Chlorine Derivatives Research Articles

Synthesis of amide derivatives of chlorin e 6

A number of secondary and tertiary chlorin e 6-13-amides were synthesized in high yield by the action of primary and secondary amines on methylpheophorbide a under mild conditions. Unlike the secondary amides, tertiary 13-amides were shown to exist as two stereoisomers differing by orientation of the amide group plane with respect to the macroring. The reaction of methylpheophorbide a with 2-aminoethanol gave chlorin e 6 derivatives containing one, two, and three hydroxy groups.

Synthesis of a Benzoannelated Spheriphane (Globular Cyclophane) on the Way to Potential Precursors of C60-Fullerene

A viable route to the novel globular cyclophane 2, a C48H36-spheriphane, is presented as a result of our research aimed at the synthesis of the hypothetical deciphenyl 3, a C60H36-sphcriphane, which has been envisaged as a potential precursor to C-60-fullerene. Several syntheses of the key intermediate of the route to 2, viz. septiphenyl 13 (C48H42), a sterically crowded 1,3,5-tris(ortho-biphenylyl)benzene derivative, are described. These include threefold Heck coupling and related threefold Pd(0)-catalyzed C-C cross-coupling reactions, as well as threefold benzoannelation involving tetrachlorothiophene-S,S-dioxide and PET-induced dehalogenation of highly chlorinated septiphenyl derivatives.

Synthesis of Styryl‐substituted Z/E‐Chlorin Derivatives with Chlorophyll‐a Skeleton

AbstractThe Wittig reaction of methyl pyropheophorbide‐d 2, obtained from methyl pyropheophorbide‐a 1, with benzyltriphenylphosphonium bromide was performed to yield isomers 3a and 3b. The Vilsmeier reaction of nickel complex 4 or 7 with 3‐dimethylaminoacrolein in the presence of phosphoryl chloride was carried out to form 20‐meso‐2′‐formylvinylpyropheophorbide‐a 5 or 8, which was reacted with Wittig reagent to afford nickel complex isomers 6a and 6b or 9a and 9b, 10a and 10b.

Introduction: Enhanced UV‐B Radiation in Natural Ecosystems as an Added Perturbation Due to Ozone Depletion

This issue of the journal contains 16 articles in a symposiumin-print about the effects of UV radiation (UVR) on natural ecosystems. These articles result from a 5 year multidisciplinary project on UVR and UV effects on natural systems carried out by a network of 17 principal investigators from 13 institutions in 5 countries. The research project’s aim was to test the effect of UVR on natural systems, including marine, freshwater and coastal environments, on a continental scale in the Americas. The symposiumin-print presents results of field sampling and field and laboratory experiments to document UVR effects in natural gradients, both latitudinal and altitudinal, and test hypotheses on what controls UVR exposure and UVR effects, such as dissolved organic carbon loading in lakes and the evolution of trophic dynamics in marine systems. The symposium-in-print is a unique contribution because of its multidisciplinary scope, the geographical scale of the experiments and the diversity of systems studied. The discovery of the Antarctic ozone hole in 1986 brought the public’s attention to the degradation of the ozone layer by anthropogenic contamination of the stratosphere (1). In one of the most successful stories of environmental international policy, the Montreal Protocol was implemented in 1990 to control emissions of chlorofluorocarbons and other gases creating chlorine and bromine derivatives that interact with ozone to produce two molecules of oxygen (2). Ozone absorbs radiation strongly in the UV and the presence of ozone and oxygen in the atmosphere results in the absorption of nearly all solar radiation with a wavelength of ,290 nm. As a result, virtually no UV-C radiation (200–280 nm) reaches the Earth’s surface, UV-B radiation (280–320 nm) is significantly absorbed (mostly by ozone) and only a small fraction (,3%) of UV-A radiation (320–390 nm) is absorbed by ozone. The effect of UVR on natural ecosystems is function of several biotic and abiotic factors that interact directly with the ecosystem components and alter the relationship among those components (3). Additionally, the system provides feedback mechanisms that either increase or decrease the direct effect of UVR. The articles in the symposium-in-print are based on the premise that natural ecosystems have dealt with UVR as a natural stress factor since the beginning of life on Earth (4) and the present increase in UVR due to stratospheric ozone decrease is an added perturbation to the system. Incident UVR depends on geometric factors such as Sun-Earth distance and solar zenith angle; UVR can be modified in the atmosphere by gases, aerosols and clouds and is further a function of altitude and surface albedo (5). In the water, UVR is strongly affected by dissolved organic matter that alters its transmission to depth because of absorption and scattering. Net damage by UVR is a balance between damage and repair (6). Damage is dependent on radiation exposure or amount of UVR absorbed by the organism or system. At the organism level the damage can be avoided, screened or repaired (7). At the system level deleterious effects at the population level can be ameliorated by differential damage to a predator thus decreasing predation pressure (8). In addition community composition can be altered because of differential damage to certain components. For example, damage to large cells in planktonic communities favors a microbial loop and small cells rather than net plankton and larger grazers. The research presented in the symposium-in-print focuses on the main pathways of net UVR damage on diverse natural ecosystems, emphasizing common processes along environmental gradients.

