cas 57561-39-4, (2-HYDROXYETHYL)METHYLCARBAMIC ACID 1,1-DIMETHYLETHYL ESTER

Articles about 57561-39-4Total 87 be found

Article title
Article abstract
Author
Journal number and time
Download

Cationic amphiphilic non-hemolytic polyacrylates with superior antibacterial activity
Acrylic copolymers with appropriate compositions of counits having cationic charge with 2-carbon and 6-carbon spacer arms can show superior antibacterial activities with concomitant very low hemolytic effect. These amphiphilic copolymers represent one of the most promising synthetic polymer antibacterial systems reported. the Partner Organisations 2014.
Punia, Ashish,He, Edward,Lee, Kevin,Banerjee, Probal,Yang, Nan-Loh
p. 7071 - 7074
(2014)
Read Online

A new delivery system for auristatin in STxB-drug conjugate therapy
A key challenge in anticancer therapy is to gain control over the biodistribution of cytotoxic drugs. The most promising strategy consists in conjugating drugs to tumor-targeting carriers, thereby combining high cytotoxic activity and specific delivery. To target Gb3-positive cancer cells, we exploit the non-toxic B-subunit of Shiga toxin (STxB). Here, we have conjugated STxB to highly potent auristatin derivatives (MMA). A former linker was optimized to ensure proper drug-release upon reaching reducing environments in target cells, followed by a self-immolation step. Two conjugates were successfully obtained, and in vitro assays demonstrated the potential of this targeting system for the selective elimination of Gb3-positive tumors.
Batisse, Cornélie,Dransart, Estelle,Ait Sarkouh, Rafik,Brulle, Laura,Bai, Siau-Kun,Godefroy, Sylvie,Johannes, Ludger,Schmidt, Frédéric
p. 483 - 491
(2015)
Read Online

A systematic study of protein labeling by fluorogenic probes using cysteine targeting vinyl sulfone-cyclooctyne tags
Fluorescent tagging of proteins via accessible cysteine residues is of paramount importance. In this study, model proteins of interest (mitogen-activated protein kinases) were labeled successfully in native state on their free thiols by direct fluorescenc
S?veges,Imre,Szende,Póti,Cserép,Hegedus,Kele,Németh
p. 6071 - 6078
(2016)
Read Online

Beyond Gene Transfection with Methacrylate-Based Polyplexes - The Influence of the Amino Substitution Pattern
Methacrylate-based polymers represent promising nonviral gene delivery vectors, since they offer a large variety of polymer architectures and functionalities, which are beneficial for specific demands in gene delivery. In combination with controlled radical polymerization techniques, such as the reversible addition-fragmentation chain transfer polymerization, the synthesis of well-defined polymers is possible. In this study we prepared a library of defined linear polymers based on (2-aminoethyl)-methacrylate (AEMA), N-methyl-(2-aminoethyl)-methacrylate (MAEMA), and N,N-dimethyl-(2-aminoethyl)-methacrylate (DMAEMA) monomers, bearing pendant primary, secondary, and tertiary amino groups, and investigated the influence of the substitution pattern on their gene delivery capability. The polymers and the corresponding plasmid DNA complexes were investigated regarding their physicochemical characteristics, cytocompatibility, and transfection performance. The nonviral transfection by methacrylate-based polyplexes differs significantly from poly(ethylene imine)-based polyplexes, as a successful transfection is not affected by the buffer capacity. We observed that polyplexes containing a high content of primary amino groups (AEMA) offered the highest transfection efficiency, whereas polyplexes bearing tertiary amino groups (DMAEMA) exhibited the lowest transfection efficiency. Further insights into the uptake and release mechanisms could be identified by fluorescence and transmission electron microscopy, emphasizing the theory of membrane-pore formation for the time-efficient endosomal release of methacrylate-based vectors.
Trützschler, Anne-Kristin,Bus, Tanja,Reifarth, Martin,Brendel, Johannes C.,Hoeppener, Stephanie,Traeger, Anja,Schubert, Ulrich S.
p. 2181 - 2194
(2018)
Read Online

