Abstract  The MAO-B catalyzed alpha-carbon oxidation of amines has been proposed to proceed via either a single electron transfer (SET) or hydrogen atom transfer (HAT) pathway. In an attempt to distinguish between these pathways, we have examined the alpha-carbon oxidation of a series of 4-substituted 1-methyl-1,2,3,6-tetrahydropyridine derivatives, compounds which are MAO-B substrates, employing chemical models of the SET pathway [using the PF-6 salt of Fe+3 (1,10-phenanthroline)3 as the electron acceptor] and HAT pathway (using the tert-butoxyl radical as the hydrogen atom acceptor). The rates of oxidation and deuterium isotope effects observed with these compounds were similar with the two model reactions. Consequently, unlike their utility in modeling the related cytochrome P450 catalyzed alpha-carbon oxidation of N,N-dimethylaniline derivatives, it appears that these reagents will not distinguish between the proposed pathways.

Abstract  This review article focuses on the recent applications of tris(trimethylsilyl)silane as a radical-based reagent in organic chemistry. Numerous examples of the successful use of (TMS)(3)SiH in radical reductions, hydrosilylation and consecutive radical reactions are given. The use of (TMS)(3)SiH allows reactions to be carried out under mild conditions with excellent yields of products and remarkable chemo-, regio-, and stereoselectivity. The strategic role of (TMS)(3)SiH in polymerization is underlined with emphasis on the photo-induced radical polymerization of olefins and photo-promoted cationic polymerization of epoxides.

Abstract  The coupling of haloarenes to styrenes and 1,1-diarylethenes has been achieved with potassium tert-butoxide in the presence of N,N'-dialkyldiketopiperazines. In contrast to previously reported reactions where phenanthroline has been used to mediate the reactions, the use of diketopiperazines can lead to either 1,1,2-triarylethenes or 1,1,2-triarylethanes, depending on the conditions used.

Abstract    Retinyl ascorbate (RA-AsA), an ester co-drug of vitamins A (RA) and C (AsA), is proposed as a topical antioxidant/cell division regulator for reducing UV-induced generation of free radicals and disrupted dermal cell growth. The efficacy of dermatological agents is influenced by their retention within the skin, which is increased by the interaction with skin components. Keratin is the major protein (<95%) in the skin, and this paper reports the binding of RA-AsA, RA, AsA, retinol, ascorbic acid palmitate and retinol palmitate to three tissues - human callus, pig ear skin and bovine horn keratin. Tissue samples were incubated with solutions of compounds and the uptake measured as the ratio of bound/free compound at equilibrium. Binding to keratin was assessed using delipidised tissue, and was much higher for the polar compounds, suggesting dipolar/H-bonding interaction. Binding strength was ranked as human > porcine > bovine, but there was no distinction for highly lipophilic compounds. The binding characteristic of native tissues was complicated by lipid content of the tissues. There seemed to be a dual effect. The binding of very lipophilic materials increased with lipid content, implying that a substantial amount is dissolved in the lipid matrix. For highly polar AsA, lipid content decreased the binding, suggesting that the lipid reduced the strong polar interactions with skin protein/keratin. Copyright © 2004 S. Karger AG, Basel   Retinyl ascorbate (RA-AsA), an ester co-drug of vitamins A (RA) and C (AsA), is proposed as a topical antioxidant/cell division regulator for reducing UV-induced generation of free radicals and disrupted dermal cell growth. The efficacy of dermatological agents is influenced by their retention within the skin, which is increased by the interaction with skin components. Keratin is the major protein (approximately 95%) in the skin, and this paper reports the binding of RA-AsA, RA, AsA, retinol, ascorbic acid palmitate and retinol palmitate to three tissues-human callus, pig ear skin and bovine horn keratin. Tissue samples were incubated with solutions of compounds and the uptake measured as the ratio of bound/free compound at equilibrium. Binding to keratin was assessed using delipidised tissue, and was much higher for the polar compounds, suggesting dipolar/H-bonding interaction. Binding strength was ranked as human > porcine > bovine, but there was no distinction for highly lipophilic compounds. The binding characteristic of native tissues was complicated by lipid content of the tissues. There seemed to be a dual effect. The binding of very lipophilic materials increased with lipid content, implying that a substantial amount is dissolved in the lipid matrix. For highly polar AsA, lipid content decreased the binding, suggesting that the lipid reduced the strong polar interactions with skin protein/keratin.

