- Dually Enzyme- And Acid-Triggered Self-Immolative Ketal Glycoside Nanoparticles for Effective Cancer Prodrug Monotherapy
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The use of glycoside prodrugs is a promising strategy for developing new targeted medicines for chemotherapy. However, the in vivo utility of such prodrugs is hindered by insufficient activation and the lack of convenient synthetic methods. We have developed an innovative strategy for synthesizing ketal glycoside prodrugs that are unique in being activated by a dual enzyme- and acid-triggered self-immolative mechanism. Amphiphilic glucosyl acetone-based ketal-linked etoposide glycoside prodrug isomers were synthesized and fabricated into excipient-free nanoparticles for effective cancer prodrug monotherapy. Hydrolysis of the glycosidic linkage or the ketal linkage triggered hydrolysis of the other linkage, which resulted in spontaneous self-immolative hydrolysis of the prodrugs. Nanoparticles of the prodrug isomer that was the most labile in a lysosome-mimicking environment displayed high intratumoral accumulation and strong antitumor activity in an A549 xenograft mouse model. Our strategy may be useful for the development of stimulus-responsive self-immolative prodrugs and their nanomedicines.
- Yu, Na,Liu, Tao,Zhang, Xi,Gong, Ningqiang,Ji, Tianjiao,Chen, Jing,Liang, Xing-Jie,Kohane, Daniel S.,Guo, Shutao
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- Real-time monitoring of etoposide prodrug activated by hydrogen peroxide with improved safety
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Etoposide is one of the most used first-line chemotherapeutic drugs. However, its application is still limited by its side effects. Herein, we designed a novel H2O2 sensitive prodrug 6YT for selectively releasing the anti-cancer drug etoposide in cancer cells. In this paper, etoposide and a hydrogen peroxide (H2O2) sensitive aryl borate ester group were linked by a fluorescent coumarin and finally the prodrug 6YT was generated. The fluorescence of coumarin was quenched before the connected aryl borate ester group was cleaved by H2O2. However, in the high level H2O2 environment of the tumor, the fluorescence could be activated simultaneously with the release of etoposide, and the drug release state of the prodrug was monitored real-time. With the support of 6YT, we obtained direct and visual evidence of etoposide release in a high H2O2 environment both in cells and zebrafish. The prodrug 6YT was also verified with comparable activity and improved safety with etoposide both in cells and in a mouse model. As a safe and effective prodrug, 6YT is expected to be one of the promising candidates in chemotherapy against cancer.
- Zhu, Jiawen,Chen, Jingting,Song, Dongmei,Zhang, Wenda,Guo, Jianpeng,Cai, Guiping,Ren, Yuhao,Wan, Chengying,Kong, Lingyi,Yu, Wenying
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Read Online
- Preparation method of etoposide, teniposide and analogs of etoposide and teniposide
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The invention discloses a preparation method of etoposide, teniposide and analogs of etoposide and teniposide. The preparation method includes the following steps of 1, selective protection of 4'domethylpodophyllotoxin4'hydroxy; 2, introduction of 4 hydroxy hydroxyl; 3, removal of a protecting group. The method is mild in reaction condition and environmentally friendly, and the yield and purity of the products are high.
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Paragraph 0106; 0107; 0108
(2017/01/02)
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- Analogues of Etoposide for the Treatment of Tumours
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Compounds for treatment of a patient having a tumour that is metastatic and/or that reduces an organ function, wherein the compounds are of the general formula: wherein X is O, NH and S, wherein n is 0, 1 or 2, wherein R1 and R2 are H, methyl or ethyl, or together form a group CR3R4, and wherein R3 and R4 are H, methyl or ethyl.
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Paragraph 0062; 0063
(2013/06/04)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- ANALOGUES OF ETOPOSIDE FOR THE TREATMENT OF TUMOURS
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Analogues of etoposide for the treatment of patients having a tumour, more particularly a tumour that is metastatic and/or that reduces an organ function, are provided. The invention also relates to an in vitro method of selecting a respective patient for treatment with an analogue of etoposide.
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Page/Page column 11; 13
(2011/11/01)
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- ANALOGUES OF ETOPOSIDE FOR THE TREATMENT OF TUMOURS
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Analogues of etoposide for the treatment of patients having a tumour, more particularly a tumour that is metastatic and/or that reduces an organ function, are provided. The invention also relates to an in vitro method of selecting a respective patient for treatment with an analogue of etoposide.
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Page/Page column 13; 15
(2011/11/01)
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- Therapeutic use of at least one botulinum neurotoxin in the treatment of pain induced by at least one anti-neoplastic agent
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The present invention relates to a method of treating or preventing pain or pains induced by an anti-neoplastic agent, comprising the step of administering an effective amount of at least one botulinum neurotoxin to a patient in need thereof.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- BIOREDUCTIVELY-ACTIVATED PRODRUGS
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A compound of formula (1), or a pharmaceutically acceptable salt thereof, wherein: - Ar is a substituted heteroaryl group bearing at least one nitro or azido group or is a benzoquinone, naphthoquinone or fused heterocyloquinone; - R1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; - R2 is a glycoside, OH, optionally substituted alkyl, optionally substituted alkoxy, C2-C8 alkenyl, C1-C8 hydroxyalkyl, optionally substituted arylamino, optionally substituted aryl C1-C4 alkylamino or hydroxyalkylamino; and - R3 and R4 are each independently H or halo.
