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A facile synthesis of isotope labeled acylcarnitines
Acylcarnitines are a big family of small molecule metabolites with various acyl groups attached to the hydroxyl moiety of l-carnitine. They are good indicators of multiple metabolic disorders. For instance, the newborn screening panel uses flow injection tandem mass spectrometry to analyze more than 30 different acylcarnitines and amino acids extracted from dried blood spots. A facile approach has been developed for the synthesis of isotope labeled acylcarnitines whose mass shift over their unlabeled counterparts can be any number in the range of 3 to 12 Da. This strategy makes it more convenient to provide authentic internal standards for acylcarnitines profiling analyses, thereby expanding their clinical applications.
Dai, Xiaojun,Lv, Chao,Sun, Jianguo,Li, Shuwei
p. 217 - 224
(2021)
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TARGETED PLASMA PROTEIN DEGRADATION
The present invention is directed to the bifunctional compounds and the use of such bifunctional compounds to lower plasma levels of extracellular target molecules by lysosomal degradation. Such bifunctional compounds have a cell surface receptor ligand covalently linked to a ligand that is capable of binding to an extracellular target molecule (such as a ligand for a growth factor, a cytokine, a chemokine, a hormone, a neurotransmitter, a capsid, a soluble receptor, an extracellular secreted protein, an antibody, a lipoprotein, an exosome, a virus, a cell, or a plasma membrane protein), where the cell surface receptor is associated with receptor mediated endocytosis, including asialoglycoprotein receptor (ASGPR) mediated lysosomal degradation and mannose-6-phosphate (M6PR) mediated lysosomal degradation. Pharmaceutical compositions comprising such bifunctional compounds and methods of treating a disease or disorder mediated by an extracellular molecule using such bifunctional compounds are also provided herein.
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Page/Page column 172

(2021/08/14)

Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties
Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.
Bellany, Fiona,Tsuchiya, Yugo,Tran, Trang M.,Chan, A.W. Edith,Allan, Helen,Gout, Ivan,Tabor, Alethea B.
supporting information

(2020/09/16)

COMPOUNDS AND THERAPEUTIC USES THEREOF
The invention relates to novel compounds with the ability to link an immune response to a defined therapeutic target, to the use of said compounds in treating cancer and infectious diseases, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
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Page/Page column 65

(2020/05/19)

BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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Paragraph 0688; 0689; 0690

(2020/05/21)

GALNAC DERIVATIVES
Modified oligonucleotides comprising a GalNAc moiety of the present disclosure along with methods of making and use, e.g., against HBV are disclosed.
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Paragraph 0130

(2019/04/11)

PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 125-126

(2019/11/12)

Analogue synthesis reveals decoupling of antibiofilm and β-lactam potentiation activities of a lead 2-aminoimidazole adjuvant against Mycobacterium smegmatis
Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro, it expresses phenotypic resistance to antimicrobial drugs. As the in vivo survival of M.?tuberculosis following drug treatment is potentially linked to a biofilm-like expression of drug tolerance, it is hypothesized that biofilm dispersion should increase antibiotic susceptibility and reduce the duration of the current antibiotic treatment regimen. Previously, we have identified a 2-aminoimidazole (2-AI) compound capable of dispersing and inhibiting M.?tuberculosis and M.?smegmatis biofilms in vitro. Additionally, this compound potentiated the activity of carbenicillin against M.?tuberculosis and, to a lesser degree, M.?smegmatis. Here, we describe a SAR study on this compound evaluating each derivative for biofilm dispersion and β-lactam potentiation capabilities against M.?smegmatis. This study identified a compound that improved upon the biofilm dispersion capabilities of the lead compound. Interestingly, a different compound was identified with an increased ability to potentiate a subset of β-lactam antibiotics. These compounds indicate that biofilm dispersion and potentiation capabilities may not be associated.
Martin, Sara E.,Nguyen, Catherine M.,Basaraba, Randall J.,Melander, Christian
p. 1403 - 1408
(2018/05/16)

MODIFIED OLIGONUCLEOTIDES AND METHODS OF USE
Modified oligonucleotides comprising modifications at the 2' and/or 3' positions(s) along with methods of making and use, e.g., against HBV are disclosed.
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Paragraph 0284

(2018/04/12)