The Power of Shielding: Low Toxicity and High Transfection Performance of Cationic Graft Copolymers Containing Poly(2-oxazoline) Side Chains
We show the potential of oligo(2-ethyl-2-oxazoline) (Oxn)-shielded graft copolymers of (2-aminoethyl)-methacrylate and N-methyl-(2-aminoethyl)-methacrylate for pDNA delivery in HEK cells. For the effect of grafting density and side chain length concerning improved transfection properties through the concept of shielding to be investigated, copolymers were synthesized via the macromonomer method using a combination of cationic ring opening polymerization and reversible addition-fragmentation chain transfer polymerization to vary the degree of grafting (DG = 10 and 30%) as well as the side chain degree of polymerization (DP = 5 and 20). Investigations of the polyplex formation, in vitro flow cytometry, and confocal laser scanning microscopy measurements on the copolymer library revealed classical shielding properties of the Ox side chains, including highly reduced cytotoxicity and a partial decrease in transfection efficiency, as also reported for polyethylene glycol shielding. In terms of the transfection efficiency, the best performing copolymers (A-g-Ox5(10) and M-g-Ox5(10)) revealed equal or better performances compared to those of the corresponding homopolymers. In particular, the graft copolymers with low DG and side chain DP transfected well with over 10-fold higher IC50 values. In contrast, a DG of 30% resulted in a loss of transfection efficiency due to missing ability for endosomal release, and a side chain DP of 20 hampered the cellular uptake.
Trützschler, Anne-Kristin,Bus, Tanja,Sahn, Martin,Traeger, Anja,Weber, Christine,Schubert, Ulrich S.
p. 2759 - 2771
(2018)
Read Online

Kras-G12C inhibitor heterocyclic compounds
The invention relates to Kras-G12C inhibitor heterocyclic compounds represented by formula I, a preparation method thereof, and application of the Kras-G12C inhibitor heterocyclic compounds in prevention and treatment of tumor diseases such as lung cancer, colorectal cancer and pancreatic cancer. In the preparation process, the compounds of the general formula I are obtained through a series of reactions such as SN2 reaction, protection, coupling reaction, deprotection, condensation reaction and the like.
-
Paragraph 0626-0632

(2021/06/23)

Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif
Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to μM concentrations), they must also be able to resist non-specific triggering by the ca. 50 mM background of non-catalytic cellular monothiols. However, no such selective reduction-sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature-known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols yet high selectivity for the key redox-Active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. We also anticipate that further tuning following this design paradigm will enable redox probes for other important dithiol-manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.
Becker, Katja,Busker, Sander,Felber, Jan G.,Maier, Martin S.,Poczka, Lena,Scholzen, Karoline,Theisen, Ulrike,Thorn-Seshold, Julia,Thorn-Seshold, Oliver,Zeisel, Lukas,Arnér, Elias S. J.,Brandst?dter, Christina
supporting information
p. 8791 - 8803
(2021/06/27)

CGRP ANTAGONIST COMPOUNDS
The disclosures herein relate to novel compounds of Formula (1): and salts thereof, wherein A1, A2, Q, X, R1, R2 and R3 are defined herein, and their use in treating, preventing, ameliorating, control
-
Page/Page column 51

(2020/12/30)

NOVEL MACROCYCLIC DERIVATIVES, PROCESS FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
Compound of formula (I): wherein A1, A2, Ra, Rb, Rc, Rd, R3, R4, X, Y and G are as defined in the description, and their use in the manufacture of medicaments.
-
Paragraph 0491-0493

(2020/08/25)

Hierarchically assembled helicates as reaction platform – from stoichiometric Diels–Alder reactions to enamine catalysis
The stereoselectivity of a Diels–Alder reaction within the periphery of hierarchically assembled titanium(IV) helicates formed from mixtures of achiral, reactive and chiral, unreactive ligands was investigated in detail. Following the pathway of the chiral induction, the chiral ligands, solvents as well as substituents at the dienophile were carefully varied. Based on the results of the stoichiometric reaction, a secondary amine-catalyzed nitro-Michael reaction is performed as well which afforded reasonable diastereoselectivities.
Albrecht, Markus,Begall, Jenny,Craen, David Van,Gro?kurth, Johannes,Himmel, Leonard,Isaak, Elisabeth,Linnenberg, Oliver
supporting information
p. 2338 - 2345
(2020/11/02)

7-SUBSTITUTED SULFONIMIDOYLPURINONE COMPOUNDS AND DERIVATIVES FOR THE TREATMENT AND PROPHYLAXIS OF LIVER CANCER
The present invention relates to compounds of formula (I), wherein R1, R2 and R3 are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for (use in) the treatment and/or prophylaxis of liver cancer.
-
Paragraph 0887-0888

(2020/09/09)

HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic compounds as Wee1 inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
-
Paragraph 0537-0539

(2019/04/25)

