- Fluorescent labeling of s2T-incorporated DNA and m5s2U-modified RNA
-
We report herein comprehensive investigations of alkylation/sulfur exchange reactions of sulfur-containing substrates including nucleosides such as s2U, m5s2U, s4U, s2A and s2T-incorporated DNA enable by comprehensive screenings of the reagents (2a–2h). It has been proven that iodoacetamide (2a) displays the most promising feasibility toward sulfur-containing substrates including s2T, s2U, m5s2U, s4U and s2A. In sharp contrast, the alkylation process with S-benzyl methanethiosulfonate (BMTS, 2h) displays the best application potential only for s4U. Based on these results, the fluorescent labeling of s2T-incorporated DNA and m5s2U-modified RNA has been achieved. Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1942044.
- Yu, Ping,Zhou, Honglin,Li, Yuanyuan,Du, Zhifeng,Wang, Rui
-
p. 754 - 766
(2021/07/06)
-
- Esterase-Responsive Polypeptide Vesicles as Fast-Response and Sustained-Release Nanocompartments for Fibroblast-Exempt Drug Delivery
-
Enzyme-responsive polypeptide vesicles have attracted considerable attention for precision theranostics because of their biocompatibility, biodegradability, and unique secondary conformation transition triggered by the catalytic actions of enzymes. These promising potentials of polypeptide vesicles could be limited in a drug delivery system by the very slow enzyme diffusion rate into vesicles that could reduce the efficacy of the drug. On the other hand, stimuli-responsive polymeric vesicles that respond to stimuli can undergo microstructure destruction for the burst release of drugs, which would penetrate through the membrane of dead cells and the tumor extracellular matrix, inducing acute toxicity to neighboring cells. Here, we designed amphiphilic PEG-polypeptide copolymers containing esterase-labile carbamate-caged primary amines. It was found that the diblock can self-assemble into vesicular structures. Esterase-triggered self-immolative decaging reactions could quickly release the primary amine moiety of monomers that can undergo an amidation reaction for transition of the bilayer of vesicles from hydrophobic to partially hydrophilic. This esterase-responsive process retains the nanostructure of vesicles but permeabilizes the vesicle membrane, which can afford the sustained release of encapsulating drugs. These esterase-responsive polypeptide vesicles mediate selective cytotoxicity in cancer cells with high esterase expression over normal fibroblasts with low esterase, enabling the potent anticancer chemotherapy with minimized side effects.
- Duan, Weihua,Ji, Sifan,Guan, Yu,Mu, Xueluer,Fang, Sha,Lu, Yingxi,Zhou, Xianfeng,Sun, Jing,Li, Zhibo
-
p. 5093 - 5103
(2020/12/02)
-
- Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1
-
Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.
- Erdmann, Frank,Günther, Stefan,Ghazy, Ehab,Hügle, Martin,Herp, Daniel,Jung, Manfred,Morales, Elizabeth R.,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Sippl, Wolfgang,Zeyen, Patrik
-
supporting information
(2020/06/03)
-
- A fluorogenic probe using a catalytic reaction for the detection of trace intracellular zinc
-
Labile zinc plays various roles in cells at low concentrations which most fluorescent probes are not able to detect. Here we report a cephem-based probe which coordinates to zinc and zinc-bound water cleaves the scaffold and releases the fluorophore. In addition, the zinc is recycled and reacts with multiple probes, amplifying the signal. This signal amplification system is useful for the detection of intracellular zinc at low concentrations and has potential for further development of probes with a similar molecular design. This journal is
- Takashima, Ippei,Inoue, Yohei,Matsumoto, Nobuyuki,Takagi, Akira,Okuda, Kensuke
-
supporting information
p. 13327 - 13330
(2020/11/10)
-
- Natural Product Evodiamine with Borate Trigger Unit: Discovery of Potent Antitumor Agents against Colon Cancer
-
In order to improve the antitumor potency of the natural product evodiamine, novel boron-containing evodiamine derivatives were designed by incorporating boronic acid and boronate as trigger units. Boronate derivative 13a could be triggered by reactive oxygen species (ROS) in the HCT116 colon cancer cell line and showed excellent antitumor activity in vitro and in vivo. It induced apoptosis in HCT116 cancer cells in a dose-dependent manner and cell growth arrest at the G2 phase.
