- ELECTROPHILIC SUBSTITUTION AT THE δ-METHINE BRIDGE OF PHEOPHORBIDE a AND a'
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A chloro-substituted derivative was prepared from chlorophyll a'.The derivative was shown to be δ-chloro-methyl pheophorbide a by UV/VIS, MS and 1H NMR.
- Hynninen, Paavo H.,Loetjoenen, Simo
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- Anti-tumor evaluation of a novel methoxyphenyl substituted chlorin photosensitizer for photodynamic therapy
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Photodynamic therapy (PDT) is a non-invasive and innovative therapeutic approach which has been increasingly applied in clinical cancer therapy. As the central element of PDT, the development of novel photosensitizers (PSs) with longer absorption wavelength, proper lipophilic/hydrophilic profiles, target tissue selectivity, and higher photo?/lowest dark-cytotoxicity is a challenging task. Previously, we designed and synthesized a series of novel long-wavelength chlorin e6 (Ce6)-based PSs via introducing aromatic groups to the vinyl of Ce6 skeleton. The new formed compounds with π-extension system exhibited improved photodynamic effects and spectral characteristics. Among these π-conjugated chlorin PSs, (E)-32-(4-methoxyphenyl)-chlorin e6, named A15, was expected to be a potent antitumor candidate as a PDT agent due to its good photobiological properties. Herein, in this work, we evaluated the effectiveness of A15 in cancer PDT. In vitro, a novel rare earth probe, ATTA-Eu3+ was applied to detect the singlet oxygen (1O2) production of A15 in solution and human hepatoma HepG2 cells, respectively. Moreover, A15 exhibited strong phototoxicity and weak dark cytotoxity to HepG2 cells. In H22 tumor bearing mice, A15 showed excellent tumor accumulation ability via i.v. administration and induced tumor regression, followed by laser treatment. These results indicated that A15 is a potential novel π–extension chlorin-type PS for PDT applications.
- Cao, Lei,Dong, Yi,Li, Guangzhe,Li, Yueqing,Wang, Liu,Zhao, Weijie
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- Effect of dietary chlorophyll derivatives on mutagenesis and tumor cell growth
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Much attention in recent years has been given to the antigenotoxicity of chlorophyll. Chlorophyll, however, is known to be converted into pheophytin, pyropheophytin, and pheophorbide in processed vegetable food and following ingestion by humans. Studies were conducted on the antimutagenic and tumoricidal potencies of these compounds. All the chlorophyll derivatives tested exhibit identical antimutagenic effect towards 3-methylcholanthrene (3-MC), suggesting that the porphyrin nucleus may complex directly with the mutagen. It does not exclude, however, another mechanism of activity involving inactivation the enzymatic transformation of 3-MC. In contrast, the action of N'-nitro-N'-nitrosoguanidine (MNNG) depends upon structural differences between the chlorophyll derivatives. It is significantly lower when the phytol-containing pheophytin and pyropheophytin are tested as to that of the phytol-lacking pheophorbide. The higher concentrations of the chlorophyll derivatives were required to reduce the mutagenicity of MNNG than needed for 3-MC. The cytotoxicity of chlorophyll derivatives against tumor cells also was evaluated. The cellular uptake and inhibition of myeloma cell multiplicity were found to be greater for pheophorbide than for pheophytin. Calculated on the amount of cell associated chlorophyll derivative, however, pheophytin was more cytostatic/cytotoxic than pheophorbide. The results presented in this report indicate that food sources that yield chlorophyll derivatives may play a significant role in cancer prevention.
- Chernomorsky, Simon,Segelman, Alvin,Poretz, Ronald D.
