, 7, 12, and 13 and -perylenes 15 in yields of 19-88 and 42-72%, respectively. Compounds 3, 7, 12, and 15 were deduced by (13)C-NMR spectra to have two C(2) symmetry axes, while compound 12 was shown to have a symmetry axis by X-ray crystallography. The most favorable stereoisomers were consistent with predictions obtained by the semiempirical molecular orbital method AM1. The structure of compound 15 was confirmed by X-ray crystallography.