Structure-Activity Relationships of Fish Oil Derivatives with Antiallergic Activity in Vitro and in Vivo
A series of unsaturated fatty acids in fish oil and their corresponding ethanolamide metabolites were explored to find active fish oil components of antiallergic activity in vitro. Ethanolamides of omega-3 fatty acids (α-linolenic acid, EPA, and DHA) were found to possess promising antiallergic activity, whereas free fatty acids and ethanolamides of other fatty acids exhibited no or weak potency. Based on this finding, structure-activity relationships of DHA-ethanolamide (DHEA) derivatives were investigated to yield better fatty acid derivatives with enhanced antiallergic activity in vitro and in vivo. When the ethanolamide moiety of DHEA was replaced by the substituted sulfonamide functionality, highly promising potency was provided in vitro. Compound 59 showed improved antiallergic activity in vivo over DHEA. The results indicate that optimized DHEA derivatives have enhanced antiallergic activity in vitro and in vivo, and the resulting structures will be an important basis for further development of bioavailable derivatives with promising allergy suppressive activity.
Kim, In-Hae,Kanayama, Yoshiki,Nishiwaki, Hisashi,Sugahara, Takuya,Nishi, Kosuke
p. 9576 - 9592
(2019/11/11)

Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents
On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.
Kim, Ho Shin,Hoang, Van-Hai,Hong, Mannkyu,Chul Kim, Kyung,Ann, Jihyae,Nguyen, Cong-Truong,Seo, Ji Hae,Choi, Hoon,Yong Kim, Jun,Kim, Kyu-Won,Sub Byun, Woong,Lee, Sangkook,Lee, Seungbeom,Suh, Young-Ger,Chen, Jie,Park, Hyun-Ju,Cho, Tae-Min,Kim, Ji Young,Seo, Jae Hong,Lee, Jeewoo
supporting information
p. 1370 - 1381
(2019/03/04)

Camptothecin-antibody conjugate
The invention discloses a camptothecin-antibody conjugate. The category of ADC (Antibody-Drug Conjugate) drugs can be used for effectively improving the drug load, meanwhile, the above aggregation phenomenon is avoided, drug PK (pharmacokinetics) is impro
-
Paragraph 0141; 0142; 0143; 0144

(2019/01/14)

7-SUBSTITUTED SULFONIMIDOYLPURINONE COMPOUNDS AND DERIVATIVES FOR THE TREATMENT AND PROPHYLAXIS OF LIVER CANCER
The present invention relates to compounds of formula (I), wherein R1, R2 and R3 are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, for (use in) the treatment and/or prophylaxis of liver cancer.
-
Page/Page column 93-95; 97; 99; 101

(2019/09/18)

NOVEL TRIAZINE COMPOUND, ALL-SOLID-STATE POLYMER ELECTROLYTE COMPOSITION AND USE THEREOF
The present invention relates to a novel triazine compound represented by chemical formula 1, an all-solid-state polymer electrolyte composition comprising the same as a cross-linking agent and uses thereof. More specifically, the triazine compound effectively inhibits crystallization of a plasticizer at a low temperature (room temperature) to show significantly improved ion conductivity, and can realize significantly improved electrochemical stability and excellent battery properties, thereby being usefully used as an all-solid-state polymer electrolyte composition such as a lithium-polymer secondary battery, a dye-sensitized solar cell, etc.COPYRIGHT KIPO 2018
-
Paragraph 0160; 0165-0167

(2018/04/12)

Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
Song, Lijun,Merceron, Romain,Gracia, Bego?a,Quintana, Ainhoa Lucía,Risseeuw, Martijn D. P.,Hulpia, Fabian,Cos, Paul,Aínsa, José A.,Munier-Lehmann, Hélène,Savvides, Savvas N.,Van Calenbergh, Serge
p. 2753 - 2775
(2018/04/23)

7-SUBSTITUTED SULFONIMIDOYLPURINONE COMPOUNDS FOR THE TREATMENT AND PROPHYLAXIS OF VIRUS INFECTION
The present invention relates to compounds of formula (I), wherein R1, R2 and R3 are as described herein, and their prodrugs or pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds as TLR7 agonists for the treatment of viral infections.
-
Page/Page column 45

(2018/03/25)

