Methods were developed and optimized for the preparation of the 2,3-cis- and the 10,11-cis-isomers of silybin by the Lewis acid catalyzed (BF3∙OEt2) isomerization of silybins A (1a) and B (1b) (trans-isomers). The absolute configuration of all optically pure compounds was determined by using NMR and comparing their electronic circular dichroism data with model compounds of known absolute configurations. Mechanisms for cis-trans-isomerization of silybin are proposed and supported by quantum mechanical calculations.

• Klíčová slova
• 10,11-cis-silybin, 2,3-cis-silybin, isomerization, silibinin, silybin, silymarin,
• Publikační typ
• časopisecké články MeSH

Rhodopsins constitute a broad class of retinal-binding photoreceptors. Microbial rhodopsins are canonically activated through an all-trans to 13-cis photoisomerization, whereas animal rhodopsins are mostly activated through an 11-cis to all-trans isomerization. Bestrhodopsins constitute a special microbial rhodopsin subfamily, with bistable rhodopsin domains that can be photoswitched between a far red-absorbing state D661 and a green-absorbing state P540. Its photochemistry involves a peculiar all-trans to 11-cis isomerization for the D661 to P540 photoreaction and vice versa. Here, we present the P. antarctica bestrhodopsin 11-cis to all-trans photoreaction as determined by femtosecond-to-submillisecond transient absorption, femtosecond stimulated Raman and flash-photolysis spectroscopy. The primary photoreaction involves ultrafast isomerizations in 240 fs from the 11-cis reactant to a mixture of highly distorted all-trans and 13-cis photoproducts. The 13-cis fraction then thermally isomerizes to a distorted all-trans RSB in 120 ps. We propose bicycle pedal models for the branched photoisomerizations with corotation of the C11═C12 and C13═C14 double bonds. One reactant fraction undergoes bicycle pedal motion aborted at the C13═C14 double bond, resulting in all-trans retinal. The other fraction undergoes a full bicycle pedal motion of both C11═C12 and C13═C14, resulting in 13-cis retinal. The primary products are trapped high up the ground-state potential energy surface with a low energetic barrier that facilitates thermal isomerization from 13-cis to all-trans retinal in 120 ps. All-trans retinal then structurally and energetically relaxes with subsequent time constants of 0.7 and 62 μs and 4.4 ms, along with counterion protonation, completing the P540 to D661 photoreaction.

• MeSH
• fotochemické procesy MeSH
• isomerie MeSH
• retinaldehyd * chemie   MeSH
• rhodopsiny mikrobiální * chemie   MeSH
• stereoizomerie MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• retinaldehyd * MeSH
• rhodopsiny mikrobiální * MeSH

2-Ethylhexyl methoxycinnamate (EHMC) is one of the most used ultraviolet filters in personal care products. It undergoes cis/trans isomerization in sunlight, and there is limited toxicological understanding of the effects of the cis-isomer. It is known that two geometric isomers of one compound can have different physico-chemical properties and effects. However, there are no studies focusing on toxicokinetics of EHMC isomerization products to compare their potential difference in dermal exposure to cis-EHMC and trans-EHMC due to the difference in their dermatotoxicokinetics. In this study, dermal absorption of the parental trans-EHMC and its cis isomer was studied. A commercially available sunscreen lotion containing trans-EHMC and spiked with laboratory-prepared cis-EHMC was locally applied on the forearm skin of two volunteers. After 8 h of skin exposure, the stratum corneum (SC) layer was removed by tape stripping. The removed thickness of the SC was determined spectrophotometrically using a total protein assay. The concentration of both isomers in the removed SC was measured by HPLC-DAD. A new diffusion and permeability coefficient of both EHMC isomers in SC were determined by Fick's second law of diffusion in vivo. The difference in dermatotoxicokinetic parameters between the two isomers was not statistically significant. However, separate toxicological studies of isomeric forms and the determination of their dermatotoxicokinetic parameters are crucial for refinement of human risk assessment.

