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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N -glucuronidated NNAL (NNAL- N -gluc), O -glucuronidated NNAL (NNAL- O -gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT 2 B 10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.

The total synthesis of alcyonolide, an antitumor xenicn diterpenoid, has been achieved. The inverse electron demand hetero-Diels-Alder reaction using a dienophile possessing an electron-withdrawing group provided the endo adduct which included a condensed lactone and dihydropyran rings with the desired three stereogenic centers. After introduction of the side chain by the Negishi coupling, the lactone ring was opened to form a Weinreb amide. The sequential transformation including conversion of Weinreb amide to aldehyde, PMB to acetate, and allylation of the aldehyde gave a mixture of separable four diastereomers. The desired stereoisomer was submitted to the 2,2,6,6-tetramethylpiperidine 1-oxyl oxidation, which afforded the δ-lactone and the methyl ketone side chain. Finally, the olefin metathesis of the desired isomer gave racemic alcyonolide.

Human urinary DNA adducts may be useful surrogate biomarkers to estimate carcinogen exposure and activation, particularly if such adducts are of high selectivity from a specific carcinogen source. In this report, we provided evidence supporting tobacco use and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being the dominant source for 3-methyladenine (3-mA), while nontobacco factors contribute significantly to 7-methylguanine and 1-methyladenine in the urine. Upon confirmation in human urine samples from larger populations in the future, urinary 3-mA may be used to estimate NNK bioactivation in smokers and to facilitate the development of a chemopreventive agent against NNK-induced carcinogenesis.

Hydride transfer from dihydronicotinamide adenine dinucleotide (NADH) analogs to a manganese(IV)-oxo porphyrin complex, (TMP)Mn(IV)(O) [TMP = 5,10,15,20-tetrakis(2,4,6-trimethylphenyl)porphyrin], occurs via disproportionation of (TMP)Mn(IV)(O) to [(TMP)Mn(III)](+) and [(TMP)Mn(V)(O)](+) that acts as the actual hydride acceptor. In contrast, electron transfer from ferrocene derivatives to (TMP)Mn(IV)(O) occurs directly to afford ferricenium ions and (TMP)Mn(III)(OH) products. The disproportionation rate constant of (TMP)Mn(IV)(O) was determined by the dependence of the observed second-order rate constants on concentrations of NADH analogs to be (8.0 +/- 0.6) x 10(6) M(-1) s(-1) in acetonitrile at 298 K. The disproportionation rate constant of (TMP)Mn(IV)(O) in hydride-transfer reactions increases linearly with increasing acid concentration, whereas the rate constant of electron transfer from ferrocene to (TMP)Mn(IV)(O) remains constant irrespective of the acid concentration. The rate constants of electron transfer from a series of ferrocene derivatives to (TMP)Mn(IV)(O) were evaluated in light of the Marcus theory of electron transfer to determine the reorganization energy of electron transfer by the (TMP)Mn(IV)(O) complex.

To investigate the chromophore structures of iodopsin and its low-temperature photoproducts, we have assigned their vibrational bands in the Fourier transform infrared (FTIR) spectra using iodopsin samples that were reconstituted with a series of (13)C- and deuterium-labeled retinals. The analyses of the vibrational bands in the fingerprint and hydrogen-out-of-plane (HOOP) regions indicated that the structure of the chromophores in the iodopsin system differs near their centers from those in the rhodopsin system. Compared to rhodopsin, the chromophore of the batho intermediate of iodopsin is twisted in the C(12) to C(14) regions but is more planar around C(11) region. The large amount of twisting was reduced by removing the chloride ion from the iodopsin, suggesting that this twisting hinders the relaxation of the torsion near C(11) necessary for the transition to the lumi intermediate and thus results in the thermal reversion of the batho intermediate back to the iodopsin. From the analyses of the C=NH and C=ND stretching bands, we conclude that the displacement of the Schiff base region upon photoisomerization of the chromophore is restricted, as is the case for rhodopsin. These results indicated that iodopsin's chromophore has a unique structure near its center and that this difference is enhanced by the binding of chloride nearby.

