- Cytotoxic pheophorbide-related compounds from Clerodendrum calamitosum and C. cyrtophyllum
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Three pheophorbide-related compounds (1-3) were isolated from the leaves and stems of Clerodendrum calamitosum. The methyl ester of 3 (6) and the known (10S)-hydroxypheophytin a (7) also were isolated from leaves of the related plant Clerodendrum cyrtophyllum. Compounds 1 and 6 were isolated for the first time as naturally occurring products from a plant source. All structures were elucidated by detailed spectroscopic analysis. Biological evaluation showed that 1 and 2 exhibited strong cytotoxicity against human lung carcinoma (A549), ileocecal carcinoma (HCT-8), kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), malignant melanoma (SK-MEL-2), ovarian carcinoma (1A9), and epidermoid carcinoma of the nasopharynx (KB), and its etoposide- (KB-7d), vincristine- (KB-VCR), and camptothecin-resistant (KB-CPT) subclones. Compound 3 was less cytotoxic than 1 and 2. Compounds 4-6, the methyl esters of 1-3, showed strongly increased cytotoxicity compared with the parent acids. Interestingly, 6 was the most active derivative among these compounds. Compound 7 was inactive.
- Cheng,Wang,Ito,Bastow,Tachibana,Nakanishi,Xu,Luo,Lee
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- Double helices of a pyridine-appended zinc chlorophyll derivative
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Self-assembled structures formed from a pyridine-appended zinc chlorophyll derivative are reported. While the zinc complex forms cyclic oligomers in chloroform solution, as indicated by 1H NMR studies (including diffusion-ordered spectroscopy), vapor pressure osmometry, and cold-spray ionization mass spectrometry, it forms double-stranded helical coordination polymers in the solid state, as revealed by single-crystal X-ray analysis.
- Shinozaki, Yoshinao,Richards, Gary,Ogawa, Keizo,Yamano, Akihito,Ohara, Kazuaki,Yamaguchi, Kentaro,Kawano, Shin-Ichiro,Tanaka, Kentaro,Araki, Yasuyuki,Wada, Takehiko,Otsuki, Joe
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- Preparation and in vitro biological evaluation of tetrapyrrole ethanolamide derivatives as potential anticancer agents
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Tetrapyrrole ethanolamide derivatives, 1 and 2, were prepared from hematoporphyrin IX (HPIX, 3) and methyl pheophorbide a (mPheo, 6). These were evaluated for their dual action as chemotherapeutics and photosensitizers in treatment of cancer. The novel compounds showed significant in vitro anticancer activity as measured in different cell lines using the MTT assay and photodynamic activity measured by erythrocytes' photohemolysis.
- Girard, Denis,Weagle, Glenn,Gupta, Atul,Berube, Gervais,Chapados, Camille
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- Synthesis, photophysical and electrochemistry of near-IR absorbing bacteriochlorins related to bacteriochlorophyll a
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A series of new bacteriochlorins was synthesized using 13 2-oxo-bacteriopyropheophorbide a (derived from bacteriochlorophyll a) as a starting material, which on reacting with o-phenylenediamine and 1,10-diaminonaphthalene afforded highly conjug
- Kozyrev, Andrei,Ethirajan, Manivannan,Chen, Ping,Ohkubo, Kei,Robinson, Byron C.,Barkigia, Kathleen M.,Fukuzumi, Shunichi,Kadish, Karl M.,Pandey, Ravindra K.
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- Physicochemical and biochemical properties of synthetic zinc 131-(un)substituted chlorophyll-a derivatives
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Zinc methyl pheophorbides a/a’, which possess oxo and methoxycarbonyl groups at the C131- and C132-positions, respectively, on the exo-five membered ring fusing the cyclic tetrapyrrole of their chlorin π-skeletons, were prepared via chemical modifications of chlorophyll a produced in phototrophs. The C131-hydroxylated and unsubstituted analogues were synthesized by reduction of the ketone moiety. The C131- and C132-stereochemistry of these semi-synthetic compounds was confirmed by 1H NMR and circular dichroism spectroscopies. A methoxycarbonyl group at the chiral C132-position in the ketone was stereo-inverted under basic conditions, whereas those in the corresponding alcoholic and dihydro-forms were not. The in vitro BciC enzymatic reaction of the (132R)-ketone was found to stereoselectively hydrolyze the C132-methoxycarbonyl group, followed by spontaneous decarboxylation. Similarly, the (132R)-COOCH3 group in the (131S)-alcohol was hydrolyzed, whereas the (132R)-COOCH3 group in the (131R)-alcohol was not. After the enzymatic reaction of the C131-dihydro-compound, its (132S)-demethoxycarbonylated and hydroxylated product was observed.
