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PubMed2003

Synthesis and characterization of N-demethylated metabolites of malachite green and leucomalachite green.

Malachite green (MG), a triphenylmethane dye used to treat fungal and protozoan infections in fish, undergoes sequential oxidation to produce various N-demethylated derivatives (monodes-, dides(sym)-, dides(unsym)-, trides-, and tetrades-) both before and after reduction to leucomalachite green (LMG). The close structure resemblance of the metabolites with aromatic amine carcinogens implicates a potential genotoxicity from exposure to MG. The availability of the synthetic standards is important for metabolic and DNA adduct studies of MG. This paper describes a simple and versatile method for the synthesis of MG, LMG, and their N-demethylated metabolites. The synthesis involves a coupling of 4-(dimethylamino)benzophenone or 4-nitrobenzophenone with the aryllithium reagents derived from appropriately substituted 4-bromoaniline derivatives, followed by treatment with HCl in methanol. The resulting cationic MG and their leuco analogues showed systematic UV/vis spectral and tandem mass fragmentation patterns consistent with sequential N-demethylation. The extensive (1)H and (13)C spectral assignments of the metabolites were aided by the availability of (13)C(7)-labeled MG and LMG. The results indicate the existence of a resonance structure with the cationic charge located in the central methane carbon (C(7)). The synthetic procedure is general in scope so that it can be extended to the preparation of N-demethylated metabolites of other structurally related N-methylated triphenylmethane dyes.

Aniline Compounds↗

PubMed2004

Photoinduced gas-phase electron transfer reactions.

The electron transfer quenching process, when a reactive excited state is singlet or triplet, for gas-phase systems (benzophenone and anthraquinone with amines and pyridine as well as carbazole with halomethanes) was systematically investigated using time-resolved fluorescence. Bimolecular rate constants were obtained. Variable-temperature measurements were performed for eight donor-acceptor pairs. It was found that under solvent-free conditions various quenchers differing in photochemical reactivity led to change in quenching rates by almost three orders of magnitude. Positive and negative temperature dependences for the electron transfer rate constants were observed. The data were analyzed in terms of the Marcus-Jortner theory.

Amines↗

PubMed1999

Orientation of GTP and ADP within their respective binding sites in glutamate dehydrogenase.

Previous studies have identified the guanine and adenine binding domains of the GTP and ADP binding sites of GDH. In this study the peptide sequences within or near to the terminal phosphate-binding domains of the GTP and ADP binding sites of bovine liver glutamate dehydrogenase (GDH) were identified using photoaffinity labeling with the benzophenone nucleotide derivatives, [gamma-32P]GTPgammaBP and [gamma-32P]ATPgammaBP. Without activating light, GTPgammaBP exhibited inhibiting effects on the GDH reaction similar to GTP; ATPgammaBP, as expected, produced activating effects similar to those of ADP. Photoinsertion into GDH by both probes exhibited saturation effects in agreement with the respective kinetic effects. Specificity of labeling was supported by specific and effective reduction of photoinsertion of [gamma-32P]GTPgammaBP and [gamma-32P]ATPgammaBP into GDH by GTP and ADP, respectively. Using a combination of immobilized Fe3+-chelate affinity chromatography and reversed-phase HPLC, photolabeled peptides located within or near the phosphate-binding domains of the GTP and ADP sites were isolated. Sequence analysis showed that GTPgammaBP primarily modified a peptide near the middle of the GDH sequence, Asn135-Lys143 and Glu290-Lys295. However, ATPgammaBP modified a single peptide corresponding to the sequence Met411-Arg419 near the C-terminal domain. Using these results and the data from the previously identified base-binding domain peptides the orientation of GTP and ADP within their respective binding sites in the catalytic cleft of GDH is proposed and explained on the basis of a proposed three-dimensional schematic model structure derived from the bacterial enzyme.

Adenosine Diphosphate↗

PubMed1998

A novel in vivo model for evaluating agents that protect against ultraviolet A-induced photoaging.