• Klíčová slova
• Cis/trans isomerization, Dermatotoxicokinetics, Ethylhexyl methoxycinnamate, Human skin permeation, Personal care products, Tape stripping,
• MeSH
• cinnamáty chemie   farmakokinetika   MeSH
• dospělí MeSH
• epidermis metabolismus   MeSH
• kožní absorpce * MeSH
• lidé MeSH
• přípravky chránící proti slunci chemie   farmakokinetika   MeSH
• stereoizomerie MeSH
• toxikokinetika MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cinnamáty MeSH
• octylmethoxycinnamate MeSH Prohlížeč
• přípravky chránící proti slunci MeSH

Ethylhexyl methoxycinnamate (EHMC) is a widely used UV filter present in a large number of personal care products (PCPs). Under normal conditions, EHMC occurs in a mixture of two isomers: trans-EHMC and cis-EHMC in a ratio of 99:1. When exposed to sunlight, the trans isomer is transformed to the less stable cis isomer and the efficiency of the UV filter is reduced. To date, the toxicological effects of the cis-EHMC isomer remain largely unknown. We developed a completely new method for preparing cis-EHMC. An EHMC technical mixture was irradiated using a UV lamp and 98% pure cis-EHMC was isolated from the irradiated solution using column chromatography. The genotoxic effects of the isolated cis-EHMC isomer and the nonirradiated trans-EHMC were subsequently measured using two bioassays (SOS chromotest and UmuC test). In the case of trans-EHMC, significant genotoxicity was observed using both bioassays at the highest concentrations (0.5 - 4 mg mL-1 ). In the case of cis-EHMC, significant genotoxicity was only detected using the UmuC test at concentrations of 0.25 - 1 mg mL-1 . Based on these results, the NOEC was calculated for both cis- and trans-EHMC, 0.038 and 0.064 mg mL-1 , respectively. Risk assessment of dermal, oral and inhalation exposure to PCPs containing EHMC was carried out for a female population using probabilistic simulation and by using Quantitative in vitro to in vivo extrapolation (QIVIVE). The risk of cis-EHMC was found to be ∼1.7 times greater than trans-EHMC. In the case of cis-EHMC, a hazard index of 1 was exceeded in the 92nd percentile. Based on the observed differences between the isomers, EHMC application in PCPs requires detailed reassessment. Further exploration of the toxicological effects and properties of cis-EHMC is needed in order to correctly predict risks posed to humans and the environment. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 569-580, 2017.

• Klíčová slova
• QIVIVE, ethylhexyl methoxycinnamate, genotoxicity, probabilistic risk assessment, trans/cis isomerisation,
• MeSH
• chromatografie plynová MeSH
• cinnamáty chemie   toxicita   MeSH
• hodnocení rizik MeSH
• isomerie MeSH
• kosmetické přípravky MeSH
• lidé MeSH
• přípravky chránící proti slunci chemie   toxicita   MeSH
• Salmonella typhimurium účinky léků   genetika   MeSH
• testy genotoxicity MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• cinnamáty MeSH
• ethylhexyl methoxycinnamate MeSH Prohlížeč
• kosmetické přípravky MeSH
• přípravky chránící proti slunci MeSH

Bestrhodopsins constitute a class of light-regulated pentameric ion channels that consist of one or two rhodopsins in tandem fused with bestrophin ion channel domains. Here, we report on the isomerization dynamics in the rhodopsin tandem domains of Phaeocystis antarctica bestrhodopsin, which binds all-trans retinal Schiff-base (RSB) absorbing at 661 nm and, upon illumination, converts to the meta-stable P540 state with an unusual 11-cis RSB. The primary photoproduct P682 corresponds to a mixture of highly distorted 11-cis and 13-cis RSB directly formed from the excited state in 1.4 ps. P673 evolves from P682 in 500 ps and contains highly distorted 13-cis RSB, indicating that the 11-cis fraction in P682 converts to 13-cis. Next, P673 establishes an equilibrium with P595 in 1.2 µs, during which RSB converts to 11-cis and then further proceeds to P560 in 48 µs and P540 in 1.0 ms while remaining 11-cis. Hence, extensive isomeric switching occurs on the early ground state potential energy surface (PES) on the hundreds of ps to µs timescale before finally settling on a metastable 11-cis photoproduct. We propose that P682 and P673 are trapped high up on the ground-state PES after passing through either of two closely located conical intersections that result in 11-cis and 13-cis RSB. Co-rotation of C11=C12 and C13=C14 bonds results in a constricted conformational landscape that allows thermal switching between 11-cis and 13-cis species of highly strained RSB chromophores. Protein relaxation may release RSB strain, allowing it to evolve to a stable 11-cis isomeric configuration in microseconds.