Abstract  BACKGROUND: Cilostazol has been reported to alleviate the metabolic syndrome induced by increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, which is also associated with osteoclast (OC) differentiation. We hypothesized that bone loss might be attenuated via an action on OC by cilostazol.

METHODOLOGY AND PRINCIPAL FINDINGS: To test this idea, we investigated the effect of cilostazol on ovariectomy (OVX)-induced bone loss in mice and on OC differentiation in vitro, using μCT and tartrate-resistant acid phosphatase staining, respectively. Cilostazol prevented from OVX-induced bone loss and decreased oxidative stress in vivo. It also decreased the number and activity of OC in vitro. The effect of cilostazol on reactive oxygen species (ROS) occurred via protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor 1, two major effectors of cAMP. Knockdown of NADPH oxidase using siRNA of p47phox attenuated the inhibitory effect of cilostazol on OC formation, suggesting that decreased OC formation by cilostazol was partly due to impaired ROS generation. Cilostazol enhanced phosphorylation of nuclear factor of activated T cells, cytoplasmic 1 (NFAT2) at PKA phosphorylation sites, preventing its nuclear translocation to result in reduced receptor activator of nuclear factor-κB ligand-induced NFAT2 expression and decreased binding of nuclear factor-κB-DNA, finally leading to reduced levels of two transcription factors required for OC differentiation.

CONCLUSIONS/SIGNIFICANCE: Our data highlight the therapeutic potential of cilostazol for attenuating bone loss and oxidative stress caused by loss of ovarian function.

Abstract  Parp-1 and Parp-2 are activated by DNA breaks and have been implicated in the repair of DNA single-strand breaks (SSB). Their involvement in double-strand break (DSB) repair mediated by homologous recombination (HR) or nonhomologous end joining (NHEJ) remains unclear. We addressed this question using chicken DT40 cells, which have the advantage of carrying only a PARP-1 gene but not a PARP-2 gene. We found that PARP-1(-/-) DT40 mutants show reduced levels of HR and are sensitive to various DSB-inducing genotoxic agents. Surprisingly, this phenotype was strictly dependent on the presence of Ku, a DSB-binding factor that mediates NHEJ. PARP-1/KU70 double mutants were proficient in the execution of HR and displayed elevated resistance to DSB-inducing drugs. Moreover, we found deletion of Ligase IV, another NHEJ gene, suppressed the camptothecin of PARP-1(-/-) cells. Our results suggest a new critical function for Parp in minimizing the suppressive effects of Ku and the NHEJ pathway on HR.

Abstract  BACKGROUND: We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process.

PRINCIPAL FINDINGS: Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3beta (GSK-3beta) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion.

CONCLUSIONS: Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial formation of ROS and the subsequent nuclear translocation of AIF, which is released from a mitochondrial pore that involves VDAC, Bax and possibly ceramides. The composition of the AIF-releasing channel seems to be much more complex than previously thought.

Abstract    Flavonoids (or bioflavonoids) are naturally occurring compounds, ubiquitous in all vascular plants. These compounds have been considered to possess anti-inflammatory properties, both in vitro and in vivo. Although not fully understood, these health-promoting effects have been mainly related to their interactions with several key enzymes, signaling cascades involving cytokines and regulatory transcription factors, and antioxidant systems. The biological effects of flavonoids will depend not only on these pharmacodynamic features but also on their pharmacokinetics, which are dependent on their chemical structure, administered dose schedule and route of administration. Thus, the therapeutic outcome mediated by flavonoids will result from a complex and interactive network of effects, whose prediction require a deep and integrated knowledge of those pharmacokinetic and pharmacodynamic factors. The aim of the present review is thus to provide an integrated update on the bioavailability and biotransformation of flavonoids and the mechanisms of activity at the molecular, cellular, organ and organism levels that may contribute to their anti-inflammatory effects.