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- Synthesis of potential antitumor agents, dimeric and trimeric chlorins, from methylpheophorbide a
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A series of dimeric and trimeric chlorins were synthesized from methylpheophorbide a. They are potential photosensitizers for photodynamic therapy in oncology. The macrocycles were conjugated due to the formation of ester and amide bonds. The carboxy groups were activated and catalytic transesterification was carried out to form the ester bond. The amide bond was formed using carboxy group activation; in several cases, amidation of the ester group in position 13(2) of the exocycle of methylpheophorbide α was carried out, which does not require activation.
- Belykh,Mal'Shakova,Yudina,Zavadskaya,Khudyaev,Kuchin
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- Design, synthesis and biological evaluation of novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives as potent photosensitizers for photodynamic therapy
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This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e6, a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives 3a, 3b, 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16–F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16–F10 cells. Apparently, simultaneous introduction of amino acid residue and n-hexyloxy chain in chlorin e6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a, 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e6-based 152- or 131-amino acid derivatives, especially 3c and 8, might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT.
- Zhang, Xing-Jie,Han, Gui-Yan,Guo, Chang-Yong,Ma, Zhi-Qiang,Lin, Mei-Yu,Wang, Yuan,Miao, Zhen-Yuan,Zhang, Wan-Nian,Sheng, Chun-Quan,Yao, Jian-Zhong
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- Synthesis and biological evaluation of new water-soluble photoactive chlorin conjugate for targeted delivery
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A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431 cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC50dark/IC50light ratio of 11–18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.
- Otvagin, Vasilii F.,Nyuchev, Alexander V.,Kuzmina, Natalia S.,Grishin, Ivan D.,Gavryushin, Andrei E.,Romanenko, Yuliya V.,Koifman, Oscar I.,Belykh, Dmitrii V.,Peskova, Nina N.,Shilyagina, Natalia Yu,Balalaeva, Irina V.,Fedorov, Alexey Yu.
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- Synthesis of chlorins with a distal vinyl group
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A series of chlorins containing a vinyl group on the periphery of the chlorin ring that was attached by linkers of various length, potential monomers for synthesis of polymers containing chlorin via copolymerization, was synthesized from methylpheophorbide a.
- Mal'Shakova,Belykh,Kuchin
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- Synthesis of pheophorbide-a conjugates with anticancer drugs as potential cancer diagnostic and therapeutic agents
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Pheophorbide-a, a chlorine based photosensitizer known to be selectively accumulated in cancer cells, was conjugated with anticancer drugs, doxorubicin and paclitaxel in the purpose of selective cancer diagnosis and therapy. Pheophorbide-a was conjugated with anticancer drugs via directly and by the use of selective cleavage linkers in cancer cell. The fluorescence of pheophorbide-a and doxorubicin conjugate by excitation at 420 or 440 nm was greatly diminished possibly by the energy transfer mechanism between two fluorescent groups. However, upon treatment in cancer cells, the conjugate showed to be cleaved to restore each fluorescence of pheophorbide-a and doxorubicin after 48 h of incubation. Also, pheophorbide-a conjugates either with doxorubicin and paclitaxel inhibited the growth of various cancer cells more potently than pheophorbide-a, which displayed very weak inhibitory activity. The results indicated that the pheophorbide-a conjugates with anticancer drugs could be utilized for selective cancer therapy as well as for the fluorescence detection of cancer.
