Takuya Kumamoto

An approach to anti-HIV-1 active Calophyllum coumarin synthesis: An enantioselective construction of 2,3-dimethyl-4-chromanone ring by quinine-assisted intramolecular Michael-type addition

Abstract (−)-Quinine effectively catalyzes an intramolecular Michael-type addition of 7-hydroxy-8-tigloylcoumarin to give a diastereoisomeric mixture of the corresponding cyclized coumarin with a 2,3-dimethyl-4-chromanone skeleton. Satisfactory enantioselectivity was observed in a cis -chromanone construction, but not in a trans -one.

Synthetic Studies on Kinamycin Antibiotics: Synthesis of a Trioxygenated Benz[f]indenone and its Diels - Alder Reaction to a Kinamycin Skeleton

A benzo[b]fluorene skeleton such as 10, a basic four-ring system in the revised diazo structures 3 of kinamycin antibiotics, was synthesized by Diels-Alder reaction between dienophile 4,7,8-trioxygenated 1H-benz[f]inden-1-one 11 and Danishefsky-type diene 7. The indenone 11 was prepared by deoxygenation of 2,3-dihydro-1H-benz[f]inden-1-one 12 with the inexpensive 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX) after modification of the known protocol. Indenone 12 in turn was obtained from naphthalene-1,5-diol (14) via an intramolecular Friedel-Crafts cyclization of naphthalene-2-propanoic acid 13 as a key step.

Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intramolecular oxo-Michael addition

Abstract Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A was achieved by a quinine-catalyzed asymmetric intramolecular oxo-Michael addition as a key step.

Q172H Replacement Overcomes Effects on the Metabolism of Cyclophosphamide and Efavirenz Caused by CYP2B6 Variant with Arg262

There are a number of reports indicating that CYP2B6*6 (c.516G>T and c.785A>G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.

The structure–activity relationship between oxycoumarin derivatives showing inhibitory effects on iNOS in mouse macrophage RAW264.7 cells

We have investigated the structure–activity relationship between 63 natural oxycoumarin derivatives and their effects on the expression of inducible-nitric oxide synthase (iNOS) induced by lipopolysaccharide. The protein expression of iNOS was screened by Western blot analysis, and four 5,7-dimethoxycoumarins were selected as potent inhibitors of iNOS expression. In terms of structural specificity, the methoxyl group on C-5 and C-7 and the short alkyl chain (1–5 carbons) on C-6 may be essential for the potent activities. These compounds also showed inhibitory effects on nitric oxide generation and mRNA expression of inflammatory mediators, namely, iNOS and COX-2. Interestingly, the inhibitory effect on mRNA expression was specific for iNOS and was not detected for neuronal NOS. It is expected that these compounds will show anti-inflammatory activities via inhibition of the expressions of iNOS and COX-2.

Modified guanidines as chiral superbases: application to asymmetric Michael reaction of glycine imine with acrylate or its related compounds

Modified guanidines efficiently catalysed the asymmetric Michael reaction of a prochiral glycine derivative with acrylate or its related compounds either in solution or without a solvent under simple and mild conditions (>95% ee).

Remarkable Stereocontrol in the Palladium-Catalysed Cyclopropanation of Vinyl- and Dienylboronates by Substituted Diazoalkanes

Substituted diazoalkanes react smoothly, in the presence of catalytic amounts of Pd(OAc)(2), with a range of vinyl- and dienylboronates, affording in good to excellent yields, the corresponding trisubstituted cyclopropanes. The reaction is remarkably regio-, chemo-, and diastereoselective. The synthetic utility of this novel protocol is illustrated by the efficient assembly of the middle fragment of ambruticin.

Simultaneous analysis of six phenethylamine-type designer drugs by TLC, LC-MS, and GC-MS

Extensive data are presented for simultaneous analysis of six phenethylamine-type designer drugs. The drugs are 2,5-dimethoxyphenethylamine (2C-H), 2,5-dimethoxyamphetamine (2,5-DMA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), and 4-iodo-2,5-dimethoxyamphetamine (DOI). The data include their proton nuclear magnetic resonance (NMR) spectra, infrared spectra, retention times detected by liquid chromatography (LC) and gas chromatography (GC), thin-layer chromatography (TLC) data using seven solvent mixture systems, electrospray ionization (ESI) mass spectra without derivatization, and electron ionization (EI) mass spectra with trifl uoroacetyl (TFA) derivatization. Quantitative reliability was also tested for these compounds by LC-mass spectrometry (MS) and GC-MS in high concentration ranges. The data concerned is intended to serve for screening, identification, and quantitation of the drugs contained in seized tablets, crystals, and powder; the data are very useful for such purposes in actual forensic toxicological practice.

Solvent effects on stereoselectivity in 2,3-dimethyl-4-chromanone cyclization by quinine-catalyzed asymmetric intramolecular oxo-Michael addition

Abstract Examination of the quinine-catalyzed asymmetric intramolecular oxo-Michael addition of o -tigloylphenol in various solvents led to high stereoselectivity in chromanone cyclization when chlorobenzene was used as a solvent, giving cis -2,3-dimethyl-4-chromanone with 60% de and 98% ee.

Chemical constituents of Aristolochia constricta: antispasmodic effects of its constituents in guinea-pig ileum and isolation of a diterpeno-lignan hybrid.

Twenty constituents were isolated from the n-hexane and chloroform extracts of Aristolochia constricta, a plant whose aerial parts have been used empirically in folk medicine for various purposes. The inhibitory effects of these constituents on smooth muscle contraction in isolated guinea-pig ileum were studied in order to observe their antispasmodic effects. 3,4-Dibenzyldihydrofuran-type lignans [(-)-cubebin, (-)-hinokinin, and (-)-pluviatolide] and a kaurene-type diterpene [(-)-kaur-16-en-19-oic acid] were isolated as active principals. They inhibited electrically induced and acetylcholine-induced contraction in the isolated guinea-pig ileum. In addition, 9- O-[(-)-kaur-15-en-17-oxyl]cubebin was isolated as a new diterpeno-lignan hybrid, although this constituent did not exhibit antispasmodic activity.