- Hirose, Mitsuaki,Harada, Jiro,Maeda, Hiroaki,Tamiaki, Hitoshi
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- Chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as preparation method and application
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The invention provides a chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as a preparation method and application thereof, and belongs to the technical field of chemical medicines. The chlorin e6 ferrocene conjugate disclosed by the invention has different degrees of inhibition effects on Hela cells in in-vitro anti-tumor activity evaluation. The introduction of the ferrocene group significantly improves the proliferation inhibition activity of the compound on tumor cells, and the proliferation inhibition activity of the chlorin e6 ferrocene conjugate on tumorcells is much higher than that of chlorin e6 used as a control group. The method can be used for preparing photosensitizers and sonosensitizers in photodynamic therapy and sonodynamic therapy methodsfor tumor therapy.
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Paragraph 0061-0063
(2020/08/07)
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- Graphene oxide nanoparticles having long wavelength absorbing chlorins for highly-enhanced photodynamic therapy with reduced dark toxicity
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The long wavelength absorbing photosensitizer (PS) is important in allowing deeper penetration of near-infrared light into tumor tissue for photodynamic therapy (PDT). A suitable drug delivery vehicle is important to attain a sufficient concentration of PS at the tumor site. Presently, we developed graphene oxide (GO) nanoparticles containing long wavelength absorbing PS in the form of the chlorin derivative purpurin-18-N-ethylamine (maximum absorption wavelength [λmax] 707 nm). The GO-PS complexes comprised a delivery system in which PS was loaded by covalent and noncovalent bonding on the GO nanosheet. The two GO-PS complexes were fully characterized and compared concerning their synthesis, stability, cell viability, and dark toxicity. The GO-PS complexes produced significantly-enhanced PDT activity based on excellent drug delivery effect of GO compared with PS alone. In addition, the noncovalent GO-PS complex displayed higher photoactivity, corresponding with the pH-induced release of noncovalently-bound PS from the GO complex in the acidic environment of the cells. Furthermore, the noncovalently bound GO-PS complex had no dark toxicity, as their highly organized structure prevented GO toxicity. We describe an excellent GO complex-based delivery system with significantly enhanced PDT with long wavelength absorbing PS, as well as reduced dark toxicity as a promising cancer treatment.
- Kang, Eun Seon,Lee, Tae Heon,Liu, Yang,Han, Ki-Ho,Lee, Woo Kyoung,Yoon, Il
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- Synthesis of a chlorophyll-a derivative fused with an additional exo-five-membered ring and its optical properties
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A C20-free chlorophyll-a derivative with an additional exo-five-membered ring was successfully prepared using an ethylene linkage at the C3- and C5-positions. A bromination at the C20-position was requisite for the cyclization of a 1-hydroxyethyl or vinyl group at the C3-position of methyl bacteriopheophorbide-d or methyl pyropheophorbide-a, respectively. By comparing optical properties of the cyclized product with those of its 3-ethyl uncyclized analog in a diluted dichloromethane solution, it was shown that the cyclization shifted the Qx and Bx absorption maxima to longer wavelengths and reduced the Stokes shift.
- Doi,Tamiaki, Hitoshi
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- Regioisomeric synthesis of chlorin-e 6 dimethyl esters and their optical properties
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Chlorin-e6 dimethyl esters possessing a single carboxy group at the 13-, 151-,or 172-position were prepared by chemically modifying chlorophyll-A. These three synthetic regioisomers were fully characterized by their mass, NMR, and visible absorption spectra. Their molecular structures were unambiguously identified by the specific 1H-13C correlation at the 13-, 15-, and/or 17-substituents in their respective HMBC spectra. Methyl esterification of 13/151-COOH and hydrolysis of 13/151-COOMe affected small shifts of the Qy absorption and fluorescence emission maxima in a diluted CH2Cl2 solution, while no substitution effect of 172-COOH/Me was observed.