Synthesis and Th1-immunostimulatory activity of α-galactosylceramide analogues bearing a halogen-containing or selenium-containing acyl chain
A novel series of CD1d ligand α-galactosylceramides (α-GalCers) were synthesized by incorporation of the heavy atoms Br and Se in the acyl chain backbone of α-galactosyl-N-cerotoylphytosphingosine. The synthetic analogues are potent CD1d ligands and stimulate mouse invariant natural killer T (iNKT) cells to selectively enhance Th1 cytokine production. These synthetic analogues would be efficient X-ray crystallographic probes to disclose precise atomic positions of alkyl carbons and lipid–protein interactions in KRN7000/CD1d complexes.
Hossain, Md. Imran,Hanashima, Shinya,Nomura, Takuto,Lethu, Sébastien,Tsuchikawa, Hiroshi,Murata, Michio,Kusaka, Hiroki,Kita, Shunsuke,Maenaka, Katsumi
supporting information
p. 3687 - 3695
(2016/07/20)

Peptide conjugates of 4-aminocyclophosphamide as prodrugs of phosphoramide mustard for selective activation by prostate-specific antigen (PSA)
In our continued effort to develop prodrugs of phosphoramide mustard, conjugates of 4-aminocyclophosphamide (4-NH2-CPA) with three PSA-specific peptides were synthesized and evaluated as substrates of PSA. These include conjugates of cis-(2R,4R)-4-NH2-CPA with a tetrapeptide Succinyl-Ser-Lys-Leu-Gln-OH, a hexapeptide Succinyl-His-Ser-Ser-Lys-Leu-Gln-OH, and a pentapeptide Glutaryl-Hyp-Ala-Ser-Chg-Gln-OH. These conjugates were cleaved by PSA efficiently and exclusively after the expected glutamine residue to release 4-NH2-CPA, the activated prodrug form of phosphoramide mustard. The cleavage was most efficient for the pentapeptide conjugate 3 (Glutaryl-Hyp-Ala-Ser-Chg-Gln-NH-CPA), which showed a half-life of 55 min with PSA, followed by the hexapeptide conjugate 2 (Succinyl-His-Ser-Ser-Lys-Leu-Gln- NH-CPA) and the tertrapeptide conjugate 1 (Succinyl-Ser-Lys-Leu-Gln-NH-CPA) with half-lives of 6.5 and 12 h, respectively. These results indicate a potential of the conjugate 3 as an anticancer prodrug of phosphoramide mustard for selective PSA activation.
Jiang, Yongying,Hu, Longqin
p. 7507 - 7514
(2013/11/19)

Inhibition of Acinetobacter baumannii biofilm formation on a methacrylate polymer containing a 2-aminoimidazole subunit
A polymeric composite containing a 2-aminoimidazole derivative was synthesized. It was found that this polymer was resistant to biofilm colonization by Acinetobacter baumannii, no leaching of the 2-aminoimidazole derivative was observed after 2 weeks of treatment with deionized water, and the resulting polymer was not hemolytic.
Peng, Lingling,Desousa, Joseph,Su, Zhaoming,Novak, Bruce M.,Nevzorov, Alexander A.,Garland, Eva R.,Melander, Christian
supporting information; experimental part
p. 4896 - 4898
(2011/06/10)

DIAZENIUMDIOLATE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
Compounds of formula (I): wherein: R1 represents a hydrogen atom or a —COOR group, R2 represents a group G or a linear or branched (C1-C6)alkyl group substituted by a group G, wherein G represents a —(CH2)n-A-(CH2)m—B—(CR4R5)p—(CH2)o-R6 group as defined in the description, R3 represents a hydrogen atom, an alkyl group or an NO2 group.
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Page/Page column 4

(2010/12/29)

PROCESS FOR PREPARING EZETIMIBE USING NOVEL ALLYL INTERMEDIATES
The present invention provides an efficient and industrially advantageous process for the preparation of ezetimibe of formula (I), using novel intermediates.
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Page/Page column 18-19

(2010/01/30)

PROCESS FOR PREPARING HIGHLY PURE EZETIMIBE USING NOVEL INTERMEDIATES
The present invention relates to an industrially advantageous process for the preparation of ezetimibe of formula (I) in high yields by using novel benzyl ester intermediates. The present invention further provides a process for the purification of ezetimibe of formula (I).
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Page/Page column 16

(2008/12/08)

Esterification of dicarboxylic acids with benzyl alcohol under the action of the microwave radiation
Reaction of dicarboxylic acid with benzyl alcohol under the microwave irradiation proceeds faster as compared to the thermal conditions. The main reaction products are alkyl dicarboxylates, and the monoester and dibenzyl ether are formed as the side products. A proposal about the nature of the nonthermal effect in the reactions stimulated by the microwave irradiation is considered.
Aver'yanov,Batrakova,Samuilov,Spiridonova,Kochnev,Galibeev,Gnezdilov
experimental part
p. 1920 - 1923
(2009/02/08)