- Li, Xinglin,Wu, Shanchao,Dong, Guoqiang,Chen, Shuqiang,Ma, Zonglin,Liu, Dan,Sheng, Chunquan
-
supporting information
p. 439 - 444
(2020/03/16)
-
- Esterase-Triggered Self-Immolative Thiocarbamates Provide Insights into COS Cytotoxicity
-
Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors is
- Levinn, Carolyn M.,Steiger, Andrea K.,Pluth, Michael D.
-
-
- Preparation method for synthesis of phenolic ester through thiocarboxylic acid mediated visible light catalyzed phenol acylation reaction
-
The invention discloses a preparation method for synthesis of phenolic ester through a thiocarboxylic acid mediated visible light catalyzed phenol acylation reaction. Thiocarboxylic acid compounds andphenol compounds are subjected to a site specific reaction under certain conditions to produce phenolic ester compounds, wherein the certain conditions are as follows: under the conditions of normaltemperature, normal pressure and visible light, K2CO3 is used as an alkaline catalyst, terpyridyl ruthenium dichloride hexahydrate is used as a photosensitizer and acetonitrile is used as a reaction solvent. Synthesis of phenolic ester under catalysis of visible light is realized, thiocarboxylic acid is used as an acylation reagent, and the site specific phenol esterification reaction is realizedefficiently under mild conditions of normal temperature, normal pressure and visible light. The method has mild reaction conditions, large substrate functional group tolerance, high applicability andhigh yield, and an efficient, reliable and economical preparation method is provided for synthesis of phenolic ester.
- -
-
Paragraph 0079; 0080; 0106; 0107; 0108
(2018/07/30)
-
- 3, 5-disubstituted hydantoin compound as well as preparation method and application thereof
-
The invention provides a 3, 5-disubstituted hydantoin compound as well as a preparation method and an application thereof. The structure of the compound is shown in formula I in the description. The application of the 3, 5-disubstituted hydantoin compound shown in the formula I or solvates, hydrates or salts of the compound in preparation of medicines for treating Alzheimer's disease, vascular dementia and other dementia diseases with memory impairment also belongs to the protection scope. Animal experiments prove that the compound has the effect of saving memory of animal models, has high safety, does not have mutagenicity, can stay in blood for several hours after oral administration and intravenous injection, and can enter the brain.
- -
-
Paragraph 0042; 0073; 0074; 0077; 0078
(2018/10/19)
-
- 4-oxo-alkylated tetramic acid compounds and preparation method thereof
-
The invention relates to novel compounds and a preparation method thereof. The general structural formula is shown as formula I in the description. Animal experiments prove that the compounds have the effect of saving memories of animal models, are high in safety, have no mutagenicity, can remain in blood for hours after oral administration and intravenous injection, can enter brains and can be used for preparing drugs for treating diseases such as Alzihemer's disease, Parkinson's disease, Huntington's disease, vascular dementia, schizophrenia, autism and the like.
- -
-
Paragraph 0100; 0101
(2017/12/09)
-
- The synthesis and antistaphylococcal activity of 9, 13-disubstituted berberine derivatives
-
A series of novel 9, 13-disubstituted berberine derivatives have been synthesized and evaluated for the antibacterial activities against Staphylococcus aureus, including Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). Compound 20 shows the most potent activity against the growth of Newman strain, with a MIC value of 0.78?μg/mL, which is comparable with the positive control vancomycin. In addition, compound 20, 21, and 33 are highly antistaphylococcal active against five strains of multidrug-resistant S.?aureus, with MIC values of 0.78–1.56?μg/mL. Of note, theses antibacterial active compounds have no obvious toxicity to the viability of human fibroblast (HAF) cells at the MIC concentration.