Photosensitization of skin fibroblasts and HeLa cells by three chlorin derivatives: Role of chemical structure and delivery vehicle

The chemical nature of the sensitizer and its selective uptake by malignant cells are decisive to choose an appropriate biocompatible carrier, able to preserve the photosensitizing characteristics of the dye. In this paper we demonstrate the photodynamic properties of three chlorins, derived from chlorophyll a, and the usefulness of liposomal carriers to design pharmaceutical formulations. The chlorins have been quantitatively incorporated into stable liposomes obtained from a mixture of l-α-palmitoyloleoylphosphatidylcholine and l-α-dioleoylphosphatidylserine in a 13.5:1.5 molar ratio (POPC/OOPS-liposomes). The chlorin uptake by skin fibroblasts increases steadily, reaching in all cases a plateau level dependent on both the chlorin structure and the vehicle employed. The photophysical properties of the three chlorins in THF are nearly identical and fulfill the requirements for a PDT photosensitizer. Incorporation of chlorins into liposomes induces important changes in their photophysics, but does not impair their cellular uptake or their cell photosensitization ability. In fact we observe in the cells the same photophysical behavior as in THF solution. Specifically, we demonstrate, by recording the near-IR phosphorescence of 1O 2, that the chlorins are able to photosensitize the production of 1O 2 in the cell membrane. The cell-photosensitization efficiency depended on the chlorin and cell line nature, the carrier, and the length of pre-incubation and post-irradiation periods. The high photodynamic activity of chlorin-loaded liposomes and the possibility to design liposomal carriers to achieve a specific target site favors this approach to obtain an eventual pharmaceutical formulation.

Chlorine derivatives of syndiotactic 1,2-polybutadiene

It is shown that chlorine-containing polymeric products may be produced on the basis of the syndiotactic 1,2-polybutadiene by incorporating chlorine atoms into macromolecules via double carbon-carbon bonds. The functionalization of the polydiene with halogen atoms markedly changes the viscosity of solutions, flowability of the melt, and thermal stability of polymeric products. Chlorine derivatives of the syndiotactic 1,2-polybutadiene may be used as high-molecular-mass modifiers improving rheological properties of polymeric compounds in poly(vinyl chloride)-based polymeric composites.

(BETS)2[RuX5NO] (X = Cl, Br): An Explanation of Different Conductive Properties Through Structural and Spectroscopic Studies

(BETS)2[RuX5NO] (X=Cl, Br) exhibit an identical 2:1 stoichiometry. However, while the chlorine derivative shows an insulating behavior, the bromine behaves as a semiconductor with very small activation energy (0.03 eV). The different electrical behaviors are analyzed through the use of a detailed study of structural data and analysis of Raman spectra

Synthesis and Anti-HIV Activity of Novel Cyclopentenyl Nucleoside Analogues of 8-Azapurine

Novel nucleoside analogues of structure 3-5 were synthesized starting from (+/-)-cis-2-amino-3-cyclopentenylmethanol (1). The chlorine derivative 3 inhibited both HIV-1 and HIV-2 replication in MT-4 cells with IC(50) values of 10.67 microM and of 13.79 microM, respectively.