- You, Hyun,Yoon, Hyo-Eun,Yoon, Jung-Hoon,Ko, Hyojin,Kim, Yong-Chul
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- Distribution of chlorophyll- and bacteriochlorophyll-derived photosensitizers in human blood plasma
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Chlorophylla and, in particular, bacteriochlorophyll a derivatives are promising candidates for photosensitizers in photodynamic therapy. The distribution of 21 (bacterio)chlorophyll derivatives among human blood plasma fractions was studied by iodixanol gradient ultracentrifugation and in situ absorption spectroscopy. Modifications of the natural pigments involved the central metal (Mg2+, Zn2+, Pd2+, none), the isocyclic ring (closed, open and taurinated), substituents at C-3 (vinyl, acetyl, 1-hydroxyethyl) and C-173 (phytyl ester, free acid). Cellular blood components bound only a small fraction of the pigments. Distribution among low-density lipoproteins (LDL), high-density lipoproteins (HDL) and high-density proteins (HDP) of the plasma was influenced as follows: (1) application in Cremophor EL slightly altered pigment distribution by lipoprotein modification, (2) only very polar pigments with multiple hydrophilic substituents showed substantial HDP binding, (3) the presence of the esterifying alcohol at C-173 caused enrichment in LDL, this was more pronounced with bacteriochlorophylls than with chlorophylls, (4) substituents at C-3 had only little influence on the distribution, (5) Zn2+-complexes were enriched in HDL compared to Mg2+ and Pd2+ complexes, indicating specific binding of the former. Equilibration of pigments among the different fractions was largely complete within 3 h.
- Dandler, Joerg,Wilhelm, Brigitte,Scheer, Hugo
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- Synthesis of Covalently Linked dimeric Derivatives of Chlorophyll a, Pyrochlorophyll a, Chlorophyll b, and Bacteriochlorophyll a
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Bis(chlorophyllide) ethylene glycol diesters were prepared for each of the title compounds.Pheophytins a and b isolated from alfalfa and bacteriochlorophyll a isolated from R.sphaeroides were treated with 80percent aqueous trifluoroacetic acid to yield the corresponding pheorbides.Pyropheophorbide was prepared by a literature procedure.Carbonic anhydride and benzotriazole-1-methanesulfonate activation methods were used in the esterification of the pheophorbides with ethylene glycol at ambient temperature.Each method yielded 75percent+ of the pheophorbide ethylene glycol monoester.These monoesters were treated with equimolar amounts of the corresponding pheophorbide by using benzotriazole-1-methanesulfonate/4-(dimethylamino)pyridine in CH2Cl2 or dicyclohexylcarbodiimide/4-(dimethylamino)pyridine in CH2Cl2 at ambient temperature.Yields of bis-(pheophorbide) ethylene glycol diesters averaged about 50percent for the former method and 70percent for the latter method.Insertion of the magnesium atoms into the a series macrocycles was accomplished with iodomagnesium 2,6-di-tert-butyl-4-methylphenolate, IMgBHT, in CH2Cl2, while the metalation of the b and bacterial series macrocycles was carried out with a mixture of IMgBHT and lithium 2,2,6,6-tetramethylpiperidie in thiophene, all at ambient temperature.Both mono- and dimethalated derivatives were isolated and characterized in each case.
- Wasielewski, Michael R.,Svec, Walter A.
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- Amino acid derivatives of pyropheophorbide-a ethers as photosensitizer: Synthesis and photodynamic activity
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Ten new water-soluble amino acid conjugates of pyropheophorbide-a ethers 4a-4j were synthesized and investigated for their in vitro photodynamic antitumor activity. The results showed that all compounds exhibited higher phototoxicity and lower dark toxicity against three kinds of tumor cell lines than BPD-MA. In particular, the most phototoxic compound 4d and 4j individually showed IC50 values of 41 nmol/L and 33 nmol/L against HCT116 cell, which represented 7.8- and 9.7-fold increase of antitumor potency compared to BPD-MA, respectively, suggesting that they were promising photosensitizers for PDT applications because of their strong absorption at long wavelength (λmax > 650 nm), high phototoxicity, low dark cytotoxicity and good water-solubility.