• Klíčová slova
• conical intersection, far-red absorbing rhodopsin, femtosecond stimulated Raman spectroscopy, femtosecond to millisecond spectroscopy, multiple retinal isomerization,
• MeSH
• diterpeny * MeSH
• isomerie MeSH
• konformace proteinů MeSH
• retinaldehyd * chemie   MeSH
• rodopsin * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 13-cis-retinal MeSH Prohlížeč
• diterpeny * MeSH
• retinaldehyd * MeSH
• rodopsin * MeSH

Two new pseudo-octahedral Co(II) complexes 1 [Co(neo)2(trans-cin)]ClO4 and 2 [Co(neo)2(cis-cin)]ClO4 with trans and cis-cinnamic acid (Hcin) and neocuproine (neo) as ligands were prepared. Both complexes were characterized via single-crystal X-ray analysis, infrared spectroscopy, magnetic measurements, and EPR spectroscopy. DC magnetic susceptibility measurements revealed large axial magnetic anisotropy with axial zero-field splitting (ZFS) parameters D = 49.9 and 59.5 cm-1 and rhombicity E/D = 0.307 and 0.147 for 1 and 2, respectively. These results were in accordance with CASSCF/NEVPT2 calculations. AC magnetic data showed the presence of slow relaxation of magnetization for both compounds in the applied DC field. UV irradiation studies in solution show that the complexes most likely undergo trans/cis photoisomerisation, which is, however, accompanied by side reactions and degradation. This was elucidated further utilizing DFT and TD-DFT calculations.

• Publikační typ
• časopisecké články MeSH

Almost 25 years ago, an enzyme named zeatin cis-trans isomerase from common bean has been described by Bassil et al. (1993). The partially purified enzyme required an external addition of FAD and dithiothreitol for the conversion of cis-zeatin to its trans- isomer that occurred only under light. Although an existence of this important enzyme involved in the metabolism of plant hormones cytokinins was generally accepted by plant biologists, the corresponding protein and encoding gene have not been identified to date. Based on the original paper, we purified and identified an enzyme from maize, which shows the described zeatin cis-trans isomerase activity. The enzyme belongs to nucleotide pyrophosphatase/phosphodiesterase family, which is well characterized in mammals, but less known in plants. Further experiments with the recombinant maize enzyme obtained from yeast expression system showed that rather than the catalytic activity of the enzyme itself, a non-enzymatic flavin induced photoisomerization is responsible for the observed zeatin cis-trans interconversion in vitro. An overexpression of the maize nucleotide pyrophosphatase/phosphodiesterase gene led to decreased FAD and increased FMN and riboflavin contents in transgenic Arabidopsis plants. However, neither contents nor the ratio of zeatin isomers was altered suggesting that the enzyme is unlikely to catalyze the interconversion of zeatin isomers in vivo. Using enhanced expression of a homologous gene, functional nucleotide pyrophosphatase/phosphodiesterase was also identified in rice.

• Klíčová slova
• flavins, isomerization, maize, nucleotide pyrophosphatase/phosphodiesterase, zeatin,
• Publikační typ
• časopisecké články MeSH

2-ethylhexyl 4-methoxycinnamate (EHMC), used in many categories of personal care products (PCPs), is one of the most discussed ultraviolet filters because of its endocrine-disrupting effects. EHMC is unstable in sunlight and can be transformed from trans-EHMC to emergent cis-EHMC. Toxicological studies are focusing only on trans-EHMC; thus the toxicological data for cis-EHMC are missing. In this study, the in vitro genotoxic effects of trans- and cis-EHMC on adult human liver stem cells HL1-hT1 and human-derived lymphoblastoid cells TK-6 using a high-throughput comet assay were studied. TK-6 cells treated with cis-EHMC showed a high level of DNA damage when compared to untreated cells in concentrations 1.56 to 25μgmL-1. trans-EHMC showed genotoxicity after exposure to the two highest concentrations 12.5 and 25μgmL-1. The increase in DNA damage on HL1-hT1 cells induced by cis-EHMC and trans-EHMC was detected at the concentration 25μgmL-1. The No observed adverse effect level (NOAEL, mg kg-1bwday-1) was determined using a Quantitative in vitro to in vivo extrapolation (QIVIVE) approach: NOAELtrans-EHMC=3.07, NOAELcis-EHMC=0.30 for TK-6 and NOAELtrans-EHMC=26.46, NOAELcis-EHMC=20.36 for HL1-hT1. The hazard index (HI) was evaluated by comparing the reference dose (RfD, mgkg-1bwday-1) obtained from our experimental data with the chronic daily intake (CDI) of the female population. Using comet assay experimental data with the more sensitive TK-6 cells, HIcis-EHMC was 7 times higher than HItrans-EHMC. In terms of CDI, relative contributions were; dermal exposure route>oral>inhalation. According to our results we recommend the RfDtrans-EHMC=0.20 and RfDcis-EHMC=0.02 for trans-EHMC and cis-EHMC, respectively, to use for human health risk assessment. The significant difference in trans-EHMC and cis-EHMC response points to the need for toxicological reevaluation and application reassessment of both isomers in PCPs.

