- Chemoselective bioconjugation of triazole phosphonites in aqueous media
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Readily accessible and versatile phosphonite building blocks with improved stability against hydrolysis were used for the efficient metal-free functionalization of peptides and proteins in aqueous buffers at low micromolar concentrations. The application of this protocol to the immobilization of a Rasa1-SH2 domain revealed high binding affinity to the human T-cell protein ADAP and supports the applicability of triazole phosphonites for protein modifications without harming their function.
- Vall??e, M. Robert J.,Majkut, Paul,Krause, Dagmar,Gerrits, Michael,Hackenberger, Christian P. R.
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Read Online
- A molecular approach to rationally constructing specific fluorogenic substrates for the detection of acetylcholinesterase activity in live cells, mice brains and tissues
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Acetylcholinesterase (AChE) is an extremely critical hydrolase tightly associated with neurological diseases. Currently, developing specific substrates for imaging AChE activity still remains a great challenge due to the interference from butyrylcholinesterase (BChE) and carboxylesterase (CE). Herein, we propose an approach to designing specific substrates for AChE detection by combining dimethylcarbamate choline with a self-immolative scaffold. The representative P10 can effectively eliminate the interference from CE and BChE. The high specificity of P10 has been proved via imaging AChE activity in cells. Moreover, P10 can also be used to successfully map AChE activity in different regions of a normal mouse brain, which may provide important data for AChE evaluation in clinical studies. Such a rational and effective approach can also provide a solid basis for designing probes with different properties to study AChE in biosystems and another way to design specific substrates for other enzymes. This journal is
- Wu, Xiaofeng,An, Jong Min,Shang, Jizhen,Huh, Eugene,Qi, Sujie,Lee, Eunhye,Li, Haidong,Kim, Gyoungmi,Ma, Huimin,Oh, Myung Sook,Kim, Dokyoung,Yoon, Juyoung
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p. 11285 - 11292
(2020/11/04)
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- Iodine(III)-Catalyzed Electrophilic Nitration of Phenols via Non-Br?nsted Acidic NO2+ Generation
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The first catalytic procedure for the electrophilic nitration of phenols was developed using iodosylbenzene as an organocatalyst based on iodine(III) and aluminum nitrate as a nitro group source. This atom-economic protocol occurs under mild, non-Br?nsted acidic and open-flask reaction conditions with a broad functional-group tolerance including several heterocycles. Density functional theory (DFT) calculations at the (SMD:MeCN)Mo8-HX/(LANLo8+f,6-311+G) level indicated that the reaction proceeds through a cationic pathway that efficiently generates the NO2+ ion, which is the nitrating species under neutral conditions.
- Juárez-Ornelas, Kevin A.,Jiménez-Halla, J. Oscar C.,Kato, Terumasa,Solorio-Alvarado, César R.,Maruoka, Keiji
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supporting information
p. 1315 - 1319
(2019/03/07)
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- Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites
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A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu4 subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.
- Selvam, Chelliah,Lemasson, Isabelle A.,Brabet, Isabelle,Oueslati, Nadia,Karaman, Berin,Cabaye, Alexandre,Tora, Amélie S.,Commare, Bruno,Courtiol, Tiphanie,Cesarini, Sara,McCort-Tranchepain, Isabelle,Rigault, Delphine,Mony, Laetitia,Bessiron, Thomas,McLean, Heather,Leroux, Frédéric R.,Colobert, Fran?oise,Daniel, Hervé,Goupil-Lamy, Anne,Bertrand, Hugues-Olivier,Goudet, Cyril,Pin, Jean-Philippe,Acher, Francine C.
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supporting information
p. 1969 - 1989
(2018/03/21)
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- CONJUGATES COMPRISING SELF-IMMOLATIVE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 180
(2017/06/27)
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- CONJUGATES COMPRISING PEPTIDE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and at least two active agents. In preferred embodiments, the linker comprises a peptide sequence of a plurality of amino acids, and at least two of the active agents are covalently coupled to side chains of the amino acids. The antibody-drug conjugate may comprise a self-immolative group, preferably two-self-immolative groups. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 190
(2017/08/08)
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- COMPOSITIONS AND METHODS RELATED TO ANTI-CD19 ANTIBODY DRUG CONJUGATES
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an anti-CD 19 antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self-immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 42; 43
(2017/04/11)
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- COMPOSITIONS AND METHODS RELATED TO ANTI-EGFR ANTIBODY DRUG CONJUGATES
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an anti-epidermal growth factor receptor ("EGFR") antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self-immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the drug; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 42; 43
(2017/04/11)
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- COMPOUNDS COMPRISING SELF-IMMOLATIVE GROUP
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Provided are compounds comprising a self-immolative group, and the compounds comprising a self-immolative group according to the present invention may include a protein (for example, an oligopeptide, a polypeptide, an antibody, or the like) having substrate-specificity for a target and an active agent (for example, a drug, a toxin, a ligand, a detection probe, or the like) having a specific function or activity.