- Wang, Jing,Yang, Teng,Chen, Huang,Xu, Yun-Nan,Yu, Li-Fang,Liu, Ting,Tang, Jie,Yi, Zhengfang,Yang, Cai-Guang,Xue, Wei,Yang, Fan
-
p. 424 - 433
(2017/01/17)
-
- 4-oxo-alkylated tetramic acid compound as well as preparation method and application thereof
-
The invention relates to a novel compound as well as preparation method and application thereof. The structural formula of the novel compound is as shown in a formula I. Animal tests show that the compound provided by the invention has a memory effect of rescuing animal models, is high in security and free of mutagenicity induction, can be retained for hours in blood after oral taking and intravenous injection, can be fed into brains and can be used for preparing medicines for treating senile dementia, Parkinsonism, Huntington diseases, vascular dementia, schizophrenia, autism and the like.
- -
-
Paragraph 0101; 0102
(2018/01/09)
-
- Fluorescent probe used for detecting carboxylesterase and preparation method and application thereof
-
The invention belongs to the technical field of analysis and detection, and discloses a fluorescent probe used for detecting carboxylesterase and a preparation method and an application thereof. The fluorescent probe is 2-{2-[4-(4'-benzyl acetate benzyloxy-formamido)-styryl]-4H-benzopyran-4-yl}-malononitrile, and has a structural formula in a formula (I). and the fluorescent probe is used for detecting carboxylesterase. Compared with the current detection technique of fluorescence, the fluorescent probe has high selective response for carboxylesterase, strong anti-interference performance, and effective and visual detection mode, low investment cost, and simple synthesis route and method, and is suitable for enlarge production and practical application.
- -
-
Paragraph 0070; 0080; 0083; 0087
(2017/08/28)
-
- Inhibition of Octreotide Acylation Inside PLGA Microspheres by Derivatization of the Amines of the Peptide with a Self-Immolative Protecting Group
-
Acylation of biopharmaceuticals such as peptides has been identified as a major obstacle for the successful development of PLGA controlled release formulations. The purpose of this study was to develop a method to inhibit peptide acylation in poly(d,l-lac
- Shirangi, Mehrnoosh,Najafi, Marzieh,Rijkers, Dirk T. S.,Kok, Robbert Jan,Hennink, Wim E.,Van Nostrum, Cornelus F.
-
p. 576 - 585
(2016/04/05)
-
- A selective and mild glycosylation method of natural phenolic alcohols
-
Several bioactive natural p-hydroxyphenylalkyl β-D-glucopyranosides, such as vanillyl β-D-glucopyranoside, salidroside and isoconiferin, and their glycosyl analogues were prepared by a simple reaction sequence. The highly efficient synthetic approach was achieved by utilizing acetylated glycosyl bromides as well as aromatic moieties and mild glycosylation promoters. The aglycones, p-O-acetylated arylalkyl alcohols, were prepared by the reduction of the corresponding acetylated aldehydes or acids. Various stereoselective 1,2-trans-O-glycosylation methods were studied, including the DDQ-iodine or ZnO-ZnCl2 catalyst combination. Among them, ZnO-iodine has been identified as a new glycosylation promoter and successfully applied to the stereoselective glycoside synthesis. The final products were obtained by conventional Zemplén deacetylation.
- Mastihubová, Mária,Poláková, Monika
-
supporting information
p. 524 - 530
(2016/04/08)
-
- Luminogenic and fluorogenic compounds and methods to detect molecules or conditions
-
A method to detect the presence or amount of at least one molecule in a sample which employs a derivative of luciferin or a derivative of a fluorophore is provided.