Mission ImPOxable-or the unknown utilization of non-toxic poly(2-oxazoline)s as cryoprotectants and surfactants at the same time
Polymer based nanoparticles offer great opportunities for diverse applications, i.e. their drug delivery potential is promising. However, their major drawback is identified in preparation via the nanoemulsion technique, which is needed for the encapsulation of hydrophilic drugs and whereby the utilization of surfactants, e.g. poly(vinyl alcohol) (PVA), is mandatory. Furthermore, the preparation of nanoparticles is critical due to the need of lyophilization for storage. For this reason it is common to use cryoprotectants, which are usually sugar based. In the current study, we present the use of non-toxic, water-soluble poly(2-oxazoline)s (P(Ox)s) in terms of polymeric nanoparticle stabilizers for preparation, purification, and lyophilization. The nanoparticles were characterized via dynamic light scattering (DLS) and cryo-transmission electron microscopy (cryoTEM). The use of hydrophilic P(Ox)s with a degree of polymerization of about 60 yielded stable nanoparticles. For the preparation via nanoemulsion a PDI below 0.2 could be obtained after adjustment of the surfactant concentration. All nanoparticles were in the size range of 100 to 200 nm according to DLS. Furthermore, the addition of P(Ox) was beneficial during particle purification via centrifugation and filtration as well as lyophilization, yielding nanoparticles with a PDI below 0.3 as determined via DLS and confirmed via cryoTEM measurements. Cytotoxicity, hemolysis and erythrocyte aggregation measurements of these P(Ox)s did not show any harmful effect on the treated cells.
Leiske, Meike N.,Trützschler, Anne-Kristin,Armoneit, Sabine,Sungur, Pelin,Hoeppener, Stephanie,Lehmann, Marc,Traeger, Anja,Schubert, Ulrich S.
supporting information
p. 9102 - 9113
(2017/12/08)

FREE-STANDING NON-FOULING POLYMERS, THEIR COMPOSITIONS, AND RELATED MONOMERS
Free-standing non-fouling polymers and polymeric compositions, monomers and macromonomers for making the polymers and polymeric compositions, objects made from the polymers and polymeric compositions, and methods for making and using the polymers and polymeric compositions.
-
Page/Page column 52

(2017/01/23)

NEW SUBSTITUTED CYANOINDOLINE DERIVATIVES AS NIK INHIBITORS
The present invention relates to pharmaceutical agents of formula (I) useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF- KB-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
-
Page/Page column 270

(2017/08/20)

POLYFLUORINATED COMPOUNDS ACTING AS BRUTON TYROSINE KINASE INHIBITORS
Described herein is a novel series of multi-fluoro-substituted pyrazolopyrimidine compounds or salts thereof. These compounds are Bruton's tyrosine kinase (BTK) inhibitors. These compounds may possess better BTK inhibition selectivity and pharmacokinetic properties. Disclosed herein are the synthesis methods of these compounds. Disclosed herein are novel synthesis methods of the multi-fluoro-substituted benzophenone and substituted phenoxy benzene. Also disclosed are pharmaceutical compositions comprising the BTK inhibitors described herein. The present invention also relates to pharmaceutical formulations comprising the compounds described herein as active ingredients. The present invention also includes the therapeutic methods by administering the BTK inhibitors and their formulations to treat and inhibit autoimmune disease, hypersensitivity disease, inflammatory diseases and cancer.
-
Paragraph 0792; 0793

(2016/08/17)

Design, synthesis and antimalarial evaluation of novel thiazole derivatives
As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.
Bueno, José María,Carda, Miguel,Crespo, Benigno,Cu?at, Ana Carmen,de Cozar, Cristina,León, María Luisa,Marco, J. Alberto,Roda, Nuria,Sanz-Cervera, Juan F.
supporting information
p. 3938 - 3944
(2016/08/01)

CONTROLLED RELEASE PREPARATION
A controlled release preparation wherein the release of active ingredient is controlled, which releases an active ingredient for an extended period of time by staying or slowly migrating in the gastrointestinal tract, is provided by means such as capsulating a tablet, granule or fine granule wherein the release of active ingredient is controlled and a gel-forming polymer. Said tablet, granule or fine granule has a release-controlled coating-layer formed on a core particle containing an active ingredient.
-
Paragraph 0384; 0385; 0386

(2016/06/06)

Design, synthesis, and biological evaluation of simplified side chain hybrids of the potent actin binding polyketides rhizopodin and bistramide
The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure-activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin-inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin-bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin-bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.
Herkommer, Daniel,Dreisigacker, Sandra,Sergeev, Galina,Sasse, Florenz,Gohlke, Holger,Menche, Dirk
p. 470 - 489
(2015/04/21)

