- Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis
-
Cancer cells are vulnerable to reactive oxygen species (ROS) due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of cancer. We report a novel seleno-prodrug of gemcitabine (Gem), Se-Gem, and evaluated its activation and biological effects in cancer cells. Se-Gem was prepared by introducing a 1,2-diselenolane (a five-membered cyclic diselenide) moiety into the parent drug Gemvia a carbamate linker. Se-Gem is preferably activated by glutathione (GSH) and displays a remarkably higher potency than Gem (up to a 6-fold increase) to a panel of cancer cell lines. The activation of Se-Gem by GSH releases Gem and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG (oxidized GSH) and ROS via redox cycling reactions. Thus Se-Gem may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of Se-Gem as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency via a combination of chemotherapy and oxidative stress.
- Fang, Jianguo,Hou, Yanan,Li, Jin,Li, Xinming,Wang, Song,Zhao, Jintao
-
p. 3215 - 3222
(2020/04/08)
-
- Synthesis and in vitro anticancer activity of new gemcitabine-nucleoside analogue dimers containing methyltriazole or ester-methyltriazole linker
-
Two series of novel gemcitabine-nucleoside analogue dimers were synthesized using the ‘click’ chemistry approach. In the first series of dimers (21–30), the nucleoside units were connected with a stable methyltriazole 4N-3′(or 5′)C linker whereas in the second series (31–40) with a cleavable ester-methyltriazole 4N-3′(or 5′)C linker. Dimers 21–40 were evaluated for their cytotoxic activity in five human cancer cell lines such as cervical (HeLa), nasopharyngeal (KB), lung (A549), brain (U87), liver (HepG2) and normal dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Compound 29 comprising two gemcitabine (dFdC) units exhibited the highest activity among dimers 21–30. The activity of compound 29 was higher than that of dFdC in all the studied cancer cell lines. A similar order of activity was observed for compounds 25, 28, and 30. The best activity among all the dimers synthesized was displayed by compound 39, comprising two gemcitabine units with a cleavable linker. The activity of compound 39 was 5 to 9 times higher than that of dFdC, depending on the cell line. In addition, marked cytotoxic activity was shown by compounds 31, 36, 38, and 40.
- Trznadel, Roksana,Singh, Aleksandra,Kleczewska, Natalia,Liberska, Joanna,Ruszkowski, Piotr,Celewicz, Lech
-
p. 2587 - 2594
(2019/08/12)
-
- A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma
-
The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate-ester-caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2-activatable GEM (A-GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A-GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A-GEM treatment compared with that following GEM treatment.
- Matsushita, Katsunori,Okuda, Takumi,Mori, Shohei,Konno, Masamitsu,Eguchi, Hidetoshi,Asai, Ayumu,Koseki, Jun,Iwagami, Yoshifumi,Yamada, Daisaku,Akita, Hirofumi,Asaoka, Tadafumi,Noda, Takehiro,Kawamoto, Koichi,Gotoh, Kunihito,Kobayashi, Shogo,Kasahara, Yuuya,Morihiro, Kunihiko,Satoh, Taroh,Doki, Yuichiro,Mori, Masaki,Ishii, Hideshi,Obika, Satoshi
-
p. 1384 - 1391
(2019/07/12)
-
- Involvement of CYP4F2 in the metabolism of a novel monophosphate ester prodrug of gemcitabine and its interaction potential in vitro
-
Compound-3 is an oral monophosphate prodrug of gemcitabine. Previous data showed that Compound-3 was more potent than gemcitabine and it was orally active in a tumor xenograft model. In the present study, the metabolism of Compound-3 was investigated in several well-known in vitro matrices. While relatively stable in human and rat plasma, Compound-3 demonstrated noticeable metabolism in liver and intestinal microsomes in the presence of NADPH and human hepatocytes. Compound-3 could also be hydrolyzed by alkaline phosphatase, leading to gemcitabine formation. Metabolite identification using accurate mass- and information-based scan techniques revealed that Compound-3 was subjected to sequential metabolism, forming alcohol, aldehyde and carboxylic acid metabolites, respectively. Results from reaction phenotyping studies indicated that cytochrome P450 4F2 (CYP4F2) was a key CYP isozyme involved in Compound-3 metabolism. Interaction assays suggested that CYP4F2 activity could be inhibited by Compound-3 or an antiparasitic prodrug pafuramidine. Because CYP4F2 is a key CYP isozyme involved in the metabolism of eicosanoids and therapeutic drugs, clinical relevance of drug-drug interactions mediated via CYP4F2 inhibition warrants further investigation.