Increasing evidence demonstrates that ultraviolet A radiation (UVA) contributes to photoaging, which results in the accumulation of massive amounts of abnormal elastic material in the dermis of photoaged skin. To study UVA-induced photoaging in an in vivo system, we utilized a line of transgenic mice containing the human elastin promoter linked to a chloramphenicol acetyl transferase reporter gene. Our prior work demonstrates promoter activation in response to ultraviolet B radiation (UVB), UVA, and psoralen plus ultraviolet A radiation in the skin of these mice. The addition of psoralen (8-MOP) prior to administration of UVA results in substantial increases in promoter activation, as compared with UVA alone. To demonstrate the utility of these mice as a model of UVA-induced photodamage, we administered four lotions to the skin of our transgenic mice that included: a sunscreen containing octyl methoxycinnamate and benzophenone-3 with a sun protection factor (SPF) of 15, the UVA filter butyl methoxydibenzoylmethane, the SPF 15 sunscreen and the UVA filter together, and the lotion vehicle alone. Following sunscreen administration, mice received a single psoralen plus ultraviolet A radiation treatment. All sunscreens decreased chloramphenicol acetyl transferase activity with the SPF 15 sunscreen, the UVA filter, and the combination SPF 15 sunscreen and UVA filter, resulting in increasing degrees of protection against psoralen plus ultraviolet A radiation. These results demonstrate that this model functions as a rapid and sensitive model of UVA photodamage for the identification and comparison of compounds that protect against UVA-induced photoaging.

Animals↗

PubMed2001

Can increasing the viscosity of formulations be used to reduce the human skin penetration of the sunscreen oxybenzone?

The effect of adding thickening agents on the penetration of a sunscreen benzophenone-3 through epidermal and a high-density polyethylene membrane was studied using both very thick (infinite dose) and thin (in use) applications. Contradictory results were obtained. Thickening agents retard skin penetration, in a manner consistent with a diffusional resistance in the formulation, when applied as an infinite dose. In contrast, when applied as in thin (in use) doses, thickening agents promote penetration, most likely through greater stratum corneum diffusivity arising from an enhanced hydration by the thicker formulations. The two key implications from this work are (i) a recognition of the danger in the potential extrapolation of infinite dosing to in use situations, and (ii) to recognize that thicker formulations may sometimes enhance the penetration of other topical agents when applied "in use".

Benzophenones↗

PubMed2003

A novel cytotoxic guttiferone analogue from Garcinia macrophylla from the Suriname rainforest.

Bioassay-guided fractionation of the EtOAc extract of the twigs of Garcinia macrophylla from Suriname produced the known benzophenone, guttiferone A (1), and a new guttiferone analogue, guttiferone G (2). Friedelin was also isolated. The structures of compounds 1 and 2 were elucidated using 1D and 2D NMR spectroscopy. Compounds 1 and 2 were weakly cytotoxic in the A2780 human ovarian cell line, with IC (50) values of 6.8 and 8.0 microg/mL, respectively.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Surfactant free fabrication of polymeric nanoparticles by combined liquid-liquid phase separation and solvent/nonsolvent mixing technology.

It is generally agreed that, in most cases, surfactants are required to obtain stable polymeric nanoparticle dispersions. Here, we report a method which can be used to produce surfactant free yet stable polymeric nanoparticle dispersions. This method is based on explored mechanism of selective solvation of nanoparticles and EPD (electron pair donor)/EPA (electron pair acceptor) complexes formed among solvent and nonsolvent molecules. Using polyimide P84 (copolyimide 3,3(') 4,4(')-benzophenone tetracarboxylic dianhydride and 80% methylphenylene diamine+20% methylene dianiline) as the model polymer, this mechanism was realized through a combined liquid-liquid phase separation and solvent/nonsolvent mixing technology. Surfactant-free polyimide nanoparticles (<100 nm) were produced. Experimental details and principles of this technology were given based on the ternary diffusion, the liquid-liquid phase separation and the advanced nucleation and growth theory. Two types of methods [denoted as the forward titration method and the backward titration (BT) method] were examined. It was found that the BT method is extremely helpful to prepare polyimide nanoparticles (<100 nm). As another important aspect, explored stabilization mechanism of the resultant nanoparticle dispersions was supported by the comparative experiments, implying that selective solvation of nanoparticles and EPD/EPA complexes may play key roles in stabilization.