- -
-
Paragraph 0394; 0395; 0397
(2016/07/27)
-
- Novel quinazoline derivative LU1507 as well as preparation method and application thereof
-
The invention discloses a novel quinazoline derivative LU1507 as well as a preparation method thereof. The quinazoline derivative LU1507 is chemically named 4-{4-[(7-methoxy)-6-[2-pyrrrolidine-1-yl)hydroxyethyl]quinazoline-4-yl}aminophenyl amino methylphenol. The quinazoline derivative as well as pharmaceutically acceptable salts, solvates and hydrates thereof has excellent in-vitro and in-vivo anti-tumor activity for MCF-7, SK-BR-3, A549, HCT 116, A172 and U-87 MG and has brighter application prospect in preparation of anti-tumor drugs.
- -
-
Paragraph 0036; 0037; 0038; 0039
(2016/10/10)
-
- Novel quinazoline derivative LU1508, and preparation method and application thereof
-
The invention discloses a novel quinazoline derivative LU1508, and a preparation method thereof. The chemical name of the derivative is 4[{4-[(7-methoxy)-6-(1-pyrrolyl-2-yl)hydroxyethyl]quinazolinyl-4-yl}aminophenylaminomethylphenol. The quinazoline deriv
- -
-
Paragraph 0039; 0040
(2016/11/09)
-
- In situ activation of benzyl alcohols with XtalFluor-E: Formation of 1,1-diarylmethanes and 1,1,1-triarylmethanes through Friedel-Crafts benzylation
-
The Friedel-Crafts benzylation of arenes using benzyl alcohols activated in situ with XtalFluor-E is described. A wide range of 1,1-diarylmethanes and 1,1,1-triarylmethanes were prepared under experimentally simple and mild conditions, without the need for a transition metal or a strong Lewis acid. Notably, the reactivity observed demonstrates the potential of XtalFluor-E to induce C-OH bond ionization and SN1 reactivity of benzylic alcohols. This journal is
- Desroches, Justine,Champagne, Pier Alexandre,Benhassine, Yasmine,Paquin, Jean-Franois
-
supporting information
p. 2243 - 2246
(2015/03/04)
-
- COMPOUNDS USEFUL IN THE TREATMENT OF NEOPLASTIC DISEASES
-
The present invention refers to compounds of formula: (formula A), wherein R1 is selected from (formula I), (formula II), (formula (III), (formula IV), (formula V), or (formula B), and wherein R2, R3, R4 and Rs
- -
-
Page/Page column 33
(2015/04/15)
-
- Chloride transport activities of trans- and cis-amide-linked bisureas
-
Of the bisurea compounds linked through trans- and cis-benzanilide spacers, the cis-amide derivatives were found to be effective in chloride transport, using which a stimuli-responsive mobile carrier was devised. This journal is
- Park, Eun Bit,Jeong, Kyu-Sung
-
supporting information
p. 9197 - 9200
(2015/06/02)
-
- Dual enzyme-responsive "turn-on" fluorescence sensing systems based on in situ formation of 7-hydroxy-2-iminocoumarin scaffolds
-
A new strategy for the simultaneous fluorogenic detection of two distinct enzyme activities namely hydrolase (amidase or esterase) and reductase is described. This innovative biosensing method is based on the powerful "covalent-assembly" principle that in
- Debieu, Sylvain,Romieu, Anthony
-
supporting information
p. 10348 - 10361
(2015/10/28)
-
- Compositions and methods for treating viral infections
-
The present invention provides compositions methods for treating susceptible viral infections, especially hepatitis C viral (HCV) infections as well as co infections of HCV with other viruses such as HBV and/or HIV. In one embodiment, the present inventio
- -
-
Page/Page column 39
(2015/10/28)
-
- Friedel-crafts reaction of benzyl fluorides: Selective activation of C-f bonds as enabled by hydrogen bonding
-
A Friedel-Crafts benzylation of arenes with benzyl fluorides has been developed. The reaction produces 1,1-diaryl alkanes in good yield under mild conditions without the need for a transition metal or a strong Lewis acid. A mechanism involving activation of the C-F bond through hydrogen bonding is proposed. This mode of activation enables the selective reaction of benzylic C-F bonds in the presence of other benzylic leaving groups.