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Page/Page column 20-21
(2008/06/13)
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- PROCESS FOR PREPARING ETOPOSIDE
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The present invention relates to a novel process for preparing the anticancer compound, etoposide, in the C-1 - beta anomeric form, as well as a novel intermediate compound.
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Page/Page column 12
(2008/06/13)
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- Medicines for treating tumoral pathologies containing the ro5-4864 compound and an apoptosis-inducing agent
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The invention concerns the use of Ro5-4864, and compounds derived therefrom, for preparing medicines for treating tumoral pathologies. The invention also concerns said compounds combined with an apoptosis-inducing agent, as combination products for simultaneous, separate or prolonged use, in cancer therapy.
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- Synthetic method for the preparation of the antineoplastic agent etoposide
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A synthetic method for the preparation of the anti-tumor drug Etoposide. In one embodiment, the method includes the direct condensation of 4′-demethyl-epipodophylloxin with 2,3-di-O-dichloroacetyl-(4,6-O-ethylidene)-β-D-glucopyranose in the presence of trimethylsilyl trifluoromethane sulfonate (TMSOTf) to yield 4′-demethylepipodophyllotoxin-4-(2,3-di-O-dichloroacetyl-4,6-O-ethylidene)-β-D-glucopyranoside, followed by conversion of the same to etoposide. Other methods include use of different Lewis acids as catalyst, as well as different substituted glucopyranosides. This method provides enhanced yields over existing synthetic techniques, reduced reaction times and permits more favorable isolation reaction procedures.
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- A crystallization-induced stereoselective glycosidation reaction in the synthesis of the anticancer drug etoposide.
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The anticancer drug etoposide, 1, is prepared in 79% overall yield from readily available 4'-demethyl-4-epipodophyllotoxin, 3, and 4, 6-O-ethylidene-2,3-O-dibenzyl-D-glucose, 4, via a crystallization-induced stereoselective glycosidation reaction followed by catalytic hydrogenation.
- Silverberg,Kelly,Vemishetti,Vipond,Gibson,Harrison,Spector,Dillon
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p. 3281 - 3283
(2007/10/03)
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- Novel "reverse Kahne-type glycosylation": Access to O-, N-, and C-linked epipodophyllotoxin conjugates
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Exposure of epipodophyllotoxin C4-sulfoxides to triflic anhydride, followed by a silyl glycoside, provides a glycoconjugate of the etoposide variety via formal "reverse Kahne glycosylation." To our knowledge, this is the first example of this variant of the Kahne activation method wherein the activating functionality is positioned on the aglycon, rather than on the sugar. Phenols, anilines, or allyl silanes are also efficiently captured at C4, producing the corresponding O-, N-, and C-linked lignan conjugates.
- Berkowitz, David B.,Choi, Sungjo,Bhuniya, Debnath,Shoemaker, Richard K.
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p. 1149 - 1152
(2007/10/03)
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- Compositions containing piperine
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A pharmaceutical composition having increased bioavailability characterized by piperine of the formula STR1 and a drug for treating a disease or condition of the human cardiovascular system, central nervous system, gastrointestinal tract, respiratory tract, endocrine system, genito urinary tract or haemopoietic system.
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- Intermediates for the preparation of demethylepipodophyllotoxin
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Demethylepipodophyllotoxin-β-glucosides are prepared by allowing demethylepipodophyllotoxin to react with a 2,3-di-O-ester of a 1-O-trialkylsilyl-4,6-O-alkylidene-β-D-glucose derivative in the presence of a Lewis acid. The 4,6-O-alkylidene group can be alkylidene, arylalkylidene, or heteroarylalkylidene and the 2,3-ester can be lower alkanoyl or haloacetyl. In a typical embodiment, demethylepipodophyllotoxin is allowed to react with 4,6-O-ethylidene-2,3-di-O-acetyl-1-O-trimethylsilyl-β-D-glucose in the presence of boron trifluoride etherate to yield etoposide 2",3"-diacetate.
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- Compositions containing piperine
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A pharmaceutical composition having increased bioavailability characterized by piperine of the formula and a drug for treating a disease or condition of the human cardiovascular system, central nervous system, gastrointestinal tract, respiratory tract, endocrine system, genito urinary tract or haemopoietic system.