Benzophenones↗

PubMed2005

Triplet excitation transfer in glassy systems: spatial and spectral diffusion.

Triplet excitation transfer among benzophenone molecules dissolved in glassy 2-methyltetrahydrofuran is studied by recording the emission and the optical depolarization as a function of wavelength and time. The transport mechanism is based upon exchange interaction and subject to the random character of both jump distances and site energies. Optical anisotropy data are used to gauge the probability of an excitation to remain on its original site. The anisotropy is observed to decrease by a factor of 2 from high to low energies within the inhomogeneously broadened emission band, clearly indicating hopping-mediated thermalization within the density of states. Within their excited-state lifetime the excitons do not reach the steady-state energies, but solvation allows the observation of that energy level. Unexpectedly, we find that the transfers at very short times do not contribute as much to spectral diffusion as the subsequent transport. Because the short-time hops target sites as close as approximately 1 nm, this observation suggests spatially correlated site energies for these short distances.

Benzophenones↗

PubMed2006

Discovery of a small-molecule HIV-1 integrase inhibitor-binding site.

Herein, we report the identification of a unique HIV-1 integrase (IN) inhibitor-binding site using photoaffinity labeling and mass spectrometric analysis. We chemically incorporated a photo-activatable benzophenone moiety into a series of coumarin-containing IN inhibitors. A representative of this series was covalently photo-crosslinked with the IN core domain and subjected to HPLC purification. Fractions were subsequently analyzed by using MALDI-MS and electrospray ionization (ESI)-MS to identify photo-crosslinked products. In this fashion, a single binding site for an inhibitor located within the tryptic peptide (128)AACWWAGIK(136) was identified. Site-directed mutagenesis followed by in vitro inhibition assays resulted in the identification of two specific amino acid residues, C130 and W132, in which substitutions resulted in a marked resistance to the IN inhibitors. Docking studies suggested a specific disruption in functional oligomeric IN complex formation. The combined approach of photo-affinity labeling/MS analysis with site-directed mutagenesis/molecular modeling is a powerful approach for elucidating inhibitor-binding sites of proteins at the atomic level. This approach is especially important for the study of proteins that are not amenable to traditional x-ray crystallography and NMR techniques. This type of structural information can help illuminate processes of inhibitor resistance and thereby facilitate the design of more potent second-generation inhibitors.

4-Hydroxycoumarins↗

PubMed1998

The b and delta subunits of the Escherichia coli ATP synthase interact via residues in their C-terminal regions.

An affinity resin for the F1 sector of the Escherichia coli ATP synthase was prepared by coupling the b subunit to a solid support through a unique cysteine residue in the N-terminal leader. b24-156, a form of b lacking the N-terminal transmembrane domain, was able to compete with the affinity resin for binding of F1. Truncated forms of b24-156, in which one or four residues from the C terminus were removed, competed poorly for F1 binding, suggesting that these residues play an important role in b-F1 interactions. Sedimentation velocity analytical ultracentrifugation revealed that removal of these C-terminal residues from b24-156 resulted in a disruption of its association with the purified delta subunit of the enzyme. To determine whether these residues interact directly with delta, cysteine residues were introduced at various C-terminal positions of b and modified with the heterobifunctional cross-linker benzophenone-4-maleimide. Cross-links between b and delta were obtained when the reagent was incorporated at positions 155 and 158 (two residues beyond the normal C terminus) in both the reconstituted b24-156-F1 complex and the membrane-bound F1F0 complex. CNBr digestion followed by peptide sequencing showed the site of cross-linking within the 177-residue delta subunit to be C-terminal to residue 148, possibly at Met-158. These results indicate that the b and delta subunits interact via their C-terminal regions and that this interaction is instrumental in the binding of the F1 sector to the b subunit of F0.

ATP Synthetase Complexes↗

PubMed1999

Subunit interactions in the clathrin-coated vesicle vacuolar (H(+))-ATPase complex.

