- Trifunctional reagents for substrate-protein conjugation: Application to pyrrolizidine alkaloid analogues
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We report the syntheses of two pyrrolizidine alkaloid (PA) analogues (1 and 2) which exploit the novel substrate-protein coupling reagents 4 and 5. Analogues 1 and 2 incorporate the targeted PA substructural unit (i.e., a macrocyclic diester of retronecine), possess a handle for protein conjugation, and potentially maintain the conformational integrity of macrocyclic PAs.
- Kurth,Milco,Miller
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Read Online
- Versatile approach to encoding combinatorial organic syntheses using chemically robust secondary amine tags
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Encoded combinatorial organic synthesis has recently emerged as a powerful tool for the discovery of biologically active compounds from complex chemical libraries. This report describes a new encoding methodology that uses chemically robust secondary amines as tags. These amines are incorporated into an N-[(dialkylcarbamoyl)methyl]glycine-coding oligomer through simple chemistry that is compatible with a wide range of polymer-supported transformations useful in combinatorial synthesis. In the decoding process acidic hydrolysis of the tagging polymer regenerates the secondary amines, which after dansylation are resolved and detected at sub-picomole levels by reversed-phase HPLC. The versatility of this strategy is demonstrated here by encoded syntheses of members of several representative heterocyclic compound classes, including β-lactams, 4-thiazolidinones, and pyrrolidines.
- Ni, Zhi-Jie,Maclean, Derek,Holmes, Christopher P.,Murphy, Martin M.,Ruhland, Beatrice,Jacobs, Jeffrey W.,Gordon, Eric M.,Gallop, Mark A.
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Read Online
- Design, synthesis and evaluation of novel bifunctional tetrahydroxamate chelators for PET imaging of89Zr-labeled antibodies
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Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2, were synthesized and evaluated for labeling antibodies with89Zr for imaging with positron emission tomography. Using 2,2′-iminodiacetamide as the backbone, four hydro
- Rousseau, Julie,Zhang, Zhengxing,Dias, Gemma M.,Zhang, Chengcheng,Colpo, Nadine,Bénard, Fran?ois,Lin, Kuo-Shyan
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Read Online
- CONJUGATES OF A CELL-BINDING MOLECULE WITH CAMPTOTHECIN ANALOGS
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Provided are conjugates of camptothecin analogs with a cell-binding molecule of formula (I), wherein R1, R2, R3, R4, R5, X, L, n, m, T and ----- are defined herein. It also provides methods of making the conjugates of camptothecin analogs to a cell-binding agent, as well as methods of using the conjugates in targeted treatment of cancer, infection, and immunological disorders.
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Page/Page column 212
(2021/10/30)
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- Selective Extraction and Complexation Studies for Thorium(IV) with Bis-triamide Extractants: Synthesis, Solvent Extraction, EXAFS, and DFT
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Three octyl-extended bis-triamide extractants (L1-L3) were designed and synthesized for the selective solvent extraction of Th(IV) over U(VI) in a kerosene-HNO3system. L1 and L2 exhibited good extraction property and selectivity toward Th(IV) o
- Kang, Jinyang,Wu, Rulei,Li, Long,Hu, Haiyang,Fan, Yu,Jin, Yongdong,Huang, Chao,Chen, Jing,Xu, Chao,Xia, Chuanqin
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p. 14212 - 14220
(2021/09/20)
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- Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges
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The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C
- Gao, Donglin,Penno, Christian,Wünsch, Bernhard
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p. 874 - 889
(2020/09/02)
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- Substance related with tophatib and preparation method and application thereof
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The invention discloses a substance related with tophatib and a preparation method and application thereof. The substance is named as N,N'-diacetyl{(3R,4R)-4-methyl-3-[methyl(7H-pyrrole[2,3-D]pyrimidine-4-yl)amine]piperidine-1-yl}imine. The impurity is characterized in that the generation level is lower in the condensation reaction process; however, the impurity has the uniform main functional groups with the tophatib, the cleaning effect is limited in the subsequent salting and refining process, and the influence to the qualities of crude drug and finished product of tophatib is larger; by detecting the existence of the impurity, the qualities of the raw material and preparation of the tophatib can be effectively determined.