- Wang, Yedong,Li, Yuan,Lu, Jia,Qi, Huixin,Cheng, Isabel,Zhang, Hongjian
-
supporting information
(2018/05/26)
-
- Selective Activation of a Prodrug by Thioredoxin Reductase Providing a Strategy to Target Cancer Cells
-
Elevated reactive oxygen species and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. As a major regulator of the cellular redox homeostasis, the selenoprotein thioredoxin reductase (TrxR) is increasingly considered as a promising target for anticancer drug development. The current approach to inhibit TrxR predominantly relies on the modification of the selenocysteine residue in the C-terminal active site of the enzyme, in which it is hard to avoid the off-target effects. By conjugating the anticancer drug gemcitabine with a 1,2-dithiolane scaffold, an unprecedented prodrug strategy is disclosed that achieves a specific release of gemcitabine by TrxR in cells. As overexpression of TrxR is frequently found in different types of tumors, the TrxR-dependent prodrugs are promising for further development as cancer chemotherapeutic agents.
- Li, Xinming,Hou, Yanan,Meng, Xianke,Ge, Chunpo,Ma, Huilong,Li, Jin,Fang, Jianguo
-
supporting information
p. 6141 - 6145
(2018/04/30)
-
- 4-N-Alkanoyl and 4-N-alkyl gemcitabine analogues with NOTA chelators for 68-gallium labelling
-
The conjugation of 4-N-(3-aminopropanyl)-2′-deoxy-2′,2′-difluorocytidine with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bn-NOTA) ligand in 0.1 M Na2CO3 buffer (pH 11) at ambient temperature provided
- Pulido, Jesse,de Cabrera, Maria,Sobczak, Adam J.,Amor-Coarasa, Alejandro,McGoron, Anthony J.,Wnuk, Stanislaw F.
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p. 5624 - 5630
(2018/10/24)
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- Difluoronucleoside antimetabolite anticancer drug for destroying cell replication
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The invention provides a difluoronucleoside antimetabolite anticancer drug for destroying cell replication as well as preparation and application of pharmaceutical composition of the antimetabolite anticancer drug. The chemical structural formula of the difluoronucleoside antimetabolite anticancer drug for destroying cell replication is shown as (A) in the description. The drug is an important anticancer drug, has the characteristic of wide antitumor spectrum, shows better anticancer activity in various tumors such as non-small cell lung cancer, breast cancer, pancreatic cancer and the like, and is one of the first choices for treatment of the non-small cell lung cancer and also one of the first choices for chemotherapy of pancreatic cancer.
- -
-
Paragraph 0040; 0053; 0053; 0057; 0065
(2018/09/13)
-
- Fluoro-nucleoside and synthesis method thereof
-
The invention discloses fluoro-nucleoside and a synthesis method thereof. The fluoro-nucleoside comprises the following steps: (1) by taking cytosine and hexamethyl disilazane as raw materials, preparing a cytosine siloxane protection radical solution; (2) dissolving a glycosyl compound into isoamylol, and performing stirring catalysis so as to obtain a glycosyl compound solution; (3) dropping thecytosine siloxane protection radical solution into the glycosyl compound solution, uniformly mixing, keeping the temperature, performing suction filtration, adding hydrochloric acid, stirring to separate a solid, and drying the solid so as to obtain an intermediate; (4) under an acid condition, performing hydroxyl deprotection on the intermediate, thereby obtaining the fluoro-nucleoside. By optimizing reaction conditions, adjusting raw material proportions and adding hydroxyapatite powder, generation and correct selection of target intermediate conformation are ensured, the reaction temperature is reduced, the purity of the fluoro-nucleoside is increased, the purity of the fluoro-nucleoside is as high as 99.8%, meanwhile the operation security is improved, the energy consumption is reduced, the cost is reduced, and the fluoro-nucleoside is applicable to large-scale production and application, can bring good economic benefits to companies and has good prospects.