2,3-Butanedione monoxime does not protect cardiomyocytes under oxidative stress

Heart muscle ischemia-reperfusion provokes a pronounced cardiomyocyte oxidative stress. In the present study, we examined a possible protective effect of the cardioprotective drug, 2,3-butanedione monoxime (BDM), on the cultured neonatal cardiac myocytes exposed to oxidative stress induced by hypochlorous acid (HOCl), that may be formed by activated polymorphonuclear neutrophils in myocardium ischemic-reperfusion areas, and a useful model oxidant, tert-butyl hydroperoxide (tBHP). Using isolated rat cardiomyocytes substantial cytotoxicity of HOCl and tBHP was demonstrated: The concentrations of HOCl and tBHP causing a 50% decrease of cardiomyocyte cell viability were estimated to be 55 +/- 5 microM and 36 +/- 6 microM, respectively. The cell viability measured immediately after the tBHP oxidative treatment was significantly higher than that measured after 22 h of cell post-incubation in a fresh culture medium. This showed delayed cell death after removing tBHP. Hypochlorous acid treatment of cardiomyocytes did not change cellular viability during the cellular post-incubation in a fresh medium. Even a long-term (22 h) incubation of oxidatively damaged cardiomyocytes with BDM (5 mM) added after the HOCl removal did not recover the viability of the HOCl-exposed cells. In the presence of BDM, the cytotoxicity of HOCl significantly increased probably due to a direct reaction of both compounds and toxic chlorinated derivative formation. 2,3-Butanedione monoxime (5 mM) did not reduce cytotoxicity of tBHP, either. Such well-known antioxidative agents as melatonin or glutathione considerably prevented oxidant-induced cell death in a concentration-dependent manner.

Oxidative ring cleavage of low chlorinated biphenyl derivatives by fungi leads to the formation of chlorinated lactone derivatives

The yeast Trichosporon mucoides and the filamentous fungus Paecilomyces lilacinus as biphenyl oxidizing organisms are able to oxidize chlorinated biphenyl derivatives. Initial oxidation of derivatives chlorinated at C4 position started at the non-halogenated ring and went on up to ring cleavage. The products formed were mono- and dihydroxylated 4-chlorobiphenyls, muconic acid derivatives 2-hydroxy-4-(4-chlorophenyl)-muconic acid and 2-hydroxy-5-(4-chlorophenyl)-muconic acid as well as the corresponding lactones 4-(4-chlorophenyl)-2-pyrone-6-carboxylic acid and 3-(4-chlorophenyl)-2-pyrone-6-carboxylic acid. Altogether T. mucoides formed 12 products and P. lilacinus accumulated five products. Whereas the rate of the first oxidation step at 4-chlorobiphenyl seems to be diminished by the decreased bioavailability of the compound, no considerable differences were observed between the degradation of 4-chloro-4′-hydroxybiphenyl and 4-hydroxybiphenyl. Twofold chlorinated biphenyl derivatives did not serve as substrates for oxidation by either organism with the exception of 2,2′-dichlorobiphenyl, transformed by the yeast Trichosporon mucoides to two monohydroxylated derivatives. The results show, that soil fungi may contribute to the aerobic degradation of low chlorinated biphenyls accumulating from anaerobic dehalogenation of PCB by bacteria.

Photophysical properties of glucoconjugated chlorins and porphyrins and their associations with cyclodextrins

Glucoconjugated analogues of the meta-hydroxyphenyl porphyrin ( m-THPP) and meta-hydroxyphenyl chlorin ( m-THPC) has been recently synthesized. The characteristics of their triplet states have been determined with regard to their involvement in the photodynamic (PDT) efficiency. In the case of porphyrin derivatives, triplet quantum yields ( Φ T) were ranging from 0.42 to 0.55 and triplet life times ( τ T) from 1 to 5 μs. High reaction rate constants ( k q) with molecular oxygen ( k q: 1.2–1.6 × 10 9 s −1) have been found. The triplet lifetimes of chlorin derivatives were about four times higher than those of porphyrins whereas the Φ T and k q values remained quite similar. Singlet oxygen yields of glucosylated and non-glucosylated porphyrins and chlorins were not significantly different within experimental errors ( Φ Δ( 1O 2): 0.41–0.58). Furthermore, it has been shown that glucoconjugated photosensitizers could undergo associations with the methyl-β-cyclodextrin (Me-β-CD) which exhibit high triplet lifetimes and singlet oxygen yields ranging from 0.27 to 0.48.