Enantioselective esterase activity of an industrial glutaryl acylase
The unexpected esterase activity of an industrial glutaryl acylase was investigated. Glutaryl esters of a series of primary and secondary alcohols as well as of phenols were all efficiently hydrolyzed, the only exception being the sterically hindered glutarate of thymol. The enantioselectivities of the acylase, which were evaluated with three of these substrates, were quite low (E values ranging between 1.9 and 7.2), but were significantly improved by substrate and/or solvent engineering. Enantiomerically enriched hydrolyzed alcohols and unreacted glutarates can be easily separated by selective extraction, thus avoiding chromatographic steps.
Adani, Sara,Raimondi, Stefano,Forti, Luca,Monti, Daniela,Riva, Sergio
p. 2509 - 2513
(2007/10/03)

Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: SAR of the N-protecting group
The synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors is reported. This article describes the synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors. The protecting group was found to contribute to caspase-3 inhibiting activity, and compounds with a large group such as Cbz are more active than compounds with a small group such as Ac. Compounds with more hydrophobic protecting groups were found to be more active in cell apoptosis protection assays, probably due to increased cell permeability. MX1122, 2,4-di-Cl-Cbz-Val-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor and is selective for caspases versus other proteases, with good activity in the cell apoptosis protection assays as well as good efficacy in the mouse liver apoptosis model.
Cai, Sui Xiong,Guan, Lufeng,Jia, Shaojuan,Wang, Yan,Yang, Wu,Tseng, Ben,Drewe, John
p. 5295 - 5300
(2007/10/03)

Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators
Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.
Moridani, Majid Y.,Tilbrook, Gary S.,Khodr, Hicham H.,Hider, Robert C.
p. 349 - 364
(2007/10/03)

Nitrosated and nitrosylated alpha-adrenergic receptor antagonists, compositions and methods of use
The present invention describes novel nitrosated and/or nitrosylated α-adrenergic receptor antagonists, and novel compositions containing at least one nitrosated and/or nitrosylated α-adrenergic receptor antagonist, and, optionally, one or more compounds
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(2008/06/13)

Caspase inhibitors and the use thereof
The present invention is directed to novel dipeptide thereof, represented by the general Formula I: where R1-R3, X and Y are defined herein. The present invention also relates to the discovery that compounds having Formula I are pote
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(2008/06/13)

NITROSATED AND NITROSYLATED ALPHA-ADRENERGIC RECEPTOR ANTAGONIST, COMPOSITIONS AND METHODS OF USE
The present invention describes novel nitrosated and/or nitrosylated α-adrenergic receptor antagonists, and novel compositions containing at least one nitrosated and/or nitrosylated α-adrenergic receptor antagonist, and, optionally, one or more compounds
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(2008/06/13)

Regioselective synthesis of acyclovir and its various prodrugs
High-yield regioselective synthesis of 9-[(2-hydroxyethoxy)methyl]guanine (Acyclovir 1, Scheme 1) was achieved from guanine via trisilylated guanine. N2-acylacyclovir 9a-9b were prepared from N2, O-diacylacyclovir (4, 8b-8d) using regioselective deacylation procedure. N2-Acylacyclovir 11 and 13 were prepared via protection of primary hydroxyl groups. Three amino acid esters of acyclovir were synthesized as water-soluble prodrugs, which form protonated cations in pH 7.4 phosphate buffer. Two water-soluble ester prodrugs with free carboxylic acids, which form anionic species in pH 7.4 phosphate buffer, were also synthesized.
Gao,Mitra
p. 1399 - 1419
(2007/10/03)

Preferential hydrogenolysis of NAP esters provides a new orthogonal protecting group strategy for carboxylic acids
Selective hydrogenolysis of 2-naphthylmethyl (NAP) esters in the presence of a benzyl ester has been observed with a wide range of dicarboxylic acids. Orthogonal deprotection of NAP esters with challenging substrates can be achieved if the other carboxylic acids in the molecule are protected with 4-trifluoromethyl benzyl group instead of benzyl groups.
Gaunt, Matthew J.,Boschetti, Carlos E.,Yu, Jinquan,Spencer, Jonathan B.
p. 1803 - 1806
(2007/10/03)

Inhibition of the HER2 tyrosine kinase and characterization of a hydrophobic site near the nucleotide binding domain
A series of compounds was prepared to investigate the hydrophobic character of the HER2 receptor tyrosine kinase active site, These bisubstrate analogs contained hydrophobic moieties in place of the polar triphosphate and nucleoside fragments of the natural ATP ligand. Despite these modifications, good affinity was observed as measured by inhibition of receptor autophosphorylation.
Maddry, Joseph A.,Kussner, Conrad,Truss, Jackie W.,Niwas, Shri,White, E. Lucile,Kwong, Cecil D.
p. 2109 - 2114
(2007/10/03)