- Champagne, Pier Alexandre,Benhassine, Yasmine,Desroches, Justine,Paquin, Jean-Franois
-
supporting information
p. 13835 - 13839
(2015/02/05)
-
- Palladium-catalyzed carboxylative coupling of benzyl chlorides with allyltributylstannane: Remarkable effect of palladium nanoparticles
-
Palladium-catalyzed carboxylative coupling of benzyl chlorides with allyltributylstannane was successfully conducted to produce benzyl but-3-enoates in satisfactory to good yields. The carboxylative coupling reaction occurred smoothly under mild conditions in the presence of palladium nanoparticles in tetrahydrofuran.
- Feng, Xiujuan,Sun, Anle,Zhang, Sheng,Yu, Xiaoqiang,Bao, Ming
-
supporting information
p. 108 - 111
(2013/04/10)
-
- Identification of a marine NADPH-dependent aldehyde reductase for chemoselective reduction of aldehydes
-
A putative aldehyde reductase gene from Oceanospirillum sp. MED92 was overexpressed in Escherichia coli. The recombinant protein (OsAR) was characterized as a monomeric NADPH-dependent aldehyde reductase. The kinetic parameters Km and kcat of OsAR were 0.89 ± 0.08 mM and 11.07 ± 0.99 s-1 for benzaldehyde, 0.04 ± 0.01 mM and 6.05 ± 1.56 s-1 for NADPH, respectively. This enzyme exhibited high activity toward a variety of aromatic and aliphatic aldehydes, but no activity toward ketones. As such, it catalyzed the chemoselective reduction of aldehydes in the presence of ketones, as demonstrated by the reduction of 4-acetylbenzaldehyde or the mixture of hexanal and 2-nonanone, showing the application potential of this marine enzyme in such selective reduction of synthetic importance.
- Li, Guangyue,Ren, Jie,Wu, Qiaqing,Feng, Jinhui,Zhu, Dunming,Ma, Yanhe
-
-
- Regio- and chemoselective palladium-catalyzed benzylallylation of activated olefins: The remarkable effect of palladium nanoparticles
-
The palladium-catalyzed three-component reactions of benzyl halides, activated olefins, and allyltributylstannane were successfully conducted to produce the corresponding benzylallylation products in satisfactory to high yields. The benzylallylation reaction proceeded smoothly under mild conditions in the presence of palladium nanoparticles in tetrahydrofuran. The Royal Society of Chemistry 2013.
- Zhang, Xuan,Feng, Xiujuan,Yu, Xiaoqiang,He, Ren,Bao, Ming
-
p. 4016 - 4024
(2013/07/05)
-
- Selective acylation of the phenolic hydroxyl of (hydroxyalkyl)phenols by using vinyl carboxylates as acyl donors in the presence of rubidium fluoride
-
Highly selective acylation of the phenolic hydroxy group can be achieved with (hydroxyalkyl)phenols carrying both alcoholic and phenolic hydroxyls by the use of vinyl carboxylates as acyl donors in the presence of rubidium fluoride.