- -
-
Paragraph 0038; 0043; 0048; 0053; 0058
(2018/03/26)
-
- Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine
-
The invention relates to a preparation method for a compound represented by a formula (I) shown in the description, i.e., a key intermediate sulfonated saccharide of Gemcitabine. The final product is prepared through subjecting a compound represented by a formula (II) shown in the description to sodium borohydride reduction, hydroxyl protection and resolution. The method is simple in process, high in yield and high in product purity and has no need of harsh reaction conditions, thereby being very suitable for industrial production.
- -
-
-
- A miazines new compounds
-
The invention relates to a new pyrimidine compound. The experiment proves that the new compound disclosed in the specification can inhibit growth of tumor cells, and has favorable effectiveness and safety when being used for preparing antineoplastic drugs. The vessel irritation experiment proves that the new compound does not have hemolysis or irritation and can be prepared into an injection for clinical use.
- -
-
Paragraph 0007; 0012; 0013
(2017/07/07)
-
- Synthesis process of fluoronucleoside
-
The invention relates to a synthesis process of fluoronucleoside. The synthesis process comprises the following steps: step 1, reflowing cytosine and hexamethyldisilazane under the catalysis effect of ammonium sulfate; adding isopropyl alcohol; raising the temperature to obtain a cytosine silyl ether protective group solution; step 2, dissolving a glycosyl compound into isoamyl alcohol and stirring; adding a catalyst and heating to obtain a glycosyl compound solution; step 3, dropwise adding the glycosyl compound solution into the cytosine silyl ether protective group solution; after dropwise adding, continually keeping heat and reacting for hours; carrying out pumping filtration and dropwise adding hydrochloric acid into filtrate; separating out a solid and drying to obtain an intermediate; and step 4, carrying out hydroxyl de-protection on the intermediate under an acidic condition to prepare the fluoronucleoside. According to the synthesis process provided by the invention, the generation of target intermediate configuration is guaranteed and the temperature is greatly reduced; the requirements on equipment are reduced and the safety of operation is improved; the energy consumption is also reduced and the cost is easy to reduce; and the synthesis process is applicable to large-scale production and application.
- -
-
Paragraph 0023
(2017/07/20)
-
- A novel anticancer theranostic pro-prodrug based on hypoxia and photo sequential control
-
A novel anticancer pro-prodrug (GMC-CAE-NO2) with diagnosis and therapy functions based on hypoxia and photo sequential control was designed. It provides a platform for constructing theranostic pro-prodrugs to release active drugs controlled by hypoxic status and UV illumination.
- Feng, Weipei,Gao, Chunyue,Liu, Wei,Ren, Huihui,Wang, Chao,Ge, Kun,Li, Shenghui,Zhou, Guoqiang,Li, Hongyan,Wang, Shuxiang,Jia, Guang,Li, Zhenhua,Zhang, Jinchao
-
supporting information
p. 9434 - 9437
(2016/07/29)
-
- Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine
-
Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd 0-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biologically inert precursors of cytotoxic gemcitabine by introducing Pd0-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacological activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced (>23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) promoiety displayed the highest sensitivity to heterogeneous palladium catalysis under biocompatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bioorthogonal organometallic chemistry.