PH Effect on the binding of chlorin derivatives with Cremophor EL, a potential drug delivery vehicle

The binding of chlorin p 6 with Cremophor EL (CrEL) at pH 5 and pH 7 has been monitored by fluorescence techniques. Upon binding with the drug delivery agent, the fluorescent species are found to be one and the same at both pH values. This is explained by a hindrance to protonation of chlorin p 6 trianions by Cremophor EL. Surprisingly, it is the more hydrophilic species between the two possible chlorin p 6 ions that is found to get bound preferentially with the hydrophobic delivery medium.

Assessment of Laboratory and Field Assays of Sunlight-Induced Killing of Mosquito Larvae by Photosensitizers

The effectiveness of light-induced killing of mosquito larvae in the presence of photosensitizers was studied with larvae of Aedes aegypti (L.), Anopheles stephensi (Liston), and Culex quinquefasciatus Say grown in the laboratory and of Cx. quinquefasciatus grown under field conditions. Tested photosensitizers included xanthene, chlorin, and porphyrin derivatives. All the larvae were treated at the fourth instar. Preliminary laboratory experiments showed a light-induced lethal effect of Rose Bengal (RB) on three species of mosquito larvae. Compared with other photosensitizers, RB seemed to be more efficient at even lower concentration than chlorin (e6) and chlorophyllin on Ae. aegypti larvae. Among the four porphyrin derivatives, i.e., chloroquinoline tetraphenyl propioamidoporphine, tetraphenyl porphine tetrasulfonate, hematoporphyrin (HP), and tetraphenylporphinepropionic acid porphine, HP was the only effective photosensitizer on Ae. aegypti larvae. The best conditions for field tests using RB were conducted on Cx. quinquefasciatus in Bobo-Dioulasso, Burkina Faso. The mortality induced by RB varied from 80 to 96% obtained with unfiltered cesspit water to 0.4 to 6.7% in cesspits with a heavy load of organic materials, thus providing the basis for further developments of this technique under field conditions.

Simple sensitive and simultaneous high-performance liquid chromatography method of glucoconjugated and non-glucoconjugated porphyrins and chlorins using near infra-red fluorescence detection

This paper reports, for the first time, a reversed-phase high performance liquid chromatographic method for the simultaneous determination of seven glucoconjugated and non-glucoconjugated porphyrins and chlorins, using near infra-red fluorescence detection. Chromatographic separation was performed on nucleosil-CN analytical column using an isocratic acetonitrile–0.1% (w/v) TFA at pH 1.8 (55:45, v/v) as mobile phase. Wavelength gradient was employed for sensitive detection, porphyrins derivates were monitored at λ exc = 440 nm and λ emi = 680 nm; and chlorins derivates at λ exc = 420 nm, λ emi = 650 nm. The method was validated and applied to monitor the biodegradation of a tri glucoconjugated chlorin derivative, TPC(glu) 3, in spiked samples of human serum.