The conformation of retinal bound to the G protein-coupled receptor rhodopsin is intimately linked to its photochemistry, which initiates the visual process. Site-directed deuterium ((2)H) NMR spectroscopy was used to investigate the structure of retinal within the binding pocket of bovine rhodopsin. Aligned recombinant membranes were studied containing rhodopsin that was regenerated with retinal (2)H-labeled at the C(5), C(9), or C(13) methyl groups by total synthesis. Studies were conducted at temperatures below the gel to liquid-crystalline phase transition of the membrane lipid bilayer, where rotational and translational diffusion of rhodopsin is effectively quenched. The experimental tilt series of (2)H NMR spectra were fit to a theoretical line shape analysis [Nevzorov, A. A., Moltke, S., Heyn, M. P., and Brown, M. F. (1999) J. Am. Chem. Soc. 121, 7636-7643] giving the retinylidene bond orientations with respect to the membrane normal in the dark state. Moreover, the relative orientations of pairs of methyl groups were used to calculate effective torsional angles between different planes of unsaturation of the retinal chromophore. Our results are consistent with significant conformational distortion of retinal, and they have important implications for quantum mechanical calculations of its electronic spectral properties. In particular, we find that the beta-ionone ring has a twisted 6-s-cis conformation, whereas the polyene chain is twisted 12-s-trans. The conformational strain of retinal as revealed by solid-state (2)H NMR is significant for explaining the quantum yields and mechanism of its ultrafast photoisomerization in visual pigments. This work provides a consensus view of the retinal conformation in rhodopsin as seen by X-ray diffraction, solid-state NMR spectroscopy, and quantum chemical calculations.

A general chiroptical protocol for determination of absolute configuration of secondary amines including acyclic and cyclic aliphatic amines, aromatic amines, amino acids, and amino alcohols is described. The chiral substrate is linked to the achiral carrier moiety (3-N-Boc-amino-propyl-N-Boc-amino)acetic acid 1 (BocHNCH(2)CH(2)CH(2)BocNCH(2)COOH), which after deprotection, yields a bidentate conjugate, capable of forming a 1:1 host/guest complex with dimeric zinc porphyrin host 2. As in the cases of primary amines and secondary alcohols reported earlier, the complexation of secondary amine conjugates to porphyrin tweezer host 2 represents a stereodifferentiating process, where the large (L) group at the stereogenic center (assigned on the basis of conformational energies A value) protrudes from the porphyrin binding pocket. This leads to formation of host/guest complexes with a preferred porphyrin helicity that exhibit intense exciton split CD spectra. It was found that the chiral sense of porphyrin twist is clearly controlled by the stereogenic center despite the Z/E conformational complexity around the tertiary amide bond of secondary amine conjugates that has greatly hampered previous configurational assignments. Thus, in cases where there is no ambiguity regarding the relative steric size of substituents, the observed CD couplet can be applied for straightforward assignment of absolute configurations. In addition, to extend the application to more difficult cases a molecular mechanics calculation approach using the Merck Molecular Force Field (MMFFs) was developed; this provides conformational information of host/guest complexes and leads to prediction of preferred porphyrin helicity independent of conformational A values. This chiroptical protocol in combination with molecular modeling represents a general method for configurational assignments of secondary amines.

A stereoselective synthesis of 11Z-retinal 2, which is the chromophore of visual pigment (rhodopsin), was accomplished from the beta-ionylideneacetaldehyde-tricarbonyliron complex 3. The Peterson reaction of 3 using ethyl trimethylsilylacetate smoothly proceeded to afford predominantly the Z-ester 6. Transformation of the Z-ester 6 to the methyl ketone 19, followed by the Emmons-Horner reaction of 19 with C2-cyanophosphonate, produced ethyl 11Z, 13E-retinonitrile-tricarbonyliron complex 21 as the only product. Decomplexation of 21 with CuCl2 and subsequent DIBAL reduction gave 11Z-retinal 2 in excellent yield. Mechanistic consideration of Z-selectivity in the Peterson reaction of the aldehyde-tricarbonyliron complex is also discussed.