- Weiss, Jason T.,Dawson, John C.,Fraser, Craig,Rybski, Witold,Torres-Sánchez, Carmen,Bradley, Mark,Patton, E. Elizabeth,Carragher, Neil O.,Unciti-Broceta, Asier
-
p. 5395 - 5404
(2014/07/08)
-
- A general and enantioselective approach to pentoses: A rapid synthesis of PSI-6130, the nucleoside core of sofosbuvir
-
An efficient route towards biologically relevant pentose derivatives is described. The de novo synthetic strategy features an enantioselective α-oxidation reaction enabled by a chiral amine in conjunction with copper(II) catalysis. A subsequent Mukaiyama aldol coupling allows for the incorporation of a wide array of modular two-carbon fragments. Lactone intermediates accessed via this route provide a useful platform for elaboration, as demonstrated by the preparation of a variety of C-nucleosides and fluorinated pentoses. Finally, this work has facilitated expedient syntheses of pharmaceutically active compounds currently in clinical use.
- Peifer, Manuel,Berger, Rapha?lle,Shurtleff, Valerie W.,Conrad, Jay C.,Macmillan, David W. C.
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p. 5900 - 5903
(2014/05/20)
-
- Gemcitabine-coumarin-biotin conjugates: A target specific theranostic anticancer prodrug
-
We present here, the design, synthesis, spectroscopic characterization, and in vitro biological assessment of a gemcitabine-coumarin-biotin conjugate (5). Probe 5 is a multifunctional molecule composed of a thiol-specific cleavable disulfide bond, a coumarin moiety as a fluorescent reporter, gemcitabine (GMC) as a model active drug, and biotin as a cancer-targeting unit. Upon addition of free thiols that are relatively abundant in tumor cells, disulfide bond cleavage occurs as well as active drug GMC release and concomitantly fluorescence intensity increases. Confocal microscopic experiments reveal that 5 is preferentially taken up by A549 cells rather than WI38 cells. Fluorescence-based colocalization studies using lysosome-and endoplasmic reticulum-selective dyes suggest that thiol-induced disulfide cleavage of 5 occur in the lysosome possibly via receptor-mediated endocytosis. The present drug delivery system is a new theranostic agent, wherein both a therapeutic effect and drug uptake can be readily monitored at the subcellular level by two photon fluorescence imaging.
- Maiti, Sukhendu,Park, Nayoung,Han, Ji Hye,Jeon, Hyun Mi,Lee, Jae Hong,Bhuniya, Sankarprasad,Kang, Chulhun,Kim, Jong Seung
-
supporting information
p. 4567 - 4572
(2013/05/08)
-
- ASYNTHESIS OF B-NUCLEOSIDES
-
A process of stereoselectively synthesizing β-nucleoside, e.g., 2′-deoxy-2,2′-difluorocytidine, is described. The process includes reacting a tetrahydrofuran compound of the following formula: in which wherein R1, R2, R3, R4, and L as defined in the specification, with a nucleobase derivative in the presence of an oxidizing agent.
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Page/Page column 9
(2012/10/18)
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- STEREOSELECTIVE SYNTHESIS OF BETA-NUCLEOSIDES
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A process of stereoselectively synthesizing β-nucleoside of formula (I), e.g., 2'-deoxy-2,2'-difluorocytidine, is described. The process includes reacting a tetrahydrofuran compound of the following formula: in which wherein R1, R2, R3, R4, and L as defined in the specification, with a nucleobase derivative in the presence of an oxidizing agent.
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Page/Page column 12-13
(2012/10/18)
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- Unprecedented gas-phase chiroselective logic gates
-
The gas-phase encounters between 2-aminobutane and proton-bound chiral resorcin[4]arene/nucleoside complexes behave in the gas phase as supramolecular "chiroselective logic gates" by releasing the nucleoside depending on the resorcin[4]arene and the 2-aminobutane configurations.