- Nagano, Yasunobu,Ogasawara, Shin,Tamiaki, Hitoshi
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p. 1039 - 1046
(2018/11/23)
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- An amidochlorin-based colorimetric fluorescent probe for selective Cu2+ detection
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The design and synthesis of selective and sensitive chemosensors for the quantification of environmentally and biologically important ionic species has attracted widespread attention. Amidochlorin p6 (ACP); an effective colorimetric and fluorescent probe for copper ions (Cu2+) in aqueous solution derived from methyl pheophorbide-a (MPa) was designed and synthesized. A remarkable color change from pale yellow to blue was easily observed by the naked eye upon addition of Cu2+; and a fluorescence quenching was also determined. The research of fluorescent quenching of ACP-Cu2+ complexation showed the detection limit was 7.5 ×10-8 mol/L; which suggested that ACP can act as a high sensitive probe for Cu2+ and can be used to quantitatively detect low levels of Cu2+ in aqueous solution. In aqueous solution the probe exhibits excellent selectivity and sensitivity toward Cu2+ ions over other metal ions (M = Zn2+; Ni2+; Ba2+; Ag+; Co2+; Na+; K+; Mg2+; Cd2+; Pb2+; Mn2+; Fe3+; and Ca2+). The obvious change from pale yellow to blue upon the addition of Cu2+ could make it a suitable "naked eye" indicator for Cu2+.
- Li, Wenting,Zhu, Guohua,Li, Jinghua,Wang, Zhiqiang,Jin, Yingxue
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- METHOD OF PREPARING PURPURIN 18 FROM LIVE CHLORELLA
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The present invention relates to a method for preparing purpurin 18 which is a photosensitizer (PS) useful for photodynamic therapy (PDT) and, more specifically, to a method for preparing purpurin 18, which comprises steps of: extracting chlorophyll alpha by using intact chlorella cells itself which is not broken; and obtaining a precursor material of purpurin 18 and methyl or ethyl pheophorbides from the extracts. According to the present invention, it is possible to produce purpurin 18 with at a high yield through a relatively simple process.(AA) Purpurin18 manufacturing process1(BB) Chlorella(CC) Chlorophyll a/li>(DD) Methyl pheophorbide a/li>(EE) Purpurin 18(FF) Purpurin 18 precursorCOPYRIGHT KIPO 2016
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Page/Page column 6-8
(2016/11/21)
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- Photobiological characteristics of chlorophyll a derivatives as microbial PDT agents
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Chlorin-e6 (chl-e6) and a hydrogenated derivative (chl-e6H) were semi-synthesized, and their photophysical properties and photodynamic activity against Escherichia coli, Staphylococcus aureus and Candida albicans evaluated. Methyl pheophorbide-a (Mepheo-a) was obtained from S. maxima using methanolic extraction with acid catalysis (CH3OH-H2SO4). Chlorin-e6 was prepared from Mepheo-a by basic hydrolysis with H 2O-acetone and NaOH. Hydrogenated Chlorin-e6 was synthesized by a similar procedure starting from the hydrogenated methyl pheophorbide-a (Mepheo-aH). Photophysical studies were performed in order to determine the singlet oxygen quantum yield of chl-e6H which is higher than that of chl-e6. The microorganism inactivation of chl-e6 and chl-e6H was investigated at two concentrations and three fluence levels. Both chl-e6 and chl-e6H showed microorganism inactivation against Gram-positive bacteria and a fungus. This journal is the Partner Organisations 2014.
- Uliana, Marciana P.,Pires, Layla,Pratavieira, Sebastiao,Brocksom, Timothy J.,De Oliveira, Kleber T.,Bagnato, Vanderlei S.,Kurachi, Cristina
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p. 1137 - 1145
(2014/08/05)
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- Structural change of pheophorbide a methyl ester by contact with titanium oxide particles
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Pheophorbide a methyl ester, which was derived from natural chlorophyll a, was converted to purpurin-18 methyl ester by contact with titanium oxide particles in the presence of oxygen under mild conditions in the dark.
- Saga, Yoshitaka,Otono, Tae
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supporting information; experimental part
p. 360 - 362
(2012/06/18)
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- Modification of 3-substituents in (bacterio)chlorophyll derivatives to prepare 3-ethylated, methylated, and unsubstituted (nickel) pyropheophorbides and their optical properties
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Methyl mesopyropheophorbide-a possessing an ethyl group at the 3-position, its 31-demethyl analogue (3-methyl homologue), and its 3 1-deethyl analogue (3-unsubstituted chlorin) were prepared by modifying naturally occurring (bacterio)chlorophylls bearing 3-vinyl, formyl, acetyl, and 1-hydroxyethyl groups. These synthetic 3-(un)substituted chlorophyll derivatives and their nickel complexes are probable intermediates during degradation of (bacterio)chlorophylls to chemically stable porphyrinoids. The optical properties (visible absorption, circular dichroism, and fluorescence emission) of the catabolic candidates in a solution were measured, and the substitution effect was investigated.