- Miyazawa, Toshifumi,Yamamoto, Masato,Danjo, Hiroshi
-
p. 1351 - 1354
(2013/10/01)
-
- Aminoferrocene-based prodrugs and their effects on human normal and cancer cells as well as bacterial cells
-
Aminoferrocene-based prodrugs are activated under cancer-specific conditions (high concentration of reactive oxygen species, ROS) with the formation of glutathione scavengers (p-quinone methide) and ROS-generating iron complexes. Herein, we explored three structural modifications of these prodrugs in an attempt to improve their properties: (a) the attachment of a -COOH function to the ferrocene fragment leads to the improvement of water solubility and reactivity in vitro but also decreases cell-membrane permeability and biological activity, (b) the alkylation of the N-benzyl residue does not show any significant affect, and (c) the attachment of the second arylboronic acid fragment improves the toxicity (IC50) of the prodrugs toward human promyelocytic leukemia cells (HL-60) from 52 to 12 μM. Finally, we demonstrated that the prodrugs are active against primary chronic lymphocytic leukemia (CLL) cells, with the best compounds exhibiting an IC50 value of 1.5 μM. The most active compounds were found to not affect mononuclear cells and representative bacterial cells.
- Marzenell, Paul,Hagen, Helen,Sellner, Leopold,Zenz, Thorsten,Grinyte, Ruta,Pavlov, Valeri,Daum, Steffen,Mokhir, Andriy
-
p. 6935 - 6944
(2013/10/01)
-
- Redox-selective generation of aldehydes and H2 from alcohols under visible light
-
Photosynthetic dehydrogenation: Potential usefulness of visible-light-induced dehydrogenation of alcohols in organic synthesis was demonstrated, in which aldehydes and H2 were afforded by using Ru/SrTiO3:Rh and water (see scheme). Water was essential for the reaction. High efficiency (TON: up to 15 400 based on Rh; H2 and aldehyde evenly generated) and high selectivity were achieved. Copyright
- Liu, Zijun,Caner, Joaquim,Kudo, Akihiko,Naka, Hiroshi,Saito, Susumu
-
supporting information
p. 9452 - 9456
(2013/07/26)
-
- FERROCENE-BASED COMPOUNDS AND THEIR USE AS ROS REGULATING PRODRUGS
-
The present invention relates to ferrocene-based compounds and their use as ROS (reactive oxygen species) regulating prodrugs. In particular, the present invention relates to ferrocene-based compounds which upon activation react as ROS regulating prodrugs
- -
-
Page/Page column 27-28
(2012/10/07)
-
- Indium tri(isopropoxide)-catalyzed selective Meerwein-Ponndorf-Verley reduction of aliphatic and aromatic aldehydes
-
Indium tri(isopropoxide)-catalyzed Meerwein-Ponndorf-Verley reduction of aliphatic and aromatic aldehydes in 2-propanol gave selectively the corresponding primary alcohols in good to excellent yields at room temperature. A wide range of functional groups including alkene, ether, ketone, ester, nitrile, and nitro were tolerated under the optimum reaction conditions. Chemoselective reductions were also achieved not only between aromatic aldehyde, aromatic ketone, and epoxide but also between aliphatic aldehyde and alkene.
- Lee, Jaeyoung,Ryu, Taekyu,Park, Sangjune,Lee, Phil Ho
-
supporting information; experimental part
p. 4821 - 4825
(2012/07/03)
-
- The catalytic promiscuity of a microbial 7α-hydroxysteroid dehydrogenase. Reduction of non-steroidal carbonyl compounds
-
A thermostable 7α-hydroxysteroid dehydrogenase from Bacteroides fragilis ATCC 25285 was found to catalyze the reduction of various benzaldehyde analogues to their corresponding benzyl alcohols. The enzyme activity was dependent upon the substituent on the benzene ring of the substrates. Benzaldehydes with electron-withdrawing substituent usually showed higher activity than those with electron-donating groups. Furthermore, this enzyme was tolerant to some organic solvents. These results together with previous studies suggested that 7α-hydroxysteroid dehydrogenase from B. fragilis might play multiple functional roles in biosynthesis and metabolism of bile acids, and in the detoxification of xenobiotics containing carbonyl groups in the large intestine. In addition, its broad substrate spectrum offers great potential for finding applications not only in the synthesis of steroidal compounds of pharmaceutical importance, but also for the production of other high-value fine chemicals.