- Meng, Zhi,Shan, Bin,Zhang, Ling,Han, Gui-Yan,Liu, Ming-Hui,Jia, Ning-Yang,Miao, Zhen-Yuan,Zhang, Wan-Nian,Sheng, Chun-Quan,Yao, Jian-Zhong
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- Chlorin p6-Based Water-Soluble Amino Acid Derivatives as Potent Photosensitizers for Photodynamic Therapy
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The development of novel photosensitizer with high phototoxicity, low dark toxicity, and good water solubility is a challenging task for photodynamic therapy (PDT). A series of chlorin p6-based water-soluble amino acid conjugates were synthesized and investigated for antitumor activity. Among them, aspartylchlorin p6 dimethylester (7b) showed highest phototoxicity against melanoma cells with weakest dark toxicity, which was more phototoxic than verteporfin while with less dark toxicity. It also exhibited better in vivo PDT antitumor efficacy on mice bearing B16-F10 tumor than verteporfin. The biological assays revealed that 7b was localized in multiple subcellular organelles and could cause both cell necrosis and apoptosis after PDT in a dose-dependent manner, resulting in more effective cell destruction. As a result, 7b represents a promising photosensitizer for PDT applications because of its strong absorption in the phototherapeutic window, relatively high singlet oxygen quantum yield, highest dark toxicity/phototoxicity ratio, good water solubility, and excellent in vivo PDT antitumor efficacy.
- Meng, Zhi,Yu, Bin,Han, Guiyan,Liu, Minghui,Shan, Bin,Dong, Guoqiang,Miao, Zhenyuan,Jia, Ningyang,Tan, Zou,Li, Buhong,Zhang, Wannian,Zhu, Haiying,Sheng, Chunquan,Yao, Jianzhong
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- Effects of noncovalently bound quinones on the ground and triplet states of zinc chlorins in solution and bound to de novo synthesized peptides
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The Qy absorption band of two chlorophyll derivatives, zinc chlorin e6 (ZnCe6) and zinc pheophorbide a (ZnPheida), in aqueous solution is bathochromically shifted on addition of quinones, e.g., 1,4-benzoquinone (BQ), with a corresponding shift of the fluorescence band. This is due to a complex formation of zinc chlorins induced by BQs and subsequent rearrangement. The time-resolved absorption spectra after laser pulse excitation show triplet quenching of the pigments by BQ and other quinones via electron transfer. The effects of electron transfer to noncovalently bound BQs were also studied with de novo synthesized peptides, into which ZnCe6 and ZnPheida were incorporated as model systems for the primary steps of photosynthetic reaction centers. Whereas the photophysical properties are similar to those of the unbound zinc chlorins, no BQ-mediated complex formation was observed. the Owner Societies.
- Mennenga, Anke,Gaertner, Wolfgang,Lubitz, Wolfgang,Goerner, Helmut
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- Pheophytinization kinetics of chlorophyll c under weakly acidic conditions: Effects of acrylic acid residue at the 17-position
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Pheophytinization of chlorophyll (Chl) c1, which was isolated from the diatom Chaetoceros gracilis, was kinetically analyzed under weakly acidic conditions, and was compared with that of protochlorophyllide (PChlide) a and chlorophyllide (Chlide) a. Chl c1 possessing a trans-acrylic acid residue at the 17-position exhibited slower pheophytinization kinetics than PChlide a and Chlide a, both of which possessed a propionic acid residue at the same position. The difference in pheophytinization properties between Chl c1 and (P)Chlide a was ascribable to the electronegativity of the 17-substituent in Chl c1 larger than that of (P)Chlide a due to the C171-C172 double bond with the conjugated 17 2-carboxy group in Chl c1. Demetalation kinetics of PChlide a was slower than that of Chlide a, which originated from the effect of the π-macrocyclic structures.