Cyclic comonomers for the synthesis of carboxylic acid and amine functionalized poly(L-lactic acid)
Degradable aliphatic polyesters such as poly(lactic acid) are widely used in biomedical applications, however, they lack functional moieties along the polymer backbone that are amenable for functionalization reactions or could be the basis for interactions with biological systems. Here we present a straightforward route for the synthesis of functional α-ω epoxyesters as comonomers for lactide polymerization. Salient features of these highly functionalized epoxides are versatility in functionality and a short synthetic route of less than four steps. The α-ω epoxyesters presented serve as a means to introduce carboxylic acid and amine functional groups into poly(lactic acid) polymers via ring-opening copolymerization.
Heiny, Markus,Shastri, V. Prasad
p. 4764 - 4779
(2015/06/02)

Structure-property relationships of antibacterial amphiphilic polymers derived from 2-aminoethyl acrylate
The findings from the investigation of an ensemble of amphiphilic polymers derived from 2-aminoethyl acrylate establish significant effects of variation in the topographical position of the cationic center and hydrophobic segments on their biological activities. For example, the isomeric polymer pair of poly(6-aminohexylacrylate) and poly(2-(butylamino)ethyl acrylate) show striking differences in their biological activities, with the former having biological activities orders of magnitude higher. The trend of the activities of alkyl tails attached to the charge center shows an abrupt increase in biological activity at butyl length in the series of methyl to butyl tail. The distribution and interaction of the charge center in the chain domain is one of the main parameters in influencing polymer activities. Within the 2-aminoethyl acrylate system of homo- and copolymer, the homopolymer has its cationic centers closely distributed along the amphiphilic macromolecular chain with proximity to the backbone leading to rigid conformations not conducive to the attachment of the polymer to the cell surface. In copolymers, the incorporation of uncharged counits increases the distance between the cationic centers, resulting in significant reduction of charge repulsion and thus enhancing the flexibility of the chain conformation. This is conducive for polymer-cell association, leading to a remarkable surge in orders of magnitude of biological activity but with low selectivity against bacteria over red blood cells.
Punia, Ashish,Debata, Priya R.,Banerjee, Probal,Yang, Nan-Loh
p. 95300 - 95306
(2015/11/24)

HETEROARYL PYRIDONE AND AZA-PYRIDONE COMPOUNDS WITH ELECTROPHILIC FUNCTIONALITY
Heteroaryl pyridone and aza-pyridone amide compounds with electrophilic functionality of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk, and for treating cancer and immune disorders such as inflammation mediated by Btk. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
-
Paragraph 0295

(2015/06/17)

New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity
Abstract A number of new nitric oxide (NO)-precursors were synthesized by grafting nitrate-containing moieties on the structures of the benzyloxy isonipecotanilide derivatives 1 and 2 already reported as moderately potent antiplatelet agents. Various nitrooxy (ONO2)-alkyl side chains were covalently linked to the piperidine nitrogen of the parent compounds through carbamate and amide linkage, and the synthesis of a benzyl nitrate analog (15) of compound 1 was also achieved. The in vitro vasodilatory activities, as well as platelet anti-aggregatory effects, of the newly synthesized organic nitrates were assessed. The (ONO2)methyl carbamate-based derivative 5a and the benzyl nitrate analog 15, which on the other hand retain activity as inhibitors of ADP-induced platelet aggregation, exhibited strong NO-mediated vasodilatory effects on pre-contracted rat aorta strips, with EC50 values in the low nanomolar range (13 and 29 nM, respectively). Experiments carried out with the selectively inhibited soluble guanylate cyclase (sGC), which is the key enzyme of the NO-mediated pathway leading to vascular smooth muscle relaxation, confirmed the involvement of NO in the observed vasodilation. The nitrate derivatives proved to be stable in acidic aqueous solution and at pH 7.4. In human serum, unlike 5a, which showed not to undergo enzyme-catalyzed decomposition, the other tested (ONO2)-alkyl carbamate-based compounds (5b and 5e) and benzyl nitrate 15 underwent a faster degradation. However, their decomposition rates in serum were quite slow (t1/2 > 2.6 h), which suggests that nitrate moiety is poorly metabolized in blood plasma and that much of the in vitro anti-platelet activity has to be attributed to the intact (ONO2)-containing molecules.
De Candia, Modesto,Marini, Elisabetta,Zaetta, Giorgia,Cellamare, Saverio,Di Stilo, Antonella,Altomare, Cosimo D.
p. 69 - 80
(2015/03/31)