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Paragraph 0284; 0285
(2016/08/03)
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- Aminophenoxazinones as inhibitors of indoleamine 2,3-dioxygenase (IDO). synthesis of exfoliazone and chandrananimycin A
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A range of 2-aminophenoxazin-3-ones has been prepared by oxidative cyclocondensation of 2-aminophenols, including the natural products exfoliazone and chandrananimycin A, both synthesized for the first time. The compounds were evaluated for their ability
- Pasceri, Raffaele,Siegel, David,Ross, David,Moody, Christopher J.
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p. 3310 - 3317
(2013/06/04)
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- Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy
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We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is signi ficantly less toxic than the parent drug. However, in the presence of b-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.
- Legigan, Thibaut,Clarhaut, Jonathan,Renoux, Brigitte,Tranoy-Opalinski, Isabelle,Monvoisin, Arnaud,Jayle, Christophe,Alsarraf, Jerome,Thomas, Mikael,Papot, Sebastien
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- One-pot synthesis of isocyanides from alcohols
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A one-pot reaction of alcohols with trimethylsilyl cyanide and methanesulfonic acid with subsequent neutralization by triethylamine and dehydration by tosyl chloride and pyridine gave the corresponding isocyanides in moderate-to-high yields. This method was used to synthesize tertiary and benzylic isocyanides from the corresponding alcohols. Georg Thieme Verlag Stuttgart · New York.
- Okada, Iku,Kitano, Yoshikazu
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experimental part
p. 3997 - 4002
(2012/01/06)
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- Study of a cyclopamine glucuronide prodrug for the selective chemotherapy of glioblastoma
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The first glucuronide prodrug of the hedgehog signaling inhibitor cyclopamine was synthesized. The carbamoyl derivatisation of cyclopamine significantly decreased its toxicity towards the U87 human glioblastoma cell line. However, when the prodrug was incubated with β-glucuronidase in the culture media, the active drug was efficiently released thereby restoring its anti-proliferative activity.
- Hamon, Florian,Renoux, Brigitte,Chadéneau, Corinne,Muller, Jean-Marc,Papot, Sébastien
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experimental part
p. 1678 - 1682
(2010/06/14)
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- Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy
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Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with β-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.
- Thomas, Mickael,Clarhaut, Jonathan,Tranoy-Opalinski, Isabelle,Gesson, Jean-Pierre,Roche, Joelle,Papot, Sebastien
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p. 8109 - 8116
(2008/12/23)
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- Self-immolative magnetic resonance imaging contrast agents sensitive to beta-glucuronidase
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The present invention relates to magnetic resonance imaging (MRI) contrast agent. In particular, the present invention provides MRI contrast agents that are sensitive to the enzyme beta-glucoronidase. The MRI contrast agents provide compositions and methods for non-invasive diagnostic imaging of tissues, including necrotic tumors.
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Page/Page column 14
(2010/11/08)
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- First enzymatically activated Taxotere prodrugs designed for ADEPT and PMT
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Described here are the syntheses and preliminary biological evaluations of the first two enzymatically activated prodrugs of docetaxel (Taxotere) reported to date. These prodrugs were designed as potential candidates for selective chemotherapy in ADEPT or
- Bouvier, Emmanuel,Thirot, Sylvie,Schmidt, Frederic,Monneret, Claude
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p. 969 - 977
(2007/10/03)
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- Saccharide sensing molecules having enhanced fluorescent properties
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The present invention provides formulae for fluorescent compounds that have a number of properties which make them uniquely suited for use in sensors of analytes such as saccharides. The advantageous fluorescent properties include favorable excitation wavelengths, emission wavelengths, fluorescence lifetimes, and photostability. Additional advantageous properties include enhanced aqueous solubility, as well as temperature and pH sensitivity. The compound comprises an aryl or a substituted phenyl botonic acid that acts as a substrate recognition component, a fluorescence switch component, and a fluorophore. Fluorescent compounds are described that are excited at wavelengths greater than 400 nm and emit at wavelengths greater than 450 nm, which is advantageous for optical transmission through skin. The fluorophore is typically selected from transition metal-ligand complexes and thiazine, oxazine, oxazone, or oxazine-one as well as anthracene compounds. The fluorescent compound can be immobilized in a glucose permeable biocompatible polymer matrix that is implantable below the skin.