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- IONIZABLE CATIONIC LIPID FOR RNA DELIVERY
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What is described is a compound of formula I consisting of a compound in which R1 is a branched chain alkyl consisting of 10 to 31 carbons;R2 is a linear alkyl, alkenyl, or alkynyl consisting of 2 to 20 carbons, or a branched chain alkyl consisting of 10 to 31 carbons;L1 and L2 are the same or different, each a linear alkane of 1 to 20 carbons or a linear alkene of 2 to 20 carbons;X1 is S or O;R3 is a linear or branched alkylene consisting of 1 to 6 carbons; andR4 and R5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof.
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Paragraph 0734; 0735; 0736; 0737
(2018/07/05)
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- Preparation and application of novel bitriamide organic compounds
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The invention belongs to the field of radioactive waste treatment and discloses CHON-element-containing amide organic compounds which can be applied to uranium [U(VI)]/thorium[Th(IV)] separation, plutonium[Pu(IV)]/uranium[U(VI)] separation, lanthanum[Ln(I
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Paragraph 0025-0027
(2017/08/28)
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- Structure-activity relationships of imidazole-derived 2-[ N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
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Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role.
- Charton, Julie,Gauriot, Marion,Totobenazara, Jane,Hennuyer, Nathalie,Dumont, Julie,Bosc, Damien,Marechal, Xavier,Elbakali, Jamal,Herledan, Adrien,Wen, Xiaoan,Ronco, Cyril,Gras-Masse, Helene,Heninot, Antoine,Pottiez, Virginie,Landry, Valerie,Staels, Bart,Liang, Wenguang G.,Leroux, Florence,Tang, Wei-Jen,Deprez, Benoit,Deprez-Poulain, Rebecca
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p. 547 - 567
(2015/03/18)
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- New Heterocyclic Product Space for the Castagnoli-Cushman Three-Component Reaction
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Significant expansion of heterocyclic product space accessible by the Castagnoli-Cushman reaction (CCR) has been achieved via the use of glutaric anhydride analogues containing endocyclic substitutions with oxygen, nitrogen, and sulfur. Incorporation of these heteroatoms in the anhydride's backbone results in enhanced reactivity and generally lower temperatures that are required for the reactions to go to completion. These findings are particularly significant in light of the CCR recently recognized as an efficient tool for lead-oriented synthesis.
- Dar'In, Dmitry,Bakulina, Olga,Chizhova, Maria,Krasavin, Mikhail
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supporting information
p. 3930 - 3933
(2015/08/18)
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- Nitroxyl radical/PhI(OAc)2: One-pot oxidative cleavage of vicinal diols to (di)carboxylic acids
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A mild and user-friendly one-pot oxidative cleavage of vicinal diols to their corresponding (di)carboxylic acids using AZADOs and PhI(OAc)2 is described. 1,2-Diols and 2,3-diols as well as 1,2,3-triol gave one- or two-carbon-unit-shorter carboxylic acids. Internal vicinal diols also smoothly underwent one-pot oxidative cleavage to afford the corresponding dicarboxylic acids. Cyclic vicinal diols are converted to their corresponding open-form dicarboxylic acids.
- Shibuya, Masatoshi,Shibuta, Takuro,Fukuda, Hayato,Iwabuchi, Yoshiharu
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supporting information
p. 5010 - 5013
(2013/01/15)
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- PAIN-RELIEVING COMPOSITION
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This invention relates to a composition for relieving pain, comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof as an effective substance. The composition of the present invention relieves pain, particularly neuropathic pa
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Page/Page column 7; 9-10
(2010/11/28)
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- PHOSPHONATE ANALOGS OF HIV INTEGRASE INHIBITOR COMPOUNDS
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Novel HIV integrase inhibitor compounds having at least one phosphonate group, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.
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Page/Page column 404-405
(2010/02/15)
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- PRE-ORGANIZED TRICYCLIC INTEGRASE INHIBITOR COMPOUNDS
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Tricyclic compounds according to the structure below, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed. Formula (I). Al and A2 are moieties forming a five, six, or seven membered ring. L is a bond or a linker connecting a ring atom of Ar to N. X is O, S, or substituted nitrogen. Ar is aryl or heteroaryl. Q is N, +NR, or CR4. The aryl carbons may be independently substituted with substituents other than hydrogen. The compounds may include prodrug moieties covalently attached at any site.