The vacuolar (H(+))-ATPases (or V-ATPases) are structurally related to the F(1)F(0) ATP synthases of mitochondria, chloroplasts and bacteria, being composed of a peripheral (V(1)) and an integral (V(0)) domain. To further investigate the arrangement of subunits in the V-ATPase complex, covalent cross-linking has been carried out on the V-ATPase from clathrin-coated vesicles using three different cross-linking reagents. Cross-linked products were identified by molecular weight and by Western blot analysis using polyclonal antibodies raised against individual V-ATPase subunits. In the intact V(1)V(0) complex, evidence for cross-linking of subunits C and E, D and F, as well as E and G by disuccinimidyl glutarate was obtained, while in the free V(1) domain, cross-linking of subunits H and E was also observed. Subunits C and E as well as D and E could be cross-linked by 1-ethyl-3-(dimethylaminopropyl)carbodiimide, while subunits a and E could be cross-linked by 4-(N-maleimido)benzophenone. It was further demonstrated that it is possible to treat the V-ATPase with potassium iodide and MgATP in such a way that while subunits A, B, and H are nearly quantitatively removed, significant amounts of subunits C, D, E, and F remain attached to the membrane, suggesting that one or more of these latter subunits are in contact with the V(0) domain. In addition, treatment of the V-ATPase with cystine, which modifies Cys-254 of the catalytic A subunit, results in dissociation of subunit H, suggesting communication between the catalytic nucleotide binding site and subunit H. Finally, the stoichiometry of subunits F, G, and H were determined by quantitative amino acid analysis. Based on these and previous observations, a new structural model of the V-ATPase from clathrin-coated vesicles is proposed.

Amino Acids↗

PubMed2004

Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway.

The gamma-secretase complex, consisting of presenilins (PS), nicastrin (NCT), APH-1, and PEN-2, catalyzes the intramembranous proteolysis of truncated beta-amyloid precursor protein (APP) and Notch derivatives to generate the APP intracellular domain (AICD) and Notch intracellular domain (NICD), respectively. To examine the intracellular sites in which active gamma-secretase resides, we expressed NCT variants harboring either an endoplasmic reticulum (ER) retention signal (NCT-ER) or a trans-Golgi network (TGN) targeting motif (NCT-TGN) along with PS1, APH-1, and PEN-2 and examined gamma-secretase activity in these settings. In cells expressing NCT-ER and the other components, PS1 fragments hyperaccumulated, but AICD levels were not elevated. On the other hand, upon coexpression of an ER-retained APP variant or a constitutionally active Notch mutant, NDeltaE, we observed enhanced production of AICD or NICD, respectively, in cells expressing NCT-ER. Moreover, we show that membranes from cells expressing NCT-ER, NCT-TGN, or NCT-WT contain identical levels of PS1 derivatives that can be photoaffinity cross-linked to a biotinylated, benzophenone-derivatized gamma-secretase inhibitor. Finally, our cell-free gamma-secretase assays revealed nearly equivalent gamma-secretase activities in cells expressing PS1, APH-1, PEN-2, and either NCT-WT or NCT-ER. Taken together, we interpret these findings as suggesting that active gamma-secretase complex is generated in the early compartments of the secretory pathway but that these complexes are transported to late compartments in which substrates are encountered and subsequently processed within respective transmembrane segments.

Amino Acid Motifs↗

PubMed2005

Determining the environment of the ligand binding pocket of the human angiotensin II type I (hAT1) receptor using the methionine proximity assay.

The peptide hormone angiotensin II (AngII) binds to the AT0 (angiotensin type 1) receptor within the transmembrane domains in an extended conformation, and its C-terminal residue interacts with transmembrane domain VII at Phe-293/Asn-294. The molecular environment of this binding pocket remains to be elucidated. The preferential binding of benzophenone photolabels to methionine residues in the target structure has enabled us to design an experimental approach called the methionine proximity assay, which is based on systematic mutagenesis and photolabeling to determine the molecular environment of this binding pocket. A series of 44 transmembrane domain III, VI, and VII X --> Met mutants photolabeled either with 125I-[Sar1,p'-benzoyl-L-Phe8]AngII or with 125I-[Sar1,p''-methoxy-p'-benzoyl-L-Phe8]AngII were purified and digested with cyanogen bromide. Several mutants produced digestion patterns different from that observed with wild type human AT1, indicating that they had a new receptor contact with position 8 of AngII. The following residues form this binding pocket: L112M and Y113M in transmembrane domain (TMD) III; F249M, W253M, H256M, and T260M in TMD VI; and F293M, N294M, N295M, C296M, and L297M in TMD VII. Homology modeling and incorporation of these contacts allowed us to develop an evidence-based molecular model of interactions with human AT1 that is very similar to the rhodopsin-retinal interaction.