Synthesis, structural investigations on organotin(IV) chlorin-e 6 complexes, their effect on sea urchin embryonic development and induced apoptosis

Four new organotin(IV) chlorin derivatives, [chlorin = chlorin-e 6 = 21H,23H-porphine-2-propanoic acid, 18-carboxy-20-(carboxymethyl)-8-ethenyl-13-ethyl-2,3-di-hydro-3,7,12,17-tetramethyl-(2 S- trans)–], with formula (R 2Sn) 3(chlorin) 2 · 2H 2O (R = Me, n-Bu) and (R 3Sn) 3chlorin · 2H 2O (R = Me, Ph) have been synthesized. The solid state and solution phase structures have been investigated by FT-IR, 119Sn Mössbauer, 1H and 13C NMR spectroscopy. In the solid state, (R 2Sn) 3(chlorin) 2 · 2H 2O complexes contain six coordinated Sn(IV), in a skew trapezoidal environment by forming trans-R 2SnO 4 polymeric units. As far as (R 3Sn) 3chlorin · 2H 2O complexes are concerned, Sn(IV) is five coordinated in a polymeric (oligomeric) trigonal bipyramidal environment and eq-R 3SnO 2 units, in the solid state. In saturated solutions, a polymeric structure comparable to the solid phase, with carboxylate groups of the ligand behaving in monoanionic bidentate fashion bridging Sn(IV) atoms, was detected for the (Me 3Sn) 3chlorin · 2H 2O complex, while in more diluted ones a tetrahedral configuration for the trimethyltin(IV) moieties was observed. Cytotoxic activity of the novel organotin(IV) chlorin was investigated in order to assay the effect on sea urchin embryonic development. The results obtained demonstrated that ( n-Bu 2Sn) 3(chlorin) 2 · 2H 2O and (Ph 3Sn) 3chlorin · 2H 2O exerted the antimitotic effect on the early stages of sea urchin development. In addition, the cytotoxic effect exerted by ( n-Bu 2Sn) 3(chlorin) 2 · 2H 2O appeared with necrosis of the blastomeres, which were clearly destroyed. After treatment with (Ph 3Sn) 3chlorin · 2H 2O, a programmed cell death was triggered, as shown by light microscope observations through morphological assays. The apoptotic events in 2-cell stage embryos revealed: (i) DNA fragmentation, with the TUNEL reaction (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling); (ii) phosphatidylserine translocation in the membrane, with Annexin-V assay and (iii) cytoplasm blebbing, with the TUNEL reaction. The results demonstrated that the novel compound (Ph 3Sn) 3chlorin · 2H 2O was the most toxic derivative, by exerting antimitotic effect very early and by triggering apoptosis in the 2-cell stage of sea urchin embryonic development.

Syntheses and screening tests of new chlorin derivatives as photosensitizer

New chlorin derivatives were synthesized from protoporphyrin IX dimethyl ester ( 1) as a starting material. The tumor-localizing abilities were determined by bathochromic and hyperchromic shift test using albumin and the photosensitivities were evaluated by photooxidation test using dansyl- l-methionine. NOH-P-H ( 3) was the most excellent in the both tests. NOH-P-H ( 3) was conjugated with aspartic acid to evaluate the biodistribution with the time progress by nitrogen pulsed laser spectrofluorometry. The concentration of NOH-P-Asp ( 15) in cancer tissues showed the highest concentration at 6 h after the administration and corresponded to five to seven times in other organs. The concentration in cancer tissues showed a rapid decrease at 24 h after the administration. PDT effect of NOH-P-Asp ( 15) was evaluated using tumor-bearing mice. Remarkable anti-tumor effect was observed. NOH-P-Asp ( 15) was expected to be applicable to a new photosensitizer for PDT.

Quantum mechanics calculations on the diastereomeric salts of cyclic phosphoric acids with ephedrine

Using three different density functional packages. DMol 3, VASP, and SIESTA, we have calculated the relaxed structures and relative energies of the diastereomers of cyclic phosphoric acid and its chlorine derivative with ephedrine. The structures predicted by the three codes are in very good agreement with experiment. Also in accordance with experiment, very small energy differences (<3 kcal/mol) are found between diastereomers. However all the three packages fail to correctly reproduce the stability order of all diastereomers. This failure is probably related to the inability of the currently available approximations for the exchange-correlation energy functional to reproduce dispersive long-range interactions (i.e. van der Waals). In spite of the large unit cell, the relative stability of the different structures is quite sensitive to the k-space sampling. On the one hand, VASP and SIESTA codes predict the correct stability order when only Γ point is used for the k-space integration. A better k-space sampling however, destroys the agreement between theory and experiment, increasing the energy of the experimentally most stable chlorine-containing diastoreomer. On the other hand, DMol 3, with which only Γ point calculations have been performed; predicts the stability order of one pair of diastereomers correctly, but the stability order of a third polymorph is predicted wrongly. An experimentally unknown chlorine-free analogue of the most stable chlorine-containing diastereomer, was calculated to be the least stable.