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- α-1-tributyltin-O-2,3-bisacetyl-4,6-ethylidene-glucose as a convenient glycosidation reagent: An efficient synthesis of etoposide
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The antineoplastic drug etoposide has been prepared by a chemically and operationally simple process. The salient reaction is the BF3.etherate promoted, room temperature condensation of 4'-demethyl-4'-acetyl-epipodophyllotoxin 4, with α-1-Bu3Sn-O-2,3-bisacetyl-4,6-ethylidene-glucose 6. The latter compound was prepared from 4,6-β-ethylidene glucose triacetate and Bu3Sn-OMe obtained in situ from (Bu3Sn)2O and dimethyl carbonate. A readily separable mixture of α and β-etoposide triacetate epimers was obtained where the desired β-epimer predominated. In contrast, 4,6-α-ethylidene glucose diacetate and 4, even at 0°C, gave an equimolar mixture of epimers. It is proposed that the stereochemical outcome may be attributed to electronic effects in the activated tin-glucose reagent.
- Vogel,Sterling,Herzig,Nudelman
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p. 3049 - 3056
(2007/10/03)
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- Method of preparing etoposide
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The present invention relates to a method of increasing the yield of etoposide produced relative to prior art processes. A residue obtained as a result of reacting etoposide triacetate with a first lower alkanol in the presence of a first transesterification catalyst is provided. This residue is then reacted with a second lower alkanol and a second transesterification catalyst.
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- A Short and Simple Synthesis of the Antitumor Agent Etoposide
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The antitumor agent etoposide has been synthesized for the first time from unprotected 4'-demethylepipodophyllotoxin. Key Words: etoposide; antitumor; anticancer; O-glycosylation; 4'-demethylepipodophyllotoxin
- Allevi, Pietro,Anastasia, Mario,Ciuffreda, Pierangela,Sanvito, Anna Maria,Macdonald, Peter
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p. 4831 - 4834
(2007/10/02)
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- Sugar phosphates and sulfonates of epipodophyllotoxin glucosides
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The present invention relates to antitumor 4?-demethyl-epipodophyllotoxin glucosides having phosphate or sulfonate substituents on the sugar portion of the molecule.
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- A new and general glycosidation method for podophyllum lignan glycosides
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A facile and stereocontrolled construction of β-glycosidic linkages of podophyllotoxin and 4′-O-demethylepipodophyllotoxin D-glucosides or 4′-O-demethylepipodophyllotoxin 2-amino-2-deoxy-D-glucoside has been achieved by exploiting glycopyranosyl P,P-diphenyl-N-(p-toluenesulfonyl)phosphinimidate and bis(dimethylamido) phosphate as glycosyl donors, respectively.
- Hashimoto, Shun-Ichi,Honda, Takeshi,Ikegami, Shiro
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p. 1653 - 1654
(2007/10/02)
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- Method of treating nausea and vomiting with certain substituted-phenylalkylamino (and aminoacid) derivatives and other serotonin depleting agents
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A method for the treatment of emesis in a mammal, which method comprises administering to said mammal an emesis inhibiting amount of a compound which depletes serotonin in the brain of mammals; among which are compounds having the formula: STR1 wherein, R is selected from hydrogen, loweralkyl, trifluoromethyl, carboxyl, or loweralkoxycarbonyl; R1 and R2 are hydrogen or loweralkyl; Z is trifluoromethyl or halogen; the optical isomers and pharmaceutically acceptable salts thereof; two of the preferred compounds of the invention are fenfluramine and norfenfluramine.
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- 3'-demethoxyepipodophyllotoxin glucoside derivatives
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This invention relates to novel 3'-demethoxy epipodophyllotoxin glucosides, their use as anti-tumor agents, and pharmaceutical compositions thereof.
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- Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and α-peltatin
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A principal mechanism of action of the clinical antitumor drugs etoposide (1) and teniposide (2) is the inhibition of catalytic activity of type II DNA topoisomerase and concurrent enzyme-mediated production of lethal DNA strand breaks. Substitution of the glycosidic moiety of 1 or 2 by ester and ethers, as well as the esterification and etherification of α-peltatin (4) including its glucosidic ethylidene and thenylidene cyclic acetals (25 and 26), has afforded compounds of much less activity than that of 1. The in vitro cytotoxicity (KB) appears to have no correlation with the inhibitory activity of the human DNA topoisomerase II.
- Thurston,Imakura,Haruna,Li,Liu,Liu,Cheng,Lee
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p. 604 - 608
(2007/10/02)
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- Process for producing etoposide
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The present invention relates to a process for producing etoposide by reacting a 4'-halogenoacetyl-4'-demethylepipodophyllotoxin-β-D-2,3-di-O-halogenoacetyl-4,6-O-ethylideneglucoside represented by the general formula: STR1 wherein R1 and R2, which may be the same or different, represent each --COCHX2 or --COCX3, wherein X represents a halogen atom, with an alcohol, an amine, and/or ammonia to remove the halogenoacetyl groups.
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- Syntheses of All Four Possible Diastereomers of Etoposide and Its Aminoglycosidic Analogues via Optical Resolution of (+/-)-Podophyllotoxin by Glycosidation with D- and L-Sugars
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Syntheses of all four possible diastereomers of etoposide and its aminoglycosidic analogues have been achieved via optical resolution of (+/-)-podophyllotoxin by glycosidation with D- and L-sugars.
- Saito, Hitoshi,Nishimura, Yoshio,Kondo, Shinichi,Umezawa, Hamao
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p. 799 - 802
(2007/10/02)
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