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- NOVEL 4-(2FUROYL)AMINOPIPERIDINES, INTERMEDIATES IN SYNTHESIZING THE SAME,PROCESS FOR PRODUCING THE SAME AND MEDICINAL USE OF THE SAME
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There are provided novel 4-(2-furoyl)aminopiperidines represented by the general formula (I), their synthetic intermediates, processes for their preparation and medicaments containing them. In the above formula, X is CH or N, and Y is a group of the following general formula (II), formula (II-a) or formula (III): wherein a, b and c are each an integer of 0-6; Z is CH2 or NH; W is O or S; T is O or N-R15 wherein R15 is H, a C1-C6 alkyl group, a benzyl group or a phenethyl group; and R1 is H, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, or the like.The 4-(2-furoyl) aminopiperidine derivatives according to this invention possess opioid μ antagonistic activity and are useful for the treatment or prevention of side effects which are caused by μ receptors agonist and which are selected from constipation, nausea/emesis or itch, or for the treatment or prevention of idiopathic constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome or chronic pruritus.
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- Terminally-branched polymeric linkers and polymeric conjugates containing the same
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The present invention is directed to polymeric-prodrug transport forms of the formula: wherein: E1-4are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12branched alkyls, C3-8cycloalkyls, C1-6substituted alkyls, C3-8substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6heteroalkyls, substituted C1-6heteroalkyls, C1-6alkoxy, phenoxy, C1-6heteroalkoxy, and at least one of E1-4includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or wherein J1is the same as J, or another member of the group defining J and E5is the same as E1-4, or another member of the group defining E1-4; Y1-2are independently O, S or NR9; M is a heteroatom selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(=Y2); R2-5and R7-9are independently selected from the group consisting of hydrogen, C1-6alkyls, C3-12branched alkyls, C3-8cycloalkyls, C1-6substituted alkyls, C3-8substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-16heteroalkyls, substituted C1-6heteroalkyls, C1-6alkoxy, phenoxy and C1-6heteroalkoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer, Z is an electron withdrawing group; and R1is a polymeric residue. which is optionally capped with a moiety of the formula:
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- Separation of oxetacaine and its metabolites
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Oxetacaine (1), known as Tepilta, may be biotransformed to 2-5. After having tried to separate 1-5 by GC we succeeded in finding the HPLC method on Silicagel Si 60 with the eluent MeOH/TBME/HClO4.
- Unterhalt,Wenning
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- Potent and specific inhibitors of trypanothione reductase from Trypanosoma cruzi: Bis(2-aminodiphenylsulfides) for fluorescent labeling studies
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In order to optimise the activity of bis 2-aminodiphenylsulfides) upon trypanothione reductase TR) from Trypanosoma cruzi, a new series of bis 2-aminodiphenylsulfides) possessing three side chains was synthesized. Various moieties were introduced at the end of the third side chain, including acridinyl or biotinyl moieties for fluorescent labeling studies. TR inhibition was improved; the most potent inhibitor IC50=200 nM) was selective towards TR versus human glutathione reductase and corresponded to a single myristyl group. Compounds were also tested in vitro upon Trypanosoma cruzi and Leishmania infantum amastigotes, upon-Trypanosoma brucei trypomastigotes, and for their cytotoxicity upon human MRC-5 cells. In the presence of serum, acridine derivative was no longer detectable in mass spectrometry and its antitrypanosomal activity no longer observed. This transformation might explain the absence of correlation between the potent TR inhibition and the in vitro antiparasitic activity with both of the first generation of 2-aminodiphenylsulfides. Copyright
- Girault, Sophie,Davioud-Charvet, Elisabeth,Maes, Louis,Dubremetz, Jean-Francois,Debreu, Marie-Ange,Landry, Valerie,Sergheraert, Christian
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p. 837 - 846
(2007/10/03)
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- Terminally-branched polymeric linkers and polymeric conjugates containing the same
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The present invention is directed to polymeric- prodrug transport forms of the formula: wherein: B is a leaving group, OH, a residue of a hydroxyl-containing moiety or wherein B1 is a leaving group, OH or a residue of a hydroxyl-containing moiety; Y1-2 are independently O or S; M is selected from either X or Q; wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(=Y2); R2-5 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls; (m) is zero or one; (n) is a positive integer; (p) is zero or a positive integer; Z is an electron withdrawing group; and R1 is a polymeric residue which is optionally capped with a moiety of the Formula (v)
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- Higher order iminodiacetic acid libraries for probing protein-protein interactions
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Full details of the preparation of iminodiacetic acid diamide dimer (2040 compounds), trimer (560 compounds), and tetramer (1596 compounds) libraries by multistep convergent solution-phase synthesis for studying protein-protein interactions are provided. The libraries were assembled in a format providing small 8-10 compound mixtures and the deconvolution of many of the small mixtures to identify screening leads by resynthesis of the individual components have been conducted for 320 of the individual compounds to date. A representative example of the subsequent exploration of the structure-activity relationships for an identified receptor binding antagonist (200 additional individual compounds) and steps taken for potential elaboration to a receptor dimerization agonist are defined with preparation of representative linked dimers (70 compounds). Copyright (C) 1998 Elsevier Science Ltd.