• Klíčová slova
• Adult human liver stem cells, Genotoxicity, High-throughput comet assay, Human risk assessment, Isomerization, trans/cis-EHMC,
• MeSH
• buněčné linie MeSH
• cinnamáty škodlivé účinky   MeSH
• hodnocení rizik MeSH
• játra cytologie   MeSH
• kmenové buňky účinky léků   MeSH
• kosmetické přípravky škodlivé účinky   MeSH
• lidé MeSH
• lymfocyty účinky léků   MeSH
• poškození DNA * MeSH
• přípravky chránící proti slunci škodlivé účinky   MeSH
• sluneční záření MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cinnamáty MeSH
• ethyl 4-methoxycinnamate MeSH Prohlížeč
• kosmetické přípravky MeSH
• přípravky chránící proti slunci MeSH

The doubly deprotonated form L2- of indigo=H2 L can bind two [Ru(acac)2 ] complex fragments in the cis (1) and trans configuration (2), as evidenced from crystal structure analysis. While the latter type of N,O; N' ,O' coordination has been observed earlier, for example, with [Ru(bpy)2 ]2+ , leading to two equivalent six-membered ring chelates, the cis arrangement in 1 is observed here for the first time in a dinuclear complex, producing one five-membered ring chelate with N,N' coordination and one seven-membered chelate with O,O' coordination. The different structures of the isomers result in differing electrochemical and spectroelectrochemical (EPR, UV-Vis-NIR) responses for various accessible charge states 1n and 2n , n=-, 0, +, 2+. The associated electronic structures were analyzed by DFT (structures, spin density) and TD-DFT calculations (electronic transitions), revealing mainly metal-based reduction but largely indigo ligand-based oxidation of both neutral precursors.

• Klíčová slova
• electron paramagnetic resonance spectroscopy, indigo, isomerism, ruthenium, spectroelectrochemistry, structure,
• Publikační typ
• časopisecké články MeSH

Classical structure-activity relationships for square-planar Pt(II) anticancer complexes were based on the activity of cis-[PtCl2(NH3)2] (cisplatin) and inactivity of the trans isomer. Many other families of cis-diamine complexes and analogous octahedral Pt(IV) prodrugs are active. Here, we report the chemical and biological activities of isomeric photoactivatable cis,trans,cis- and all-trans-[Pt(N3)2(OH)2(MNZ)2] complexes (MNZ = metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole). While both are relatively nontoxic in the ground state, only the all-trans isomer is cytotoxic toward bladder cancer cells on excitation with visible light and under hypoxia. Studies of DNA interstrand cross-links and photocytotoxicity toward wild-type and nucleotide-excision-repair deficient cells suggest that, unlike cisplatin, DNA is not the major target site of these isomers. Differences in photoactivation pathways were also explored using time-dependent DFT calculations. The key differences between the isomers on irradiation are the more rapid photoactivation of the all-trans complex, generation of azidyl radicals, retention of its metronidazole ligands, higher accumulation in cancer cells, binding to DNA, RNA, and proteins, and induction of apoptosis and mitochondrial membrane damages. These findings provide a basis for the design of future photochemotherapeutic platinum anticancer prodrugs.

• MeSH
• diaminy * chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny * chemie   farmakologie   chemická syntéza   MeSH
• protinádorové látky * chemie   farmakologie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• teorie funkcionálu hustoty MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• diaminy * MeSH
• organoplatinové sloučeniny * MeSH
• protinádorové látky * MeSH