Abstract  Curcumin [bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] was studied by means of UV-VIS absorption spectroscopy and nanosecond laser flash photolysis in 1,4-dioxane-water mixtures in a series of dioxane-water volume ratios. The transient characteristics were found to be dependent on the amount of water. In pure dioxane the triplet state of the molecule in its enolic form was detected (lambda(max) = 720 nm, tau = 3.2 micros), whereas upon water addition, the diketo form was found to prevail, because of the perturbation of intramolecular H-bonded structure. This led to hydrogen abstraction from dioxane by curcumin triplet state and the formation of the corresponding ketyl radical (lambda(max) = 490 nm, tau approximately 10 micros). Laser flash photolysis measurements, carried out in solvents of different polarity and proticity (benzene, cyclohexane and various alcohols), allowed the transient assignments to be confirmed, supporting our interpretation.

Abstract  A time-resolved kinetic study on the reactions of the cumyloxyl radical (CumO(•)) with intramolecularly hydrogen bonded 2-(1-piperidinylmethyl)phenol (1) and 4-methoxy-2-(1-piperidinylmethyl)phenol (2) and with 4-methoxy-3-(1-piperidinylmethyl)phenol (3) has been carried out. In acetonitrile, intramolecular hydrogen bonding protects the phenolic O-H of 1 and 2 from attack by CumO(•) and hydrogen atom transfer (HAT) exclusively occurs from the C-H bonds that are α to the piperidine nitrogen (α-C-H bonds). With 3 HAT from both the phenolic O-H and the α-C-H bonds is observed. In the presence of TFA or Mg(ClO4)2, protonation or Mg(2+) complexation of the piperidine nitrogen removes the intramolecular hydrogen bond in 1 and 2 and strongly deactivates the α-C-H bonds of the three substrates. Under these conditions, HAT to CumO(•) exclusively occurs from the phenolic O-H group of 1-3. These results clearly show that in these systems the interplay between intramolecular hydrogen bonding and Brønsted and Lewis acid-base interactions can drastically influence both the HAT reactivity and selectivity. The possible implications of these findings are discussed in the framework of the important role played by tyrosyl radicals in biological systems.

Abstract  The effect of 1,3-butanediol on reproductive performance as well as its teratogenic, dominant lethal and cytogenetic effects were studied in five generations of Wistar rats. Animals of both sexes were fed either control diet or diet supplemented with 1,3-butanediol at dose levels of 5, 10 or 24% of the diet by weight. Reproduction and lactation parameters were comparative to controls for four of five generations of dams and pups. In contrast, the pregnancy rate of F1A rats decreased during five successive mating cycles; no pups were obtained in the high-dose level group of the fifth series of litters (F2E generation). Excluding this group, the viability of F2 generation pups revealed no significant differences between litters or between control and test groups. No definitive dose-related teratological findings were found in either soft or skeletal tissue examinations of F3B generation rats. However, incomplete ossification of sternebrae occurred frequently in mid- and high-dose fetuses, whereas missing sternebrae were noted especially in high-level fetuses. Both skeletal tissue findings suggest slight delayed fetal growth. For the dominant lethal assay of the F1B generation, the mutagenic index (percentage resorptions per implant sites) revealed no dose-related trend. In the three-generation cytogenetic study, no 1,3-butanediol related chromosomal aberrations were noted.

