Chlorine Derivatives Research Articles

Photodynamic Mechanisms induced by a Combination of Hypericin and a Chlorin Based‐Photosensitizer in Head and Neck Squamous Cell Carcinoma Cells

The aim of this study was to elucidate photodynamic therapy (PDT) effects mediated by hypericin and a liposomal meso-tetrahydroxyphenyl chlorin (mTHPC) derivative, with focus on their 1:1 mixture, on head and neck squamous cell carcinoma cell lines. Absorption, excitation and photobleaching were monitored using fluorescence spectrometry, showing the same spectral patterns for the mixture as measured for single photosensitizers. In the mixture mTHPC showed a prolonged photo-stability. Singlet oxygen yield for light-activated mTHPC was Φ(Δ) = 0.66, for hypericin Φ(Δ) = 0.25 and for the mixture Φ(Δ) = ~0.4. A linear increase of singlet oxygen yield for mTHPC and the mixture was found, whereas hypericin achieved saturation after 35 min. Reactive oxygen species fluorescence was only visible after hypericin and mixture-induced PDT. Cell viability was also more affected with these two treatment options under the selected conditions. Examination of death pathways showed that hypericin-mediated cell death was apoptotic, with mTHPC necrotic and the 1:1 mixture showed features of both. Changes in gene expression after PDT indicated strong up-regulation of selected heat-shock proteins. The application of photosensitizer mixtures with the features of reduced dark toxicity and combined apoptotic and necrotic cell death may be beneficial in clinical PDT. This will be the focus of our future investigations.

Boronated derivatives of chlorin e 6 and fluoride-containing porphyrins as penetrating anions: a study using bilayer lipid membranes

Boronated derivatives of porphyrins are studied extensively as promising compounds for boron-neutron capture therapy and photodynamic therapy. Understanding of the mechanism of their permeation across cell membranes is a key step in screening for the most efficient compounds. In the present work, we studied the ability of boronated derivatives of chlorin e(6) and porphyrins, which are mono-, di-, and tetra-anions, to permeate through planar bilayer lipid membranes (BLM). The translocation rate constants through the hydrophobic part of the lipid bilayer were estimated for monocarborane and its conjugate with chlorin e(6) by the method of electrical current relaxation. They were similar, 6.6 and 6.8 sec(-1), respectively. Conjugates of porphyrins carrying two and four carborane groups were shown to permeate efficiently through a BLM although they carry two charges and four charges, respectively. The rate of permeation of the tetraanion estimated by the BLM current had superlinear dependence on the BLM voltage. Because the resting potential of most mammalian cells is negative inside, it can be concluded that the presence of negatively-charged boronated groups in compounds should hinder the accumulation of the porphyrins in cells.

32 Comparative evaluation of antitumoral efficiency of preparation chlorin-amine-amide-1 in a various forms for photodynamic therapy of sarcoma M-1

The tetrapyrrolic compound chlorin e6 is currently used as a pharmaceutical substance for Photolon formulation, which is utilized in photodynamic therapy of various diseases. It was found that chlorin e6 could contain both process- and degradation-related impurities. In order to understand their origin, the most abundant impurities were prepared by liquid extraction, preparative chromatography or chemical synthesis. By means of HPLC-PDA–MS, 1D and 2D NMR spectroscopy, these impurities were identified as chlorin e6 174-ethyl ester, chlorin e4, 15-hydroxyphyllochlorin, rhodochlorin, 151-hydroxymethylrhodochlorin δ-lactone, rhodochlorin-15-oxymethyl δ-lactone, rhodochlorin-15-oxymethyl δ-lactone 174-ethyl ester, 151-hydroxymethylrhodoporphyrin δ-lactone, rhodoporphyrin-15-oxymethyl δ-lactone and purpurin 18. The possible routes of formation of the chlorin derivatives upon the production and storage of chlorin e6 are discussed.