- Boger, Dale L.,Goldberg, Joel,Jiang, Weiqin,Chai, Wenying,Ducray, Pierre,Lee, Jae Kyoo,Ozer, Rachel S.,Andersson, Carl-Magnus
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p. 1347 - 1378
(2007/10/03)
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- Synthesis and structure of macrocyclic dioxa-, dithia-, diazatetralactams and derivatives
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The high yield stepwise synthesis of 18-membered dioxa-, dithia- and diazatetralactams is described. The two key steps are: i) the dissymetrization of the reactivity of a diacid via its cyclic anhydride and ii) the activation-cyclization of the intermediate diamide diacid avoiding the high-dilution technique. Two series of diazatetralactam derivatives are prepared: bibranched compounds bearing various substituents and macrobicyclic or macrotricyclic species with phenantroline units. Tim main conformer of the dioxatetralactam was found by 13C nmr and molecular modelling to have a D2 symmetry while the dithiatetralactam in vacuo and the Boc substituted diazatetralactam in the solid state have a C2 symmetry.
- Cathala, Bernard,Raouf-Benchekroun, Khadija,Galaup, Chantal,Picard, Claude,Cazaux, Louis,Tisnes, Pierre
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p. 9793 - 9804
(2007/10/03)
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- Tumor metastasis inhibiting compounds and methods
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A peptide derivative containing 1 to 20 units of peptide unit represented by the following general formula [I] or a pharmaceutically acceptable salt thereof; wherein Arg represents L- or D-arginine residue, Asp represents L-aspartic acid residue, X represents L- or D-leucine, D-isoleucine, L- or D-norleucine, L- or D-phenylalanine, D-phenylglycine or D-alanine residue, and [Z] and [Y] each represents an amino acid or a peptide residue, which may be present or absent, selected from glycine, L-serine, L-threonine, L- and D-aspartic acid, L-alanine, L- and D-glutamic acid, L-proline residues and a peptide residue constituted by the foregoing amino acid residues, and a pharmaceutical composition comprising the peptide derivative. The composition of the present invention is useful as an agent for inhibiting tumor metastasis.
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- Macrobicyclic and macrotricyclic tetralactams with 1,10-phenanthroline units. Dinuclear Eu3+ cryptate of the macrotricyclic ligand
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The synthesis of a key 18-membered diazatetralactam and of subsequent macrobicycle and macrotricycle with 1,10-phenanthroline units is described. The predominant macrotricyclic cryptand gives a dinuclear europium cryptate characterized by MS techniques and luminescence emission.
- Cathala,Cazaux,Picard,Tisnes
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p. 1863 - 1866
(2007/10/02)
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- Enhanced Cyclization of N-Benzyloxycarbonyl-N-substituted Dipeptide Methyl Esters with Ammonia
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Cyclization of N,N'- dimethyl ester to the hydantoin derivative took place easily under mild ammonolysis conditions.Replacement of Z by p-methoxy-benzyloxycarbonyl also led to the cyclizatio
- Kawashiro, Katsuhiro,Nishiguchi, Kazuhisa,Kurosaka, Ikuo
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p. 2404 - 2406
(2007/10/02)
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- SYNTHESE D'α-AMINODIALDEHYDES
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The first N-protected aminodialdehydes have been syntesized by oxidation of N-protected aminodiols or from aminodiacids by reduction of N-Boc di (N-metoxy N-methyl) amides.
- Garrigues, Bernard,Lazraq Et, Mohamed
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p. 1685 - 1686
(2007/10/02)
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