- Botta, Bruno,Fraschetti, Caterina,D'Acquarica, Ilaria,Sacco, Fabiola,Mattay, Jochen,Letzel, Matthias C.,Speranza, Maurizio
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supporting information; experimental part
p. 1717 - 1719
(2011/05/03)
-
- HALOGENATED 2-DEOXY-LACTONES, 2'-DEOXY--NUCLEOSIDES, AND DERIVATIVES THEREOF
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Disclosed are halogenated 2-deoxy-lactone, 2'-deoxy-nucleosides, and derivatives thereof, for example, a compound of formula (I). Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one compound or salt of the invention, and a method of treating a disorder is selected from the group consisting of an abnormal cellular proliferation, a viral infection, and an autoimmune disorder.
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Page/Page column 60-61
(2011/02/24)
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- CONJUGATES OF A LIPOIC ACID DERIVATIVE AND ANTI-PROLIFERATION AGENT AND MEDICAL USES THEREOF
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The invention provides conjugate compounds, pharmaceutical compositions, therapeutic methods, and kits for use in treating cell proliferation disorders, such as cancer. The conjugates comprise a redox-modulating compound, such as a lipoic acid derivative, chemically bonded to an anti-proliferation agent, such as gemcitabine.
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Page/Page column 22
(2011/12/02)
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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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- Efficient syntheses of clofarabine and gemcitabine from 2-deoxyribonolactone
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The development of a new methodology to achieve electrophilic fluorination of triisopropylsilyl-protected 2-deoxyribonolactone has been employed to synthesize clofarabine and gemcitabine with improved synthetic efficiency versus prior synthetic methods. These studies highlight the versatility of this new methodology to obtain medically relevant 2′-fluoronucleosides.
- Cen, Yana,Sauve, Anthony A.
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p. 113 - 122
(2011/08/05)
-
- Process for the preparation of gemcitabine chlorohydrate
-
Disclosed is the preparation of 2-deoxy-D-erythro-2,2-difluororibofuranose-3,5-dibenzoate: a known intermediate for the preparation of Gemcitabine, by means of a reduction process; further disclosed is the purification of Gemcitabine by chromatography and the purification of Gemcitabine hydrochloride by crystallization techniques from ternary solvent mixtures. The main advantage of the invention is providing Gemcitabine hydrochloride with purity in conformity with the Pharmacopoeia requirements, as well as a process particularly convenient from the industrial point of view.
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Page/Page column 8
(2010/05/13)
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- An efficient large-scale synthesis of gemcitabine employing a crystalline 2, 2-difluoro-α-ribofuranosyl bromide
-
An efficient large-scale synthesis of gemcitabine was achieved without chromatography or fractional crystallization. The key steps include stereospecific conversion of a novel β-ribofuranosyl phosphate into a highly crystalline a-ribofuranosyl bromide and coupling of the α-ribofuranosyl bromide and trime- thylsilyl cytosine to produce a β-nucleoside. p-Phenylbenzoyl group was introduced for the protection of one of hydroxy groups in order to enhance the crystallinity of intermediates. Continuous removal of trimethylsilyl bromide, generated during the coupling reaction, by distillation from the reaction medium substantially enhanced the β-selectivity of the crucial coupling reaction.