- Sadaoka, Kana,Shoji, Sunao,Hirota, Keiya,Tsukatani, Yusuke,Yoshitomi, Taichi,Tamiaki, Hitoshi,Kashimura, Shigenori,Saga, Yoshitaka
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- Design and synthesis of novel water-soluble amino acid derivatives of chlorin p6 ethers as photosensitizer
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Eight new water-soluble amino acid conjugates 6a-h of chlorin p6 ethers (5a-d) were synthesized and preliminarily investigated for their in vitro PDT antitumor activity and structure-activity relationship (SAR). The results showed that all compounds exhibited much higher phototoxicity against tumor cells than talaporfin. SAR analysis indicated that PDT antitumor effect enhanced with the increase of carbon chain length of alkoxyl ether bonds at 31-position, and L-aspartic acid was superior to L-glutamic acid. In particular, the IC50 values of most phototoxic compound 6d were 0.20 μmol/L against A549 cell and 0.41 μmol/L against B16-F10 cell, which individually represented 31- and 24-fold increase of antitumor potency compared to talaporfin, suggesting that it was a promising candidate photosensitizer (PS) for PDT applications due to its strong absorption at long wavelength, high phototoxicity, low dark cytotoxicity and good water-solubility.
- Zhang, Xingjie,Meng, Zhi,Ma, Zhiqiang,Liu, Junhong,Han, Guiyan,Ma, Fujia,Jia, Ningyang,Miao, Zhenyuan,Zhang, Wannian,Sheng, Chunquan,Yao, Jianzhong
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- In vitro demethoxycarbonylation of various chlorophyll analogs by a BciC enzyme
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Unique light-harvesting antennas in the green sulfur bacterium Chlorobaculum tepidum, called chlorosomes, consist of self-aggregates of bacteriochlorophyll (BChl) c. In the biosynthesis of BChl c, BciC demethoxycarbonylase removes the C132-methoxycarbonyl group to facilitate the self-aggregation of BChl c. We previously reported the in vitro BciC-enzymatic reactions and discussed the function of this enzyme in the biosynthesis of BChl c. This study aims to examine the substrate specificity of BciC in detail using several semi-synthetic (bacterio)chlorophyll derivatives. The results indicate that the substrate specificity of BciC is measurably affected by structural changes on the A/B rings including the bacteriochlorin π-systems. Moreover, BciC showed its activity on a Zn-chelated chlorophyll derivative. On the contrary, BciC recognized structural modifications on the D/E rings, including porphyrin pigments, which resulted in the significant decrease in the enzymatic activity. The utilization of BciC provides mild conditions that may be useful for the in vitro preparation of various chemically (un)stable chlorophyllous pigments.
- Teramura, Misato,Harada, Jiro,Tamiaki, Hitoshi
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- Semi-synthesis and HPLC analysis of (bacterio)chlorophyllides possessing a propionic acid residue at the C17-position
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Various chlorophyll and bacteriochlorophyll derivatives possessing a magnesium or zinc atom at the central position and a free carboxylic acid group at the C172-position, also known as (bacterio)chlorophyllides, were synthesized through a combination of organic synthesis techniques and enzymatic steps. The semi-synthetic (bacterio)chlorophyllides were purified and analyzed using reversed-phase high-performance liquid chromatography with UV-vis spectroscopy and mass spectrometry. These free propionic acid-containing chlorophyllous pigments can be useful research materials for the study of (bacterio)chlorophyll metabolisms.
- Teramura, Misato,Tamiaki, Hitoshi
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- Opening of the extra ring in pheophorbide a methyl ester by the action of amines as a one-step method for introduction of additional fragments at the periphery of chlorin macroring
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Opening of the extra ring in pheophorbide a methyl ester by the action of amines differing in the number, size, and structure of substituents on the nitrogen atom was studied with a view to synthesize chlorine e 6 13-carboxamides. Main factors restricting one-step preparation of 13-carboxamides with a desired substituent were revealed. The obtained experimental data can be used as a basis for predicting the possibility for onestep preparative synthesis of particular chlorin e 6 13-carboxamide via reaction with one or another amine.