Amino Acid Substitution↗

PubMed2005

Cysteine-mediated cross-linking indicates that subunit C of the V-ATPase is in close proximity to subunits E and G of the V1 domain and subunit a of the V0 domain.

The vacuolar (H+)-ATPases (V-ATPases) are multisubunit complexes responsible for ATP-dependent proton transport across both intracellular and plasma membranes. The V-ATPases are composed of a peripheral domain (V1) that hydrolyzes ATP and an integral domain (V0) that conducts protons. Dissociation of V1 and V0 is an important mechanism of controlling V-ATPase activity in vivo. The crystal structure of subunit C of the V-ATPase reveals two globular domains connected by a flexible linker (Drory, O., Frolow, F., and Nelson, N. (2004) EMBO Rep. 5, 1-5). Subunit C is unique in being released from both V1 and V0 upon in vivo dissociation. To localize subunit C within the V-ATPase complex, unique cysteine residues were introduced into 25 structurally defined sites within the yeast C subunit and used as sites of attachment of the photoactivated sulfhydryl reagent 4-(N-maleimido)benzophenone (MBP). Analysis of photocross-linked products by Western blot reveals that subunit E (part of V1) is in close proximity to both the head domain (residues 166-263) and foot domain (residues 1-151 and 287-392) of subunit C. By contrast, subunit G (also part of V1) shows cross-linking to only the head domain whereas subunit a (part of V0) shows cross-linking to only the foot domain. The localization of subunit C to the interface of the V1 and V0 domains is consistent with a role for this subunit in controlling assembly of the V-ATPase complex.

Adenosine Triphosphate↗

PubMed2005

Migration of contaminants by gas phase transfer from carton board and corrugated board box secondary packaging into foods.

The gas phase transfer of substances from carton board (CB) and corrugated box board (CBB) through intervening layers to foods was studied. Substances covering a boiling point range of 252-425 degrees C and a range of polarities were incorporated into CB and CBB secondary packaging. Benzophenone was present in some CB materials. Where it was not already present in CB or CBB secondary packaging, it was deliberately incorporated for transfer studies. Transfer of substances was measured in nine foodstuff types stored in the secondary packaging at ambient and sub-ambient temperature. The foods were packaged in primary packaging materials that would be used in retail. Two food types were packed and stored in both single- and multipack formats. Foods were sampled at 0, 10, 30, 90 and 200 days and analysed by gas chromatography-mass spectrometry after high-performance size exclusion chromatography clean-up. Percentage transfer was between 0 and 100%. The overall trends were increased transfer of substances with increased storage time; a more rapid transfer of the more volatile substances compared with the less volatile ones and higher levels of transfer of the more volatile substances. No transfer of diheptyl phthalate (DHP) (bp 425 degrees C) as an incorporated substance was detected to any foods over the test period. The presence of an additional layer of packaging (multipack versus single pack) was shown to reduce transfer up to fourfold over 200 days and to increase the lag period for transfer. In terms of slowing transfer, metallized PP/PP laminate proved a more effective barrier than PP which was more effective than paper. It is postulated that there is a cut-off threshold for transfer at ambient and sub-ambient temperatures. Substances that are less volatile than the cut-off are anticipated not to transfer from secondary packaging to foods stored for up to 200 days, where the substances are present in the packaging at or below the levels tested in this study (up to 1 mg dm-2). In this study the volatility cut-off threshold lay between that of 2,2-dimethoxyphenylacetophenone (2,2-DMPAP) (an incorporated substance with bp 352 degrees C) and DHP. Ideally, the cut-off threshold should be expressed in terms of vapour pressure in the packaging material. In practical terms, it may be more appropriate to express as partition coefficient as this is simpler to determine experimentally.