Benzene‐assisted atmospheric‐pressure chemical ionization: a new liquid chromatography/mass spectrometry approach to the analysis of selected hydrophobic compounds

Charge-exchange reactions involving benzene have been successfully exploited to increase the sensitivity of atmospheric-pressure chemical ionization mass spectrometry (APCI-MS) towards hydrophobic compounds of significant environmental relevance which are not detectable with the ordinary APCI techniques. Among them, good sensitivity have been found for (a) highly chlorinated biphenyl derivatives such as dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane (DDD) and dichlorodiphenyldichloroethene (DDE); (b) cyclopentadienes such as Aldrin and its epoxy derivatives Dieldrin and Endrin; and (c) dibenzofurans and dibenzo-para-dioxins such as 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF) and 2,3,7,8-tetrachloro-dibenzo-para-dioxin (2,3,7,8-TCDD). The reactant benzene molecules were introduced into the source either through the nebulizer gas or by direct post-column addition of neat liquid, whereas the targeted compounds were analyzed using a high-performance liquid chromatography (HPLC) RP-18 column using methanol/water solutions as mobile phase. By using benzene as post-column reagent, positive ion mode detection was proven to be significantly enhanced as compared with APCI measurements carried out without benzene assistance.

Hydride Affinities of Borane Derivatives: Novel Approach in Determining the Origin of Lewis Acidity Based on Triadic Formula

The problem of intrinsic Lewis acidities of simple boron compounds (BH3-mXm, m = 0-3, X = F, Cl, Br, CH3, and OH) is assessed by their gas-phase hydride affinities (HAs). A simple and intuitively appealing picture of the interaction process including detachment of an electron from the hydride ion H-, capture of the pruned electron to the investigated Lewis acid (LA), and subsequent formation of the homolytic chemical bond between two newly created radicals is proposed. It enables transparent and straightforward dissection of the initial and final state effects, which taken together with the intermediate relaxation stabilization determine the trend of changes in the hydride affinities. The former effect is reflected in the electron affinities of the neutral Lewis acids given within Koopmans' approximation, while the final state effect involves properties of the formed Lewis acid-base adducts mirrored in the bond dissociation energy of the formed [LA-H]- chemical bond. It is demonstrated that unexpectedly low Lewis acidity of fluoroboranes relative to the corresponding chlorine and bromine derivatives can be traced down to the unfavorable Koopmans' electron affinities. Hence, it is a consequence of the initial state effect. In contrast, chloroboranes are more potent Lewis acids than fluoroboranes, because the relaxation and final state effects decisively influence their Lewis acidity. Finally, bromine-substituted borane compounds provide the most powerful studied Lewis acids. Their hydride affinities are result of a synergic interplay of the initial state, intermediate stabilization via relaxation, and final state effects. It is shown that Pearson's global hardness indices defined within his hard and soft acid-base (HSAB) principle fail to adequately predict and interpret the calculated hydride affinities.

Structure and reactivity of C54q+(q= 0, 1, 2 and 4) fullerenes

Using density functional theory we have studied the structural properties of eleven C54 isomers that appear in the C60 fragmentation. We have evaluated the relative stability of the different isomers with respect the most stable one, which corresponds to the structure with the minimum number (four) of adjacent pentagons. On average, the length of a bond shared by pentagons and/or hexagons increases in the order hexagon-hexagon, hexagon-pentagon and pentagon-pentagon. However, we have found that the central bond in the confluence of four hexagons, i.e. a pyrene substructure, is anomalously large, becoming in some cases the largest one. We have also evaluated the nucleus-independent chemical shifts (NICS) at the center of every individual ring in the most stable isomers. For the chlorine derivatives, our calculations show that the favorite position for chlorine addition are the bonds shared by pentagons.