Synthesis of sialyl Lewis X mimetics and related structures using the glycosyl phosphite methodology and evaluation of E-selectin inhibition
This paper describes our recent study of glycosyl phosphites for glycosylation reactions, with particular emphasis on the investigation of protecting group and stereochemistry effects on the anomeric reactivity and stereoselectivity, and the application of this methodology to the synthesis of Lewis X (Le(x)), Lewis Y (Le(y)), glycopeptides, and sialyl Lewis X (SLe(x)) mimetics. Both α-O-fucosyl-L-threonine and α-O-fucosyl-(1R,2R)-2-aminocyclohexanol were found to be effective templates for the chemical/enzymatic synthesis of SLe(x) mimetics, and some fucopeptides prepared were 5-10 times more active than SLe(x) as inhibitors of E-selectin.
Lin, Chun-Cheng,Shimazaki, Makoto,Heck, Marie-Pierre,Aoki, Shin,Wang, Ruo,Kimura, Teiji,Ritzèn, Helena,Takayama, Shuichi,Wu, Shih-Hsiung,Weitz-Schmidt, Gabriel,Wong, Chi-Huey
p. 6826 - 6840
(2007/10/03)

Synthesis of sialyl Lewis X mimetics: Use of O-α-fucosyl-(1R, 2R)-2-aminocyclohexanol as core structure
Six glycopeptides containing O-α-fucosyl-(1R, 2R)-2-aminocyclohexanol were designed and prepared as sialyl Lewis X mimetics. Compounds 2 and 6 showed better binding affinities than SLe(X) (IC50 = 0.5 mM) to E-selectin with IC50 values of 0.4 and 0.2 mM respectively.
Wang, Ruo,Wong, Chi-Huey
p. 5427 - 5430
(2007/10/03)

C-fucopeptides as selectin antagonists: Attachment of lipid moieties enhances the activity
The biological activity of a potent selectin antagonist could be 40-fold enhanced by attachment of a lipid moiety. Also an enantioselective synthesis of β,ω-dihydroxyamino acids by Sharpless asymmetric dihydroxylation (AD-reaction) allowed general access to this important class of compounds. Copyright (C) 1996 Elsevier Science Ltd.
Weltering, Thomas J.,Weitz-Schmidt, Gabriele,Wong, Chi-Huey
p. 9033 - 9036
(2007/10/03)

The potential application of catalytic antibodies to protecting group removal: Catalytic antibodies with broad substrate tolerance
A catalytic antibody was developed to selectively cleave the alcohol ester of 4-nitrophenylacetyl moiety while also tolerating a wide variety of structural variation on the alcohol portion of the molecule. The basis to the success of this study was that antibody epitope recognition was directed toward only key elements contained within the 4-nitrophenylacetyl group and not the entire haptenic molecule. This study offers the potential application of catalytic antibodies as practical reagents for the selective deprotection of complex multifunctionalized molecules possessing class similar protecting groups. Such a chemoabzymatic approach could eventually minimize synthetic complications which can arise from functional group protection in the synthesis of complex natural products.
Li,Hilton,Janda
p. 2123 - 2127
(2007/10/02)

Orally effective acid prodrugs of the β-lactamase inhibitor sulbactam
Sulbactam (1) is a β-lactamase inhibitor with limited oral bioavailability. Lipophilic double-ester prodrug sulbactam pivoxil (2) significantly improves the oral absorption of sulbactam, as does the mutual prodrug double ester sultamicillin (3). We have found that double-ester prodrugs of sulbactam terminating in a carboxyl group (8) also were effective oral-delivery vehicles in rats. Carboxyl-terminated double esters have several potential advantages over their nonionizable lipophilic counterparts, including water solubility, crystallinity, choice of salts for dosage forms, and formation of innocuous byproducts on hydrolysis.
English,Girard,Jasys,Martingano,Kellogg
p. 344 - 347
(2007/10/02)

SELECTIVE MONOETHERIFICATION AND MONOESTERIFICATION OF DIOLS AND DIACIDS UNDER PHASE-TRANSFER CONDITIONS
Research on the selectivity of etherification reactions of diols and esterification reactions of diacids by alkyl halides under phase-transfer catalysis has shown that under such conditions, selectivity of monoetherification increases in the order prim sec tert diols, though overall yield of monoether decreases from sec to tert diols.Monoesterification of diacids was accomplished with a high degree of selectivity.Optimal extraction of diols and diacids was found to correspond in general to chain lengths of around 5 carbons.This could mean that the complex formed between the catalyst and the anion to react is stabilized for certain carbon lengths by inner solvation in virtue of its spatial conformation.
Zerda, Jaime de la,Barak, Gabriela,Sasson, Yoel
p. 1533 - 1536
(2007/10/02)