Acetophenones↗

PubMed2000

The effects of weak magnetic fields on radical recombination reactions in micelles.

PURPOSE: To demonstrate the effects of weak magnetic fields (> approximately 1 mT) on chemical reactions involving free radicals, in the context of possible effects of environmental electromagnetic radiation on biological systems. MATERIALS AND METHODS: Transient absorption, flash photolysis experiments have been performed to study the kinetics and yields of radical reactions. The triplet state of benzophenone has been used as a convenient source of radical pairs, whose identity is largely immaterial to the investigation of the so-called Low Field Effect. Hydrogen abstraction from surfactant molecules in micelles yields a pair of neutral radicals, one large and one small, in a region of restricted translational and rotational motion. RESULTS: In alkyl sulphate and sulphonate micelles a weak field increases the concentration of free radicals that escape from the micelle to an extent that depends on the structure, dynamics and volume of the space in which the radical pairs are confined. The effect (up to 10%) is typically largest at 1-2 mrT. Smaller effects are found for Brij and TX100 micelles. CONCLUSIONS: Low Field Effects depend strongly on the local environment of the radical pair. Larger effects than observed here might be expected for radicals formed from singlet (rather than triplet) precursors, as would be the case in biological reactions.

Alkanesulfonates↗

PubMed1993

Isolation and characterization of a new product produced by ionizing irradiation and type I photosensitization of 2'-deoxyguanosine in oxygen-saturated aqueous solution: (2S)-2,5'-ANHYDRO-1-(2'-deoxy-beta-D-erythro-pentofuranosyl)-5-guanidin ylidene- 2-hydroxy-4-oxoimidazolidine.

A major product of the radiation-induced decomposition of 2'-deoxyguanosine in oxygen-saturated aqueous solution has been isolated by reverse phase high performance liquid chromatography and characterized by carbon and proton NMR spectroscopy, fast-atom bombardment mass spectrometry, and chemical analysis as (2S)-2,5'-anhydro-1-(2'-deoxy-beta-D-erythro-pentofuranosyl)-5-guanid inylidene- 2-hydroxy-4-oxoimidazolidine(d < G). This compound is stable in aqueous solution at room temperature but decomposes upon heating (45 degrees C). The lesion is also observed following type I (riboflavin, benzophenone, and acetophenone) photosensitized irradiation of 2'-deoxyguanosine at 350 nm in oxygen-saturated aqueous solution. A similar reaction mechanism, involving a neutral guanine radical intermediate, is proposed to explain the generation of d < G following both types of irradiation.

Acetophenones↗

PubMed1999

Modification of DNA bases by photosensitized one-electron oxidation.

PURPOSE: To determine the distribution of base damage within isolated DNA upon oxidation by three type I photosensitizers in aerated aqueous solution. MATERIALS AND METHODS: Aqueous solutions of DNA were exposed to UVA in the presence of riboflavin, benzophenone or menadione. Then, eight modified nucleobases were measured, using HPLC-EC, GC-MS or HPLC with fluorescence detection. RESULTS: The three photosensitizers led to a predominant degradation of guanine bases within DNA. The relative yield of the three main guanine degradation products measured in DNA was similar with the three sensitizers. 8-OxodAdo was also produced in an almost constant yield with respect to its guanine analogue. The yield of oxidized pyrimidines was lower and was found to depend on the photosensitizer used. The results were compared with the yield of photosensitization-induced degradation of the 2'-deoxyribonucleosides. CONCLUSION: The favoured photosensitized degradation of guanine within DNA may be explained by its lower oxidation potential with respect to that of the other bases, together with the occurrence of charge transfer through DNA. The base modification pattern determined in the present work is different from that obtained upon reaction of hydroxyl radicals. Under the latter conditions, pyrimidine oxidation products were generated more efficiently than by photosensitized one-electron oxidation.

Benzophenones↗