Effects of hypericin and a chlorin based photosensitizer alone or in combination in squamous cell carcinoma cells in the dark

The toxic influence of photosensitizers in the dark is poorly investigated. In our study we used the photosensitizers liposomal meso-tetrahydroxyphenyl chlorin derivative (Foslipos(®)) and hypericin as well as their 1:1 combination on two different head and neck squamous cell carcinoma (HNSCC) cell lines (UMB-SCC 745 and UMB-SCC 969). We examined uptake, efflux and localization of the photosensitizers with confocal microscopy. Fluorescence quantification was measured with a micro-plate spectrometer. Special interest was given to effects on cell proliferation (BrdU proliferation assay), RNA quality (Bioanalyzer measurements) and DNA damage (comet assays) in the dark. Foslipos(®) uptake was linear over time and its efflux was not achieved even after 24 h while uptake of hypericin reached a plateau after 5 h and was almost eliminated after 24 h. Localization of Foslipos(®) was organelle-unspecific. Hypericin was found mainly at membranes and in trans-golgi network. Foslipos(®) treated cells showed cell toxicity for the highest concentration (10 μg/mL). In contrast, hypericin was toxic for all concentrations (10-0.6 μg/mL). The photosensitizer combination was non-toxic for all concentrations (10-0.6 μg/mL). No changes in RNA quality were monitored. Initial DNA damage was found only in hypericin treated UMB-SCC 745, which recovered after 3h. No significant DNA damage was found for UMB-SCC 969. Our data shows that the combinatorial application decrease photosensitizer toxicity, which can be advantageous in PDT treatments.

Georgia Gulf Rebuffs Westlake

Georgia Gulf has rejected an unsolicited $1 billion buyout offer from polyvinyl chloride rival Westlake Chemical. The $30.00-per-share offer represents a premium of nearly 23% for Georgia Gulf’s shares over their market close on Jan. 12, the day before the offer was publicly disclosed. Westlake had been privately courting Georgia Gulf since last September. Both Georgia Gulf and Westlake make chlorine, vinyl chloride, PVC, and PVC derivatives such as pipe, windows, and doors. Westlake earned $221 million on $3.2 billion in sales in 2010, whereas Georgia Gulf made $43 million on $2.8 billion in sales. Combined, the two firms would be the second-largest U.S. producer of PVC, after Shintech. Recent years have been tumultuous for Georgia Gulf. It paid $1.6 billion for building products maker Royal Group Technologies in 2006, only to be hit soon thereafter by the housing downturn. In February 2009, the New York Stock Exchange warned the ...

Allomerization of Methyl Pheophorbide-a and Synthesis of Chlorin Derivatives

Allomerization of Methyl Pheophorbide-a and Synthesis of Chlorin Derivatives

Alkynylation of Pyropheophorbide-a and Synthesis of Chylorophyllous Chlorin Derivatives

Alkynylation of Pyropheophorbide-a and Synthesis of Chylorophyllous Chlorin Derivatives

Aminolysis Reaction of Purpurin-18 and Synthesis of Chlorin Derivatives Related to Chlorophyll

Aminolysis Reaction of Purpurin-18 and Synthesis of Chlorin Derivatives Related to Chlorophyll

Halogenation Reaction of Purpurin-18 and Synthesis of Chlorin Derivatives

Halogenation Reaction of Purpurin-18 and Synthesis of Chlorin Derivatives

Modification for the E-Ring of 132-Oxo-pyropheophorbide-a and Synthesis of Chlorin Derivatives

Modification for the E-Ring of 13²-Oxo-pyropheophorbide-a and Synthesis of Chlorin Derivatives

Acetylation of Chlorophyll-a Degradation Products and Synthesis of Chlorin Derivatives

Methyl pheophorbide-a (MPa) was used as starting material and converted to Ni(II) complexes by modifying for chemical structures and metallizing with Ni(acac)2. Their Vilsmerier reactions with phosphoryl chloride and 3-(dimethylamino)-acrolein or N,N-dimethylformamide were performed regioselectively to introduce formyl or formylvinyl group on the periphery of chlorin. The formylmethyl group also was established by oxidation reaction of the C(3)-vinyl group with thallium nitrate. The hydroxyalkyloxyl or hydroxyalkylamino group on the macrocycle was constructed based on the chemical activities of the vinyl group at 3-position and ketone group in E-ring and subsequently the hydroxyl group was oxidized with the conbination of tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide to the corresponding formyl group, respectively. The structures of all the new chlorins containing acyl structure were characterized by UV, IR, H NMR spectra and elemental analysis.

One-pot synthesis of pyrano[4,3-b]quinolinones from 2-alkynyl-3-formylquinolines via oxidative 6-endo-dig ring closure

A new regioselective one-pot procedure to synthesize pyranoquinolinones from readily available 2-alkynyl 3-formylquinolines under mild NaClO2/H2O2 conditions in good yields has been explored. This reaction sequence, involving oxidation followed by regioselective electrophilic 6-endo-dig cyclization is more efficient over the traditional Pd(0)-mediated synthesis. When scavenger-free conditions were used, unusual chlorinated furoquinolinone derivatives were obtained.