NOVEL OXAZOLIDINONE DERIVATIVE AND MEDICAL COMPOSITION CONTAINING SAME
Disclosed is a novel oxazolidinone derivative represented by Formula 1 above, in particular, a novel oxazolidinone compound having a cyclic amidoxime or cyclic amidrazone group. In Formula 1, R and Q are the same as defined in the detailed description. In addition, disclosed is a pharmaceutical composition for an antibiotic which includes the novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The novel oxazolidinone derivative, the prodrug thereof, the hydrate thereof, the solvate thereof, the isomer thereof, and the pharmaceutically acceptable salt thereof have broad antibacterial spectrum against resistant bacteria, low toxicity and strong antibacterial effects against Gram-positive and Gram-negative bacteria and thus may be effectively used as antibiotics.
-
Paragraph 0139-0142

(2014/02/16)

NOVEL OXAZOLIDINONE DERIVATIVE AND MEDICAL COMPOSITION CONTAINING SAME
Disclosed is a novel oxazolidinone derivative represented by Formula 1 above, in particular, a novel oxazolidinone compound having a cyclic amidoxime or cyclic amidrazone group. In Formula 1, R and Q are the same as defined in the detailed description. In addition, disclosed is a pharmaceutical composition for an antibiotic which includes the novel oxazolidinone derivative of Formula 1, a prodrug thereof, a hydrate thereof, a solvate thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The novel oxazolidinone derivative, the prodrug thereof, the hydrate thereof, the solvate thereof, the isomer thereof, and the pharmaceutically acceptable salt thereof have broad antibacterial spectrum against resistant bacteria, low toxicity and strong antibacterial effects against Gram-positive and Gram-negative bacteria and thus may be effectively used as antibiotics.
-
Paragraph 0150-0152

(2014/07/08)

CONJUGATES OF THE B-SUBUNIT OF SHIGA TOXIN FOR ANTICANCER THERAPIES
Conjugates or pharmaceutical compositions comprising conjugates of the B-subunit of Shiga toxin that are useful for cancer therapies are disclosed. More specifically, the pharmaceutical compositions comprise STxB conjugated to at least one antimitotic age
-
Page/Page column 41; 42; 43

(2014/06/24)

Conjugates of the B-subunit of Shiga toxin for anticancer therapies
Conjugates or pharmaceutical compositions comprising conjugates of the B-subunit of Shiga toxin that are useful for cancer therapies are disclosed. More specifically, the pharmaceutical compositions comprise STxB conjugated to at least one antimitotic agent such as auristatin or pharmaceutically acceptable salts thereof through a bifunctional linker. Processes to make the conjugates, as well as methods to treat cancers are also disclosed.
-
Paragraph 0126; 0127; 0128; 0129

(2014/06/24)

MACROCYCLIC COMPOUNDS AS IRAK4 INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES
Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein i.a. Ring A is phenylene or 5- to 6-membered heteroarylene; Ring B is phenylene, 5- to 6-membered heterocycloalkylene or 5- to 6-membered heteroarylen; R4/s
-
Page/Page column 187

(2014/09/29)

2,3-DISUBSTITUTED 1 -ACYL-4-AMINO-1,2,3,4-TETRAHYDROQUINOLINE DERIVATIVES AND THEIR USE AS BROMODOMAIN INHIBITORS
The present invention relates to novel compounds of formula (I), wherein R1 is C1-4alkyl; R2 is C1-4alkyl, C3-7cycloalkyl, -CH2CF3, -CH2OCH3 or heterocyclyl; R3 is C1-4alkyl, -CH2F, -CH2OH or -CH2O(O)CH3; R4 when present is as defined in claim 1; R5 when present is H, halo, hydroxy or C1-6alkoxy; A is -NH-, -O-, -S-, -SO-, -SO2-, -N(C1-4alkyl)- or -NC(O)(CH3)-; V is phenyl, heteroaromatic or pyridone any of which may be optionally substituted by 1, 2 or 3 substituents; W is CH or N; X is C or N; Y is C or N; and Z is CH or N; subject to the proviso that no more than 2 of W, X, Y and Z are N, pharmaceutical compositions containing such compounds and to their use as bromodomain inhibitors.
-
Page/Page column 120; 121

(2014/09/29)

PRODRUG DERIVATIVES OF SUBSTITUTED TRIAZOLOPYRIDINES
The present invention relates to prodrug derivatives of Mps-1 kinase inhibitors, processes for their preparation, and their use for the treatment and/or prophylaxis of diseases.
-
Page/Page column 134

(2015/01/09)