- Chang, Young-Kil,Lee, Jaeheon,Park, Gha-Seung,Lee, Moonsub,Park, Chul Hyun,Kim, Han Kyong,Lee, Gwansun,Lee, Bo-Young,Baek, Ju Yuel,Kim, Kwan Soo
-
experimental part
p. 5687 - 5691
(2010/09/18)
-
- Inactivation of lactobacillus leichmannii ribonucleotide reductase by 2',2'-difluoro2'-deoxycytidine s'-triphosphate: Covalent modification
-
Ribonucleotide reductase (RNR) from Lactobacillus leichmannii, a 76 kDa monomer using adenosylcobalamin (AdoCbl) as a cofactor, catalyzes the conversion of nucleoside triphosphates to deoxynucleotides and is rapidly ( 3H]- and [5-3H]F2CTP were synthesized and used independently to inactivate RNR. Sephadex G-50 chromatography of the inactivation mixture revealed that 0.47 equiv of a sugar was covalently bound to RNR and that 0.71 equiv of cytosine was released. Alternatively, analysis of the inactivated RNR by SDS-PAGE without boiling resulted in 33% of RNR migrating as a 110 kDa protein. Inactivation of RNR with a mixture of [1'-3H]F2CTP and [1'-2H]F 2CTP followed by reduction with NaBH4, alkylation with iodoacetamide, trypsin digestion, and HPLC separation of the resulting peptides allowed isolation and identification by MALDI-TOF mass spectrometry (MS) of a 3H/2H-labeled peptide containing C731 and C736 from the C-terminus of RNR accounting for 10% of the labeled protein. The MS analysis also revealed that the two cysteines were cross-linked to a furanone species derived from the sugar of F2CTP. Incubation of [1-3H]F2CTP with C119S-RNR resulted in 0.3 equiv of sugar being covalently bound to the protein, and incubation with NaBH4 subsequent to inactivation resulted in trapping of 2'-fluoro-2'-deoxycytidine. These studies and the ones in the preceding paper (DOI: 10.1021/bi9021318) allow proposal of a mechanism of inactivation of RNR by F2CTP involving multiple reaction pathways. The proposed mechanisms share many common features with F2CDP inactivation of the class I RNRs.
- Lohman, Gregory J.S.,Stubbe, Joanne
-
body text
p. 1404 - 1417
(2011/02/21)
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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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- Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same
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The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers and for conjugating to molecules such as targeting, diagnostic and therapeutic agents.
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- NOVEL SYNTHESIS OF BETA-NUCLEOSIDES
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This invention relates to a process of stereoselectively synthesizing β-nucleoside, e.g., 2′-deoxy-2,2′-difluorocytidine.
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Page/Page column 9-10
(2009/05/28)
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- Manufacturing Process of 2' ,2' - Difluoronucleoside and Intermediate
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The present invention relates to more improved process for preparing 2′-deoxy-2′,2′-difluoronucleoside and its intermediate. The present invention provide a process for preparing an erythro enantiomer in greater than 98% purity, comprising forming a lactone ring by hydrolyzing ethyl (3RS)-2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxolan-4-yl)propionate is hydrolyzed in the presence of hydrolysis reagents selected from acetic acid or chloroacetic acid, water and a mixture of organic solvents selected from the group comprising acetonilrile, dioxane, tetrahydrofuran or toluene, introducing a substituted benzoyl protecting group at the 3-position and 5-position, and recrys- tallizing said erythro enantiomer. Further, the present invention provides a process for selectively preparing, in greater than 99% purity, a beta-anomer 2′-deoxy-2′,2′-difluoronucleoside at the 3′-position and 5′-position that are protected by a substituted benzoyl in a 2:3 alpha/beta anomeric ratio.
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Page/Page column 7
(2009/12/04)
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- Facile rearrangement of N4-(α-aminoacyl)cytidines to N-(4-cytidinyl)amino acid amides
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Under near neutral and mildly basic conditions, primary N4-(α-aminoacyl)cytidines (4a-g) undergo a facile rearrangement to form N-(4-cytidinyl)amino acid amides (5a-g). Secondary aminoacyl derivatives rearrange with other competing pathways. Tertiary aminoacyl derivatives do not rearrange.
- Zhang, Deyi,Bender, David M.,Victor, Frantz,Peterson, Jeffrey A.,Boyer, Robert D.,Stephenson, Gregory A.,Azman, Adam,McCarthy, James R.