- Tamiaki, Hitoshi,MacHida, Shinnosuke,Mizutani, Keisuke
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p. 4751 - 4758
(2012/07/14)
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- Complex formation of zinc-containing metalloporphyrins and nucleophilic substitution reactions involving pyridines
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Linear correlations were found between the thermodynamic and kinetic parameters for the nucleophilic substitution and coordination of metalloporphyrins in various solvents with the participation of pyridines. Complex formation of zinc(II) tetraphenylporphyrin with n-donor ligands in chloroform at 25°C is proposed for use as a model system in the electronic spectroscopic investigation of the nucleophilicity and basicity of compounds capable of forming complexes of the n,? type.
- Andreev,Sobolev,Larkina,Tkachevskaya
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p. 497 - 504
(2012/11/07)
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- Synthesis and photodynamic activities of pyrazolyl and cyclopropyl derivatives of purpurin-18 methyl ester and purpurin-18-N-butylimide
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The synthesis of new pyrazolyl and cyclopropyl derivatives of purpurin-18 methyl ester and purpurin-18-N-butylimide 1a, 1b, 2a, 2b and 8 is described. The new compounds were characterized by NMR, UV-vis spectroscopy and mass spectrometry. UV-vis spectra of the new compounds showed long wavelength absorption of ranges 692-708 nm (λmax). Photodynamic effects of the chlorin derivatives 1a, 1b, 2a and 2b were investigated by WST-1 assay in A549 cells, and showed good photodynamic activities with high photocytotoxicity and low cytotoxicity in the dark. In comparison between pyrazolyl and cyclopropyl derivatives, purpurin-18 methyl ester compounds 1a and 1b showed comparable photocytotoxicity result of the cell viabilities, otherwise, pyrazolyl derivative of purpurin-18-N-butylimide 2a showed better cell viabilities than those of cyclopropyl derivative 2b. And cyclopropyl derivative of purpurin-18-N-butylimide 2b showed higher dark cytotoxicity than that of others.
- Yoon, Il,Park, Ho Sung,Cui, Bing Cun,Kim, Jung Hwa,Shim, Young Key
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experimental part
p. 169 - 174
(2011/11/14)
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- Syntheses and cellular investigations of 173-, 152-, and 131-amino acid derivatives of chlorin e6
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A series of amino acid conjugates of chlorin e6, containing lysine or aspartic acid residues in positions 173, 152, or 131 of the macrocycle were synthesized and investigated as photosensitizers for photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in five steps or less from pheophytin a (1). In vitro investigations using human carcinoma HEp2 cells show that the 15 2-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 131 regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 173-substituted chlorin e6 conjugates are L-shaped, the 152 and 131 regioisomers assume extended conformations, and the 131 derivatives are nearly linear. It is hypothesized that the 131-aspartylchlorin e6 conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 15 2 derivative.
- Jinadasa, R. G. Waruna,Hu, Xiaoke,Vicente, M. Gra?a H.,Smith, Kevin M.
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scheme or table
p. 7464 - 7476
(2012/01/04)
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- Mono-(L)-aspartylchlorin-e6
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Mono-(l)-aspartylchlorin-e6 (also known as Talaporfin, NPe6, MACE, and most recently LS-11) is a potent sensitizer for photodynamic therapy that is currently undergoing clinical trials. Using a combination of unambiguous partial synthesis from pheophytin-a and methyl pheophorbide-a, NMR spectroscopy, and single crystal X-ray diffraction, the structure of mono-(l)-aspartylchlorin-e6 is definitively shown to be the isomer in which the aspartyl residue is attached at the 152-side chain position. This conclusion is contrary to earlier assumptions, but affirms the conclusions of a study based on NMR spectroscopy; a rationale for the unique formation of the 152-aspartyl derivative is proposed.
- Hargus, Jodie A.,Fronczek, Frank R.,Vicente, M. Graa H.,Smith, Kevin M.