- Belykh,Kopylov,Gruzdev,Kuchin
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- Novel chlorin e4 derivative, pharmaceutically acceptable salt thereof, and preparation methods and application of novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof
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The invention belongs to the technical field of medicines, and relates to a novel chlorin e4 derivative and pharmaceutically acceptable salts thereof, and preparation methods and application of the novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof. The chlorin e4 derivative comprises a structure shown as a general formula I and an optical isomer contained in the structural general formula I; according to the preparation method, 17-propionyl or 13-formyl in chlorin e4 and amino acid are subjected to peptide formation and/or 3-vinyl etherification. The chlorin e4 derivative and the pharmaceutically acceptable salt thereof can be applied as a photodynamic antitumor drug. Compared with the existing similar photosensitizer talaporfin which is clinically applied, the chlorin e4 derivative disclosed by the invention has the advantages of strong photodynamic antitumor activity, high dark toxicity-light toxicity ratio and the like; the derivative can be used for preparing novel photodynamic antitumor drugs including photodynamic cancer treatment drugs, drugs for photodynamic treatment of benign vascular diseases such as age-related macular degeneration and nevus flammeus and drugs for photodynamic treatment of condyloma acuminata.
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Page/Page column 14
(2021/10/27)
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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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- Chlorin p6 amino acid derivative, preparation method therefor and use of chlorin p6 amino acid derivative
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The invention relates to the technical field of medicines and particularly relates to a novel chlorin photosensitizer, i.e., a chlorin p6 amino acid derivative, a preparation method therefor and use of the chlorin p6 amino acid derivative in preparation of antitumor drugs. The chlorin p6 amino acid derivative disclosed by the invention has a chemical structure represented by a general formula (I) shown in the description. The chlorin p6 amino acid derivative disclosed by the invention has the advantages of high efficiency, low toxicity and the like and can be used for preparing novel photodynamic cancer therapy drugs, drugs for photodynamic therapy on benign vascular diseases such as senile macular degeneration and nevus flammeus and drugs for photodynamic therapy on verruca acuminata.
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Paragraph 0054; 0055; 0056
(2017/01/02)
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- Purpurin-18 ether derivative, and preparation method and use thereof
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The invention relates to the technical field of medicines, and concretely relates to a novel dihydroporphine photosensitizer - purpurin-18 ether derivative, a preparation method thereof, and a use of the purpurin-18 ether derivative in the preparation of antitumor medicines. The chemical structure of the purpurin-18 ether derivative is represented by general formula (I) shown in the description. The purpurin-18 ether derivative has the advantages of high efficiency and low toxicity, and can be used for preparing new photodynamic therapy medicines of cancers, photodynamic therapy medicines of benign diseases, such as senile macula lutea denaturation and nevus flammeus, and photodynamic therapy medicines of condyloma acuminatum.
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Paragraph 0049; 0050; 0051
(2017/01/02)
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- Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof
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The invention relates to the technical field of medicines and in particular relates to a novel chlorine photosensitizer-pyropheophorbide-a ether amino acid derivative, a preparation method thereof and an application to preparation of antitumor medicines. A chemical structure of the pyropheophorbide-a ether amino acid derivative is shown in a general formula (I) in the specification. The pyropheophorbide-a ether amino acid derivative has the advantages of high efficiency, low toxicity and the like, and can be used for preparing new medicines for photodynamic therapy of cancers, medicines for photodynamic therapy of benign vascular diseases, such as age-related macular degeneration and nevus flammeus and medicines for photodynamic therapy of condyloma acuminate.
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Paragraph 0035; 0061
(2016/10/08)
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- Chlorins e6 metal salt compound and preparing method and application thereof
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The invention relates to a chlorins e6 metal salt compound.The chemical structure is shown in the formula (I) in the description, wherein R is common metal ions such as K+ or Na+.A preparing method comprises the following steps that firstly, silkworm excrement crude product chlorophyll serves as a raw material and is dissolved in diethyl ether, concentrated hydrochloric acid is added, and magnesium-removed chlorophyllin a is generated; secondly, magnesium-removed chlorophyllin a is reacted in a strong-base methanol solution, a little of water is added later to generate chlorins e6 mono-methyl ester; thirdly, obtained chlorins e6 mono-methyl ester is reacted in a strong-base alcoholic solution reaction reagent, and a compound (I) is obtained through separation and purification.The chlorins e6 metal salt compound is a raw material in the study field of medicine for resisting gastric ulcers, resisting anemia and protecting the liver and promoting leucopoiesis.