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p. 2052 - 2055
(2008/09/18)
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- A MANUFACTURING PROCESS OF 2',2'-DIFLUORONUCLEOSIDE AND INTERMEDIATE
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The present invention relates to more improved process for preparing 2'-deoxy-2',2'-difluoronucleoside and its intermediate. The present invention provide a process for preparing an erythro enantiomer in greater than 98% purity, comprising forming a lactone ring by hydrolyzing ethyl (3RS )-2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxolan-4-yl)propionate is hydrolyzed in the presence of hydrolysis reagents selected from acetic acid or chloroacetic acid, water and a mixture of organic solvents selected from the group comprising acetonitrile, dioxane, tetrahydrofuran or toluene, in? troducing a substituted benzoyl protecting group at the 3-position and 5-position, and recrys- tallizing said erythro enantiomer. Further, the present invention provides a process for selectively preparing, in greater than 99% purity, a beta-anomer 2'-deoxy-2',2'-difluoronucleoside at the 3'-position and 5'-position that are protected by a substituted benzoyl in a 2:3 alpha/beta anomeric ratio.
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Page/Page column 13
(2010/11/27)
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- AN IMPROVED PROCESS FOR PREPARATION OF GEMCITABINE HYDROCHLORIDE.
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A process for isolating ?-anomer enriched Gemcitabine hydrochloride by converting Gemcitabine base into Gemcitabine hydrochloride followed by its purification using solvents from the series of water soluble ethers like 1,4-dioxane or Monoglyme.
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Page/Page column 9-10
(2010/11/27)
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- A PROCESS FOR THE PREPARATION OF GEMCITABINE USING NOVEL INTERMEDIATES
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The present invention provides a commercially viable process for preparing gemcitabine and its pharmaceutically acceptable acid addition salts thereof in high yield and purity using novel intermediates.
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Page/Page column 9
(2010/11/25)
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- Method for the Preparation of 2'-Deoxy-2',2'-Difluorocytidine
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This invention relates to an improved method for stereoselectively preparing 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I).
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Page/Page column 10-11
(2008/06/13)
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- CRYSTALLINE FORMS OF GEMCITABINE AMIDE PRODRUG, COMPOSITIONS AND USE THEREOF
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The present invention relates to novel crystal forms of an amide prodrug of gemcitabine, compositions thereof and methods for using.
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Page/Page column 7
(2008/06/13)
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- PREPARATION OF GEMCITABINE
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A process for preparation of gemcitabine hydrochloride and purification thereof.
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Page/Page column 20-21
(2008/06/13)
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- INTERMEDIATE AND PROCESS FOR PREPARING OF BETA- ANOMER ENRICHED 21DEOXY, 21 ,21-DIFLUORO-D-RIBOFURANOSYL NUCLEOSIDES
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A highly stereoselective, simple and economical glycosylation process for preparation of β-anomer enriched 21-deoxy-21,21-D-ribofuranosyl difluoronucleosides of formula (II), and physiologically acceptable slats thereof, in particular, the β- enriched anomer of gemcitabine hydrochloride of formula (lib) in purity of >99% is provided through utilization of a novel trichloroacetimidate of formula (I).
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Page/Page column 41; 42
(2010/11/23)
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- BIOREDUCTIVELY-ACTIVATED PRODRUGS
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The present invention relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, Formula: (1); wherein: R1 is a substituted aryl or heteroaryl group bearing at least one nitro or azido group or is an optionally substituted benzoquinone, optionally substituted naphthoquinone or optionally substituted fused heterocycloquinone; R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, aryl or heteroaryl; and R3 is selected such that R3NH2 represents a cytotoxic nucleoside analogue or an ester or phosphate ester prodrug of a cytotoxic nucleoside analogue, with the proviso that if R1 is an aryl group then R2 is not H.
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Page/Page column 25
(2010/10/20)
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- METHOD FOR THE PREPARATION OF 2#-DEOXY-2#,2#-DIFLUOROCYTIDINE
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This invention relates to an improved method for stereoselectively preparing 2′-deoxy-2′,2′-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2′-deoxy-2′,2′-difluorocytidine of formula (I).