Abstract  A photochemical model study of benzophenone triplet ((3)BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP (1)] and two of it's derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (2) and (±)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine (3) were performed. Literature precedent and calculations reported herein suggest that the barrier to ring opening for aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) will be low. The LFP results reported herein demonstrate that pathways for the reaction of (3)BP with 1, 2, and 3 are very similar. In each instance, disappearance of (3)BP is accompanied solely by appearance of bands corresponding to the diphenylhydroxylmethyl radical and neutral radical derived from MPTP and it's two derivatives 2 and 3. These results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway.

Abstract  In the present contribution, wavelength has been used as a tunable parameter to achieve selective control of the photophysics of two novel asymmetric bichromophoric dyads composed of naphthalene units, i.e., 6-methoxynaphthalene (NPX) and 1-methylnaphthalene (NAP) derivatives, with different electronic properties, connected by an amide spacer [(S,S) and (S,R)-NPX-NAP]. As model systems, relevant monochromophoric compounds (NPX-M and NAP-M) have also been investigated. While upon excitation at 325 nm the light energy remained in the NPX moiety, at 290 nm an efficient singlet-singlet energy transfer (phi(SSET) of about 97%) from the NAP unit to the NPX chromophore dominated. A remarkable stereodifferentiation was observed in the excited-state quenching by triethylamine via exciplex formation. The results demonstrate that it is possible to control configuration-dependent interactions in the excited state by wavelength tuning. This can be rationalized through intramolecular interactions of pi systems leading to modulation of the redox properties.

Abstract  Chromones, six-membered oxygen heterocycles, and pyrazoles, five-membered two-adjacent-nitrogen-containing heterocycles, represent two important classes of biologically active compounds. Certain derivatives of these scaffolds play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis. In this context, we will discuss the most relevant advances on the chemistry that involves both chromone and pyrazole rings. The methods reviewed include the synthesis of chromone-pyrazole dyads, synthesis of chromone-pyrazole-fused compounds, and chromones as starting materials in the synthesis of 3(5)-(2-hydroxyaryl)pyrazoles, among others. This review will cover the literature on the chromone and pyrazole dual chemistry and their outcomes in the 21st century.

Abstract  Four new beta-lactam derivatives of 1,5-benzothiazepine were obtained by the reaction of 3-(3S-t-butoxyl)succinimidyl acetyl chloride with 1,5-benzothiazepines and their structures were confirmed by H-1 NMR, IR, MS techniques and elemental analysis. The other two products of this reaction were also obtained, and their structures were determined by X-ray diffraction analyses methods.

Abstract  The first iridium(I) complex containing siloxyl and N-heterocyclic carbene ligand such as [Ir(cod)(Mes)(OSiMe(3))] (1) and [Ir(CO)(2)(IMes)(OSiMe(3))] (3) have been synthesized and their structures solved by spectroscopy and X-ray methods as well as catalytic properties in selected hydrogenation reactions have been presented in comparison to their chloride analogues, i.e. [Ir(Cl)(cod)(IMes)] (2) and [Ir(Cl)(CO)(2)(IMes)] (4). The attempts at synthesis of iridium(l) complex with tert-butoxyl ligand has failed as leading instead to the iridium hydroxide complex [Ir(cod)(OH)(IMes)] (5) whose X-ray structure has also been solved. All complexes (1)-(5) show square planar geometry typical of the four-coordinated iridium complexes. Catalytic activity of complexes 1 and 2 was tested in transfer hydrogenation of acetophenone and hydrogenation of olefins. (C) 2007 Published by Elsevier B.V.

Abstract  A metal-free ring opening/halogenation of cycloalkanols, which combines both PPO/TBAX oxidant system and blue LEDs irradiation, is presented. This method produces diverse γ, δ, and even more remotely halogenated ketones in moderate to excellent yields under mild conditions. Interestingly, experimental and computational studies demonstrate the novel ring size-dependent concerted/stepwise (four-/five- to eight-membered rings) hydrogen atom transfer-electron transfer induced by Brønsted base-tethered acyloxy radical, which indicates distinct advantages brought by the cyclic structure of diacyl peroxides.