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p. 1006 - 1015
(2008/03/15)
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- Determination of Stereochemistry of Bacteriochlorophyll gF and 81-Hydroxy-chlorophyll aF from Heliobacterium modesticaldum
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The reaction center complex of heliobacteria contains three kinds of chlorophyll pigments, bacteriochlorophyll gF (BChI gF), its 132-epimer BChl g′F and 81-hydroxy- chlorophyll aF (81-OH-Chl aF). Because the full stereochemistry of these naturally occurring chlorophyllous pigments has remained unknown, we determined the stereochemistry of both BChl gF and 81-OH-Chl aF extracted from Heliobacterium modestical-dum. The configurations of the specific functional groups at ring-B as well as those at ring-D and -E were investigated by use of nuclear Overhauser effect correlations in their 1H-NMR spectra and circular dichroism spectra, as well as by modified Mosher's method in their chemical modification: (1) E-configuration was confirmed for the 8-ethylidene group at ring-B in BChl gF, (2) R-configuration was identified for the 1-hydroxyethyl group at ring-B in 81-OH-Chl aF and (3) 132-(R)-, 17-(S)- and 18-(S)-configurations at ring-D and -E in both BChl gF and 81-OH-Chl aF were confirmed. These stereo-chemistries enabled us to discuss their biosynthesis and to propose possible routes for preparation of ethylidene and 1-hydroxyl ethyl groups at the 8-position.
- Mizoguchi, Tadashi,Oh-oka, Hirozo,Tamiaki, Hitoshi
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p. 666 - 673
(2008/02/03)
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- Methyl pyropheophorbide-a analogues: Potential fluorescent probes for the peripheral-type benzodiazepine receptor. Effect of central metal in photosensitizing efficacy
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Pyropheophorbides and their metal complexes were synthesized to investigate their applications as nonradioactive peripheral benzodiazepine receptor (PBR) binding probes and photosensitizers for use in photodynamic therapy. They were found to be localized in mitochondria and showed significant binding to PBR. In some cases, the PBR binding values were similar to that for 17 (PK11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)isoquinoline-3-carboxamide). However, no direct correlation between 17 displacement ability and photosensitizing efficacy of photosensitizers was observed.
- Chen, Yihui,Zheng, Xiang,Dobhal, Mahabeer P.,Gryshuk, Amy,Morgan, Janet,Dougherty, Thomas J.,Oseroff, Allan,Pandey, Ravindra K.
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p. 3692 - 3695
(2007/10/03)
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- Antitumor agents. Part 209: Pheophorbide-a derivatives as photo-Independent cytotoxic agents.
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A methanolic crude extract of the plant Garuga pinnata Roxb. (Burseraceae) showed promising cytotoxic activity against a panel of human tumor cell lines in vitro, including KB and its drug-resistant sublines (Ferguson et al. Cancer Res. 1988, 48, 5956). Pheophorbide-a and-b methyl esters (3,4) were isolated as active principles with broad photo-dependent cytotoxic activities in the micromolar range. These findings prompted SAR studies of known and novel pheophorbide-a derivatives as photo-dependent and photo-independent cytotoxic agents. The results showed that zinc-protoporphyrin IX (10), zinc 13(R)-hydroxypheophorbide-a methyl ester (22), and zinc chlorin-e6 trimethyl ester (13) possessed photo-independent cytotoxic activity. Compounds 13 and 22 were the most active cytotoxic agents of the series (mean ED(50) 4.6 +/- 1.0 microM and 5.7 +/- 0.7 microM, respectively) against KB cells incubated in the dark.
- Wongsinkongman, Prapai,Brossi, Arnold,Wang, Hui-Kang,Bastow, Kenneth F,Lee, Kuo-Hsiung
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p. 583 - 591
(2007/10/03)
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- Synthesis and Study of Chlorin and Porphyrin Dimers with Ether Linkage
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Novel dimers of chlorophyll compounds (pheophorbide a, chlorin p6) and model porphyrin with ether linkage were synthesized and separated into components A and B (less and more polar).The ratio of these components was the same for all dimers and irrespective of reaction conditions.Method of dimerization through trifluoroacetoxyethylderivative gave higher yields. Key words: porphyrin dimer; chlorin dimer, pheophorbide; purpurin; stereoisomers
- Brandis, Alexander S.,Kozyrev, Andrey N.,Mironov, Andrey F.
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p. 6485 - 6494
(2007/10/02)
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- Der Einbau von Magnesium in Liganden der Chlorophyll-Reihe mit (2,6-Di-t-butyl-4-methylphenoxy)magnesiumjodid
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Experimental details are given for the new method of introducing magnesium into porhpinoid ligands by (2,6-di-t-butyl-4-methylphenoxy)magnesium iodide (1), previously published in preliminary form .Besides magnesium octaethylporphyrinate (14), methyl pyrochlorophyllide a (10), methyl chlorophyllide a (8), and methyl bacteriochlorophyllide a (12), the complexation of pheophytin a (2) to chlorophyll a (3) and of pheophytin b (4) to chlorophyll b (5) are described.
- Zass, Engelbert,Isenring, Hans Peter,Etter, Rolf,Eschenmoser, Albert
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p. 1048 - 1067
(2007/10/02)
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