Copper chlorophyllin: A food colorant with bioactive properties?

Copper chlorophyllin (Cu-Chl) is a chlorophyll-derived food colorant, commercially available as a complex mixture of different chlorin molecules. Several studies have reported great variability in the composition of the mixture as well as the presence of porphyrins and uncoppered chlorin derivatives. The intake of chlorophyllin and its relationship with possible health benefits have been also the subject of several studies and the results have drawn attention to the possibility that this compound may serve not just as a food colorant, but also as a potential bioactive product with antimutagenic, anticarcinogenic and antioxidant activities; however, its mechanisms of action are not yet well understood. Attaining knowledge of its mechanisms of absorption, bioavailability and consequent bioactivity is essential for the exploration of its potential health-related applications. The purpose of this paper is to present an overview of bioactivities concerning Cu-Chl and provide a discussion on the latest scientific research findings on its human health benefits.

Chlorin Photosensitizers Sterically Designed To Prevent Self-Aggregation

The synthesis and photophysical evaluation of new chlorin derivatives are described. The Diels-Alder reaction between protoporphyrin IX dimethyl ester and substituted maleimides furnishes endo-adducts that completely prevent the self-aggregation of the chlorins. Fluorescence, resonant light scattering (RLS) and (1)H NMR experiments, as well as X-ray crystallographic have demonstrated that the configurational arrangement of the synthesized chlorins prevent π-stacking interactions between macrocycles, thus indicating that it is a nonaggregating photosensitizer with high singlet oxygen (Φ(Δ)) and fluorescence (Φ(f)) quantum yields. Our results show that this type of synthetic strategy may provide the lead to a new generation of PDT photosensitizers.

Chloroscabrolides, chlorinated norcembranoids from the Indonesian soft coral Sinularia sp.

Chemical analysis of the Indonesian soft coral Sinularia sp. (order Alcyonacea, family Alcyoniidae) afforded two known and three new C-4 norcembranoids, named chloroscabrolides A ( 3) and B ( 4) and prescabrolide ( 5). Chloroscabrolide A is a pentacyclic norcembranoid including an unprecedented THF-type ring to connect C-13 and C-15; furthermore, it is only the second chlorinated cembranoid derivative to be reported in the literature. The relative configuration of chloroscabrolide A has been established on the basis of a comparison between experimental 13C NMR data and DFT-calculated 13C NMR chemical shifts. All the isolated norcembranoids have been evaluated for iNOS protein inhibition.

Effect of structural features of molecules (Cl3PNZ)2 (Z = CH3 and CH2CH2Cl) on the position exchange of chlorine atoms in the P-Cl fragments

Based on the analysis of structural parameters of molecules (Cl3PNCH3)2 (I) and (Cl3PNCH2CH2Cl)2 (II) by the quantum-chemical nonempirical calculations the following was revealed. The structure of I and II dimers has geometric features, which have a decisive influence on the degree of inhibition of positional exchange of the chlorine atoms in the P-Cl fragments known for the chlorine derivatives of pentacoordinated phosphorus atom. The obstacles to this dynamic process in the mentioned intramolecular dimers is shown to result from the spatial nonvalent interactions due to the short contacts of the chlorine and hydrogen atoms.

Pharmacokinetic Optimization of 4-Substituted Methoxybenzoyl-aryl-thiazole and 2-Aryl-4-benzoyl-imidazole for Improving Oral Bioavailability