- Liu, Yang,Lv, Tong,Ren, Jie,Wang, Min,Wu, Qiaqing,Zhu, Dunming
-
experimental part
p. 1136 - 1140
(2011/08/22)
-
- Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-Diaminopyridine prodrug design and characterization
-
Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K+ channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over butyrylcholinesterase-a plasma-based high activity esterase. Future in vivo studies could provide validation of prodrug 32 as a potential treatment against BoNT intoxication as well as other neuromuscular disorders.
- Zakhari, Joseph S.,Kinoyama, Isao,Hixon, Mark S.,Di Mola, Antonia,Globisch, Daniel,Janda, Kim D.
-
supporting information; experimental part
p. 6203 - 6209
(2011/12/02)
-
- Synthesis and biological activity of acetyl-protected hydroxybenzyl diethyl phosphates (EHBP) as potential chemotherapeutic agents
-
Several acetyl-protected hydroxybenzyl diethyl phosphates (EHBPs) that are capable of forming quinone methide intermediates were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. Compounds 1, 1a, and 1b, corresponding to (4-acetyloxybenzyl diethylphosphate), (3-methyl-4-acetyloxybenzyl diethylphosphate), and (3-chloro-4-acetyloxybenzyl diethylphosphate), were significantly more potent than compounds 2 and 3, (2-acetyloxybenzyl diethylphosphate) and (3-acetyloxybenzyl diethylphosphate), respectively. Using HT-29 human colon cancer cells, compounds 1 and 3 increased apoptosis, inhibited proliferation, and caused a G2/M block in the cell cycle. Our data suggest that these compounds merit further investigation as potential anti-cancer agents.
- Kodela, Ravinder,Chattopadhyay, Mitali,Nath, Niharika,Cieciura, Lucyna Z.,Pospishill, Liliya,Boring, Daniel,Crowell, James A.,Kashfi, Khosrow
-
scheme or table
p. 7146 - 7150
(2012/01/13)
-
- PHOSPHONATED RIFAMYCINS AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
-
The present invention relates to phosphonated Rifamycins, and methods of making and using such compounds. These compounds are useful as antibiotics for prophylaxis and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
- -
-
Page/Page column 117
(2010/04/03)
-
- Hydroxybenzyl or hydroxypyranonemethyl esters as tyrosinase inhibitors
-
Method for the preparation of ester compounds for use as skin brightening agents and compositions for brightening skin containing the ester compounds.
- -
-
Page/Page column 7
(2009/01/20)
-
- Bioreversible protection of nucleoside diphosphates
-
(Figure Presented) Going incognito: A new prodrug approach has been developed to facilitate the diffusion of highly polar polyphosphorylated nucleosides across cell membranes (see scheme). Inside the cell, the masking groups on the nucleoside diphosphate
- Jessen, Henning Jacob,Schulz, Tilmann,Balzarini, Jan,Meier, Chris
-
supporting information; experimental part
p. 8719 - 8722
(2009/05/15)
-
- METHODS, COMPOUNDS, COMPOSITIONS AND VEHICLES FOR DELIVERING 3-AMINO-1-PROPANESULFONIC ACID
-
The invention relates to methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid (3APS) in a subject, preferably a human subject. The invention encompasses compounds that will yield or generate 3APS, either in vitro or in vivo. Preferred compounds include amino acid prodrugs of 3APS for use, including but not limited to, the prevention and treatment of Alzheimer's disease.
- -
-
Page/Page column 43-44
(2008/12/06)
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- Chemical insights in the concept of hybrid drugs: The antitumor effect of nitric oxide-donating aspirin involves a quinone methide but not nitric oxide nor aspirin
-
Hybrid drug 1 (NO-ASA) continues to attract intense research from chemists and biologists alike. It consists of ASA and a -ONO2 group connected through a spacer and is in preclinical development as an antitumor drug. We report that, contrary to current beliefs, neither ASA nor NO contributes to this antitumor effect. Rather, an unsubstituted QM was identified as the sole cytotoxic agent. QM forms from 1 after carboxylic ester hydrolysis and, in accordance with the HSAB theory, selectively reacts with cellular GSH, which in turn triggers cell death. Remarkably, a derivative lacking ASA and the -ONO 2 group is 10 times more effective than 1. Thus, our data provide a conclusive molecular mechanism for the antitumor activity of 1. Equally importantly, we show for the first time that a "presumed invisible" linker in a hybrid drug is not so invisible after all and is in fact solely responsible for the biological effect.