Profluorogenic reductase substrate for rapid, selective, and sensitive visualization and detection of human cancer cells that overexpress NQO1
Achieving the vision of identifying and quantifying cancer-related events and targets for future personalized oncology is predicated on the existence of synthetically accessible and economically viable probe molecules fully able to report the presence of these events and targets in a rapid and highly selective and sensitive fashion. Delineated here are the design and evaluation of a newly synthesized turn-on probe whose intense fluorescent reporter signature is revealed only through probe activation by a specific intracellular enzyme present in tumor cells of multiple origins. Quenching of molecular probe fluorescence is achieved through unique photoinduced electron transfer between the naphthalimide dye reporter and a covalently attached, quinone-based enzyme substrate. Fluorescence of the reporter dye is turned on by rapid removal of the quinone quencher, an event that immediately occurs only after highly selective, two-electron reduction of the sterically and conformationally restricted quinone substrate by the cancer-associated human NAD(P)H:quinone oxidoreductase isozyme 1 (hNQO1). Successes of the approach include rapid differentiation of NQO1-expressing and -nonexpressing cancer cell lines via the unaided eye, flow cytometry, fluorescence imaging, and two-photon microscopy. The potential for use of the turn-on probe in longer-term cellular studies is indicated by its lack of influence on cell viability and its in vitro stability.
Silvers, William C.,Prasai, Bijeta,Burk, David H.,Brown, Matthew L.,McCarley, Robin L.
supporting information
p. 309 - 314
(2013/02/25)

TETRAAZA-CYCLOPENTA[A]INDENYL AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS
The present invention provides compounds of Formula (I) as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the muscarinic M1 mediator.
-
Page/Page column 79

(2013/07/05)

Conversion of cysteine into dehydroalanine enables access to synthetic histones bearing diverse post-translational modifications
Six for the price of one: From a single precursor, dehydroalanine, six distinct post-translational modifications can be site-selectively installed on histone proteins (see figure), including the first site-selective phosphorylation and glycosylation of histones. Direct observation of histone deacetylase activity on a full-length modified histone as well as its interactions with both chromatin reader and writer/eraser proteins are reported.
Chalker, Justin M.,Lercher, Lukas,Rose, Nathan R.,Schofield, Christopher J.,Davis, Benjamin G.
supporting information; experimental part
p. 1835 - 1839
(2012/04/04)

In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery
Aim:Dexibuprofen, the S(+)-isomer of ibuprofen, is an effective therapeutic agent for the treatment of neurodegenerative disorders. However, its clinical use is hampered by a limited brain distribution. The aim of this study was to design and synthesize brain-targeting dexibuprofen prodrugs and to evaluate their brain-targeting efficiency using biodistribution and pharmacokinetic analysis.Methods:In vitro stability, biodistribution and pharmacokinetic studies were performed on male Sprague-Dawley rats. The concentrations of dexibuprofen in biosamples, including the plasma, brain, heart, liver, spleen, lung, and kidney, were measured using high pressure lipid chromatography (HPLC). The pharmacokinetic parameters of the drug in the plasma and tissues were calculated using obtained data and statistics.Results:Five dexibuprofen prodrugs that were modified to contain ethanolamine-related structures were designed and synthesized. Their chemical structures were confirmed using 1 H NMR, 13 C NMR, IR, and HRMS. In the biodistribution study, 10min after intravenous administration of dexibuprofen (11.70 mg/kg) and its prodrugs (the dose of each compound was equivalent to 11.70 mg/kg of dexibuprofen) in male Sprague-Dawley rats, the dexibuprofen concentrations in the brain and plasma were measured. The C brain /C plasma ratios of prodrugs 1, 2, 3, 4, and 5 were 17.0-, 15.7-, 7.88-, 9.31-, and 3.42-fold higher than that of dexibuprofen, respectively (P0.01). Thus, each of the prodrugs exhibited a significantly enhanced brain distribution when compared with dexibuprofen. In the pharmacokinetic study, prodrug 1 exhibited a brain-targeting index of 11.19 {DTI=(AUC brain /AUC plasma) 1 /(AUC brain /AUC plasma) dexibuprofen }.Conclusion:The ethanolamine-related structures may play an important role in transport across the brain blood barrier.
Xuan, Zhang,Xing, Liu,Tao, Gong,Xun, Sun,Zhang, Zhi-Rong
experimental part
p. 279 - 288
(2012/07/01)