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- Synthesis and biological evaluation of new 2-(4,5-dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine derivatives
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2-(4,5-Dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine derivatives and tricyclic analogues with a fused additional ring on the nitrogen atom of the benzoxazine moiety have been prepared and evaluated for their cardiovascular effects as potential antihypertensive agents. The imidazoline ring was generated by reaction of the corresponding ethyl ester with ethylenediamine. Affinities for imidazoline binding sites (IBS) I1 and I2 and α1 and α2 adrenergic receptors were evaluated as well as the effects on mean arterial blood pressure (MAP) and heart rate (HR) of spontaneously hypertensive rats. With few exceptions the most active compounds on MAP were those with high affinities for IBS and α2 receptor. Among these, compound 4h was the most interesting and is now, together with its enantiomers, under complementary pharmacological evaluation.
- Touzeau, Frédérique,Arrault, Axelle,Guillaumet, Gérald,Scalbert, Elizabeth,Pfeiffer, Bruno,Rettori, Marie-Claire,Renard, Pierre,Mérour, Jean-Yves
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p. 1962 - 1979
(2007/10/03)
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- Saccharide sensing molecules having enhanced fluorescent properties
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The present invention provides formulae for fluorescent compounds that have a number of properties which make them uniquely suited for use in sensors of analytes such as saccharides. The advantageous fluorescent properties include favorable excitation wav
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- Synthesis and β-glucuronidase mediated cleavage of an alcohol prodrug incorporating a double spacer moiety
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An alcohol prodrug has been prepared by incorporation of two spacer groups between the trigger (glucuronic acid) and nitroveratryl alcohol, used as a model. Release of the later has been observed after hydrolysis of the glycoside by β-glucuronidase. Such prodrugs may find application in ADEPT or PMT potocols in cancer chemotherapy.
- Papot,Rivault,Tranoy,Gesson
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p. 164 - 166
(2007/10/03)
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- A daunorubicin β-galactoside prodrug for use in conjunction with gene- directed enzyme prodrug therapy
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N-[4-(β-D-Galactopyranosyl)-3-nitrobenzyloxycarbonyl]daunomycin was synthesized as a neutral prodrug of daunomycin. Although stable in 0.05 M phosphate buffer, pH 7.4 at 37°C, it was rapidly converted to daunomycin and 3-nitro-4-hydroxybenzyl alcohol under the same conditions in the presence of E. coli β-galactosidase. (C) 2000 Elsevier Science Ltd.
- Ghosh, Ajit K.,Khan, Saeed,Marini, Frank,Nelson, J. Arly,Farquhar, David
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p. 4871 - 4874
(2007/10/03)
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- Substituent effects on the mechanism-based inactivation of prostatic acid phosphatase
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The mechanism of the inactivation of prostatic acid phosphatase (PAP) by 4-halomethylaryl phosphates, such as 4-(fluoromethyl)phenyl phosphate (FMPP), was probed by varying the benzylic leaving group and adding a nitro group to the 2 position. These studi
- Myers, Jason K.,Cohen, Jonathan D.,Widlanski, Theodore S.
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p. 11049 - 11054
(2007/10/02)
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- HETEROCYCLIC COMPOUNDS
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Compounds of Formula I are described STR1 in which X and Y are independently--NH--,--O--or--S--; Z may be a pyrimidine, triazine, triazole, thiazole, thiadiazole ring. The methods of preparation are described. The compounds are useful as antipeptic ulcer agents.
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- SELECTIVE NITRATION OF PHENOLS CATALYZED BY LANTHANUM (III) NITRATE
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Phenols are easily mononitrated at room temperature by NaNO3 in a two-phase system (water - ether) in presence of HCl and a catalytic amount of La(NO3)3.The experimental conditions leave completely unaltered many other aromatic systems.
- Ouertani, M.,Girard, P.,Kagan, H.B.
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p. 4315 - 4318
(2007/10/02)
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