- Hulsman, Niels,Medema, Jan Paul,Bos, Carina,Jongejan, Aldo,Leurs, Rob,Smit, Martine J.,De Esch, Iwan J. P.,Richel, Dick,Wijtmans, Maikel
-
p. 2424 - 2431
(2008/02/03)
-
- Nucleotide and oligonucleotide prodrugs
-
The present invention discloses compounds of formula (I): which exhibit antiviral properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of anti-HBV
- -
-
Page/Page column 24
(2008/06/13)
-
- Sulfurated borohydride exchange resin: A novel reagent for selective reduction of aldehydes
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Selective reduction of aldehydes is carried out by using sulfurated borohydride exchange resin as a novel reducing reagent. Other sensitive groups like F, Cl, Br, NO2, CN, OMe, ester and methylenedioxy remain intact under these reaction conditions. The isolation of pure products by simple filtration and evaporation is an important feature of this method.
- Bandgar,Kamble
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p. 3037 - 3040
(2007/10/03)
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- Chemoenzymatic synthesis of N-Ras lipopeptides
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For the study of biological phenomena influenced by the plasma-membrane- bound Ras proteins and other lipidated proteins, characteristic peptides which embody the correct lipid modifications of their parent proteins (palmitoyl thioesters and farnesyl thio
- N?gele, Edgar,Schelhaas, Michael,Kuder, Norman,Waldmann, Herbert
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p. 6889 - 6902
(2007/10/03)
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- Thiadiazole derivatives for the treatment of depressive states
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Thiadiazole derivatives of general formula (I) wherein R1 is selected from the class consisting of: C1-C10 linear or branched alkyl, benzyl, optionally substituted at the aromatic ring with one or more groups se
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- SELECTIVE DESILYLATION OF PHENOLIC AND ALCOHOLIC TRIMETHYLSILYL ETHERS
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A quaternary ammonium resin ( phenolated HO form ) and a carboxylate resin ( H form ) will selectively remove phenolic and alcoholic trimethylsilyl group, respectively, under controlled conditions.
- Kawazoe, Yutaka,Nomura, Makoto,Kondo, Yumiko,Kohda, Kohfuku
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p. 4307 - 4310
(2007/10/02)
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- SELECTIVE ACYLATIONS OF AMINOPHENOLS AND HYDROXYALKYLPHENOLS WITH 1-ACETYL-v-TRIAZOLOPYRIDINE.
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The title triazolide serves as a convenient reagent for highly chemoselective acetylations of aminophenols and hydroxyalkylphenols.
- Paradisi, Mario Paglialunga,Zecchini, Giampiero Pagani,Torrini, Ines
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p. 5029 - 5032
(2007/10/02)
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- A USEFUL METHOD FOR SELECTIVE ACYLATION OF ALCOHOLS USING 2,2'-BIPYRIDYL-6-YL CARBOXYLATE AND CESIUM FLUORIDE
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Primary and secondary alcohols are acylated under mild conditions by the of use 2,2'-bipyridyl-6-yl carboxylates and cesium fluoride.Furthermore, the reaction is successfully applied to selective acylation of a primary carbinol group of diols containing primary and secondary carbinol groups or exclusive O-acylation of aromatic amino alcohols.
- Mukaiyama, Teruaki,Pai, Fong-Chang,Onaka, Makoto,Narasaka, Koichi
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p. 563 - 566
(2007/10/02)
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