METHOD FOR PREPARING (S)-5-CHLORO-N-((3-(4-(5,6-DIHYDRO-4H-1,2,4-OXADIAZIN-3-YL)PHENYL)-2-OXOOXAZOLIDIN-5-YL)METHYL)THIOPHENE-2-CARBOXAMIDE DERIVATIVES
Provided is a method for preparing (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives of Formula (I) which are useful as blood coagulation factor Xa inhibitors, and said metho
-
Page/Page column 11

(2011/02/24)

Ugi amine-derived P,N- and P,P-ligands with N-alkyltriethoxysilyl tethers: Synthesis and evaluation of mesoporous silica-supported Pd complexes in asymmetric allylic substitution reactions
A facile approach to the synthesis of several types of chiral P,N- and P,P-ligands bearing triethoxysilyl groups starting from N,N-diemthyl-1- ferrocenylethylamine (Ugi amine) has been developed. Allyl palladium complexes of these ligands have been prepar
Kultyshev, Roman G.,Miyazawa, Akira
supporting information; experimental part
p. 2139 - 2148
(2011/04/18)

NOVEL CONJUGATES OF CC-1065 ANALOGS AND BIFUNCTIONAL LINKERS
This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multipl
-
Page/Page column 202

(2011/11/06)

SHIGA TOXIN B-SUBUNIT/CHEMOTHERAPEUTICS CONJUGATES
The present invention relates to the use of a Shiga toxin B-subunit moiety as carrier for therapeutic agents, for example, anti-cancer agents such as anti-cancer agents that require intracellular uptake to exert their anti-cancer effects. In particular, the present invention provides conjugates comprising a Shiga toxin moiety covalently linked to an anti-cancer agent through a self-immolative spacer, and methods of using such conjugates to increase cellular uptake and/or specificity for cancer cells of the anti-cancer drug. Also provided are methods of treatment involving administration of such conjugates, and pharmaceutical compositions and kits useful for carrying out such methods of treatment.
-
Page/Page column 16

(2011/07/06)

Engineering an antibiotic to fight cancer: Optimization of the novobiocin scaffold to produce anti-proliferative agents
Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ?700- fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure- activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition.
Zhao, Huiping,Donnelly, Alison C.,Kusuma, Bhaskar R.,Brandt, Gary E. L.,Brown, Douglas,Rajewski, Roger A.,Vielhauer, George,Holzbeierlein, Jeffrey,Cohen, Mark S.,Blagg, Brian S. J.
scheme or table
p. 3839 - 3853
(2011/09/13)

Practical asymmetric synthesis of β-hydroxy γ-amino acids via complimentary aldol reactions
Orthogonally protected chiral β-hydroxy-γ-amino acids can be accessed in >100 g quantities from readily available starting materials and reagents in three to four steps. These chiral synthons contain two adjacent stereocenters along with suitably protecte
Pandya, Bhaumik A.,Dandapani, Sivaraman,Duvall, Jeremy R.,Rowley, Ann,Mulrooney, Carol A.,Ryba, Troy,Dombrowski, Michael,Harton, Marie,Young, Damian W.,Marcaurelle, Lisa A.
scheme or table
p. 6131 - 6137
(2011/09/19)

1H-[1,2,3]TRIAZOLO[4,5-c]PYRIDINE-4-CARBONITRILE DERIVATIVES
The invention relates to 1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile derived Cathepsin S inhibitors of Formula (I), wherein R1 is H or (C1-3)alkyl; R2 is halogen or (C1-4)alkyl, optionally substituted with one or more halogens; n is 1 -3; X is O or CH2; U, V and W are CH; or one of U, V and W is N; Y is a group capable of interacting with the Sn....S2 substites of the active site of Cathepsin S; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same as well as to the use of these derivatives for the preparation of a medicament for the treatment of cathepsin S related diseases such as atherosclerosis, obesity, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis, cancer, and chronic pain, such as neuropathic pain.
-
Page/Page column 86

(2011/08/04)

Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold
Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
Ishikawa, Tomoyasu,Seto, Masaki,Banno, Hiroshi,Kawakita, Youichi,Oorui, Mami,Taniguchi, Takahiko,Ohta, Yoshikazu,Tamura, Toshiya,Nakayama, Akiko,Miki, Hiroshi,Kamiguchi, Hidenori,Tanaka, Toshimasa,Habuka, Noriyuki,Sogabe, Satoshi,Yano, Jason,Aertgeerts, Kathleen,Kamiyama, Keiji
experimental part
p. 8030 - 8050
(2012/01/14)

METHODS OF USING SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
Methods of using semi-synthetic glycopeptides of formula I-XIV having antibacterial activity are described.
-
Page/Page column 76

(2011/11/30)