Microtubules are critical components of the cytoskeleton. Perturbing their function arrests the growth of a broad spectrum of cancer cell lines, making microtubules an excellent and established target for chemotherapy. All of the U.S. Food and Drug Administration-approved antitubulin agents bind to paclitaxel or vinblastine binding sites in tubulin. Because of the complexity of their structures, it is difficult to structurally modify the vinca alkaloids and taxanes and develop orally bioavailable agents. Antitubulin agents that target the colchicine-binding site in tubulin may provide a better opportunity to be developed for oral use because of their relatively simple structures and physicochemical properties. A potent antitubulin agent, 4-(3,4,5-trimethoxybenzoyl)-2-phenyl-thiazole (SMART-H), binding to the colchicine-binding site, was discovered in our laboratory. However, the bioavailability of SMART-H was low because of its poor solubility. Structural modification of SMART-H led to the development of 2-aryl-4-benzoyl-imidazole analog (ABI-274), with improved bioavailability and potency but still considerable first-pass metabolism. A chlorine derivative (ABI-286), replacing the methyl site of ABI-274, resulted in 1.5-fold higher metabolic stability in vitro and 1.8-fold lower clearance in rats in vivo, indicating that metabolic stability of ABI-274 can be extended by blocking benzylic hydroxylation. Overall, ABI-274 and ABI-286 provided 2.4- and 5.5-fold increases in exposure (area under the curve) after oral dosing in rats compared with SMART-H. Most importantly, the structural modifications did not compromise potency. ABI-286 exhibited moderate clearance, moderate volume of distribution, and acceptable oral bioavailability. This study provided the first evidence that ABI-286 may be the first member of a new class of orally bioavailable antitubulin agents.

Tissue Uptake Study and Photodynamic Therapy of Melanoma‐Bearing Mice with a Nontoxic, Effective Chlorin

Chlorins have intense red absorptions and high tumor affinities that make them interesting candidates for photodynamic therapy (PDT) of cancer. This paper reports cytotoxicity, phototoxicity, in vitro cellular uptake, and in vivo biodistribution and PDT efficacy of a synthetic chlorin derivative (TCPCSO₃H) towards Cloudman melanoma cells (S91). No cytotoxic effects were observed in vitro at concentrations up to 20 μm, and no toxicity was observed in vivo in DBA mice with doses up to 2 mg kg⁻¹. Pharmacokinetics and biodistribution of TCPCSO₃H were evaluated in vivo in DBA mice bearing S91 tumors. TCPCSO₃H demonstrated preferential accumulation in S91 mouse melanoma, with tumor-to-normal tissue ratios of 5 and 11 for muscle and skin, respectively, 24 h after intravenous injection of 2 mg kg⁻¹. Photodynamic therapy performed under these conditions with 70 mW cm⁻² diode laser irradiation at 655 nm for 25 min (total light dose=105 J cm⁻²) resulted in scab formation, followed by temporary or permanent (>60 days) tumor remission. According to the Kaplan-Meier analysis, the median survival time of the control group was 9 days, whereas that of the treated group was 38 days.

Theoretical study on the highly chlorinated smaller fullerenes of C 30–C 48

Stimulated by recent preparation and characterization of the first C 50Cl 10 fullerene derivative with five fused pentagons and four novel chlorinated fullerene derivatives, C 54Cl 8, C 56Cl 12, C 66Cl 6 and C 66Cl 10 with the triple sequentially fused pentagons, 30 exohedral chlorine derivatives of small fullerenes C 30–C 48 have been reported here. The geometrical structures and electronic properties of them are studied using density functional theory (DFT) at the B3LYP/6-31G ∗ level. The HOMO–LUMO gaps, reaction energies, and aromaticities commonly used for chemical viability of chlorinated small fullerenes were compared with these values of the two most stable fullerene derivatives C 50Cl 10 and C 60Cl 30. The presented data reveal that many unknown fullerene derivatives are stable molecules, especially for C 32Cl 20 (3, D 3d), C 36Cl 18 (13, D 3h), and C 40Cl 16 (40, T d). The stable behavior of them resembles the well-known C 50Cl 10. It is quite possible that they can be synthesized experimentally in the solid after C 50.

Dihydrogen bond in C2H4− n Cl n ··· NaH (n = 0, 1, 2, 3) complexes: ab initio, AIM and NBO studies

The dihydrogen-bonded complexes of ethylene and its chlorine derivatives with sodium hydride have been systematically investigated at the MP2/6-311++G(d,p) level. The studied complexes are divided into three groups (including Linear, Five- and Six-membered cyclic structures) based on the optimized structures. The structural, energetic and topological parameters are presented and analysed in terms of their possible correlation with the interaction energies and the intermolecular H ··· H distances. The nature of the electrostatic interaction in this type of dihydrogen bond has also been unveiled by means of atoms in molecules (AIM) and natural bond orbital (NBO) analysis. The effect of ring structure on the dihydrogen bonding systems has been considered by comparing with the corresponding linear structure. NBO analysis suggests that the electron density transfer (EDT) in cyclic structures have dual-channel character.