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Page/Page column 22-23
(2008/06/13)
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- METHOD FOR THE PREPARATION OF 2'-DEOXY-2',2'-DIFLUOROCYTIDINE
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This invention relates to an improved method for stereoselectively preparing 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I).
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Page/Page column 24-25
(2008/06/13)
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- AMIDE PRODRUG OF GEMCITABINE, COMPOSITIONS AND USE THEREOF
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The present invention relates to novel amide prodrugs of gemcitabine, compositions thereof and methods for using.
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Page/Page column 10; 11
(2008/06/13)
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- Method for preparation of 2'-deoxy-2', 2'-difluoro-beta-cytidine or pharmaceutically acceptable salts thereof by using 1,6-anhydro-beta-D-glucose as raw material
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The present invention provides a method for preparation of 2′-deoxy-2′,2′-difluoro-β-cytidine or pharmaceutically acceptable salt thereof, comprising starting from 1,6-anhydro-β-D-glucose as raw material, oxidizing, and fluorinating to obtain 2-deoxy-2,2-difluoro-D-ribofuranose as intermediate. The 2′-deoxy-2′,2′-difluoro-β-cytidine was finally prepared from the intermediate of 2-deoxy-2,2-difluoro-D-ribofuranose. The method is simple in operation and has a high yield. The method can effectively be used in large-scale production.
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Page/Page column 5-6
(2010/02/15)
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- COMPOUNDS FOR IMMUNOPOTENTIATION
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Methods of stimulating an immune response and treating patients responsive thereto with 3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-diones, staurosporine analogs, derivatized pyridazines, chromen-4-ones, indolinones, quinazolines, nucleoside analogs, and other small molecules are disclosed.
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Page/Page column 152
(2010/02/15)
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- Novel oligonucleotides and related compounds
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The present invention relates generally to oligonucleotides and more specifically to oligonucleotides which have a sequence including at least two CDG dinucleotides and a prodrug of an antimetabolite. The prodrug can be part of a CpG dinucleotide or may be attached elsewhere on the oligonucleotide.
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Page/Page column 16
(2008/06/13)
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- PHARMACEUTICAL COMPOSITION COMPRISING GEMCITABINE AND CYCLODEXTRINES
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The present invention provides a pharmaceutical composition comprising gemcitabine and cyclodextrin. The pharmaceutical formulation is suitable for liquid parenteral administration.
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Page/Page column 4
(2008/06/13)
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- Anti-HCV nucleoside derivatives
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The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
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- Terminally-branched polymeric linkers and polymeric conjugates containing the same
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The present invention is directed to polymeric-prodrug transport forms of the formula: wherein: E1-4are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12branched alkyls, C3-8cycloalkyls, C1-6substituted alkyls, C3-8substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6heteroalkyls, substituted C1-6heteroalkyls, C1-6alkoxy, phenoxy, C1-6heteroalkoxy, and at least one of E1-4includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or wherein J1is the same as J, or another member of the group defining J and E5is the same as E1-4, or another member of the group defining E1-4; Y1-2are independently O, S or NR9; M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(=Y2); R2-5and R7-9are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12branched alkyls, C3-8cycloalkyls, C1-6substituted alkyls, C3-8substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-16heteroalkyls, substituted C1-6heteroalkyls, C1-6alkoxy, phenoxy and C1-6heteroalkoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer, Z is an electron withdrawing group; and R1is a polymeric residue. which is optionally capped with a moiety of the formula:
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- Process for the preparation of a 2-substituted 3,3-difluorofuran
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A process for the preparation of a 2-substituted-3,3-difluorofuran using diethyl ammonium sulfur trifluoride (DAST) and pyridine hydrogen fluoride. The process is particularly useful for producing a 2',2'-difluoronucleoside, particularly 1-(2',2'-difluoro-β-D-arabinofuranosyl)cytosine (also known as 2'-deoxy-2',2'-difluorocytidine), a known antiviral and antitumor agent.
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