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Paragraph 0021
(2016/10/17)
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- PHEOPHORBIDE-alpha CONJUGATES AND THEIR USES
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The present invention relates to a pheophorbide-α conjugate or its salt, solvate or hydrate. The pheophorbide-α conjugate of the present invention exhibiting fluorescence upon its introduction into cells and degradation inhibits the survival of various cancer cells. Especially, the conjugate of pheophorbide-α and doxorubicin shows higher fluorescence intensity at lower pH (cancer environment). Therefore, the present composition for photodynamic therapy (PDT) of cancers is also very useful in detecting cancers. Interestingly, the anticancer effects of the present composition are dually exerted with help of both the photosensitizer and the anticancer drug of the present conjugates.
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Paragraph 0050
(2013/08/28)
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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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p. 7464 - 7476
(2012/01/04)
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- Design, synthesis, and in vitro photodynamic activities of benzochloroporphyrin derivatives as tumor photosensitizers
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Novel benzochloroporphyrin derivatives (BCPDs) were designed, synthesized, and characterized. In vitro dark cytotoxicity and photodynamic efficacy of BCPDs were evaluated by MTT assay on human hepatoma BEL-7402 cells. The experimental results showed that BCPDs 15, 16, 17, and 18 have strong long wavelength absorptions around 670 nm and exhibit significantly lower dark cytotoxicity than BPDMA and possess potent photocytotoxicity, IC50 values 1.32 μg/mL for 15, 0.26 μg/mL for 16, 0.47 μg/mL for 17 of 0.27 μg/mL for 18, and 0.23 μg/mL for BPDMA. Among them, BCPDs 16 and 18 are more effective and promising PDT photosensitizers based on the studies with BEL-7402 cells and show nearly the same photodynamic efficacy as BPDMA. MG-P staining qualitative analysis also indicated that PDT with BCPDs 16 can induce apoptosis in BEL7402 cells.
- Yao, Jianzhong,Zhang, Wannian,Sheng, Chunquan,Miao, Zhenyuan,Yang, Feng,Yu, Jianxin,Zhang, Ling,Song, Yunlong,Zhou, Ting,Zhou, Youjun
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p. 293 - 297
(2008/09/18)
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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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- Conformations of Chlorophylls a and a' and their Magnesium-Free Derivatives as Revealed by Circular Dichroism and Proton Magnetic Resonance
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The electronic absorption (UV/VIS), circular dichroism (CD) and proton magnetic resonance (1H NMR) spectra have been recorded for C-10 epimeric chlorophylls a and a', pheophytins a and a' as well as pheophorbides a and a'.Although the epimers in each pair showed virtually identical UV/VIS spectra, their CD spectra were profoundly different and exhibited opposite signs at most wavelengths in the UV region.The differences were interpreted as arising, in part, from different C-10 configurations, and, in part, from conformational alterations induced by the steric strain in the crowded periphery of the macrocycle.The conformational alterations were also clearly indicated by the 1H NMR Δδ-values observed for the α,β and δ methine protons, the C-10 protons and most methyl group protons of the epimers in each pair.This was considered to imply changes in the geometry of the whole macrocycle.The Δδ-values were larger for the Mg-free epimers than for the chlorophyll epimers, which shows that the central Mg-atom makes the macrocycle more rigid.Correlations between the signs of the CD bands and configurations are discussed. - Key words: Stereochemistry, Conformational Analysis, Chlorophyll and Pheophytin Epimers, 1H NMR Spectra, Circular Dichroism
- Hynninen, Paavo H.,Sievers, Gunnel
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p. 1000 - 1009
(2007/10/02)
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