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    Identification of active-site inhibitors of glycosyltransferases using a generalizable high-throughput screen
    2.
    发明申请
    Identification of active-site inhibitors of glycosyltransferases using a generalizable high-throughput screen 失效
    使用可推广的高通量筛选鉴定糖基转移酶的活性位点抑制剂

    公开(公告)号：US20050142629A1

    公开(公告)日：2005-06-30

    申请号：US10748335

    申请日：2003-12-30

    申请人： Suzanne Kahne ,  Daniel Kahne

    发明人： Suzanne Kahne ,  Daniel Kahne

    IPC分类号： C12Q1/48

    CPC分类号： C12Q1/48 ,  G01N2500/02

    摘要： A method is described for identifying a compound that modulates the ability of a glycosyltransferase to bind a substrate comprising combining a glycosyltransferase, a labeled substrate, and a compound, in a reaction vessel, under conditions known to be suitable for the glycosyltransferase to bind the labeled substrate, measuring an amount of labeled substrate bound to the glycosyltransferase, and comparing the amount to a standardized amount to identify a relative increase or decrease in substrate bound glycosyltransferase, thereby identifying a compound that modulates the ability of the glycosyltransferase to bind the substrate. A composition comprising an effective amount of a compound of Formula I (the substituents of which are described herein), or a stereoisomer, or pharmaceutically acceptable salt thereof, that inhibits the ability of a glycosyltransferase to bind a substrate, in a pharmaceutically acceptable carrier is provided

    摘要翻译： 描述了一种用于鉴定调节糖基转移酶结合底物的能力的化合物的方法，包括在已知适合于糖基转移酶结合标记的糖基转移酶的条件下在反应容器中组合糖基转移酶，标记的底物和化合物 底物，测量与糖基转移酶结合的标记底物的量，并将该量与标准化量进行比较，以鉴定底物结合的糖基转移酶的相对增加或减少，从而鉴定调节糖基转移酶结合底物的能力的化合物。 在药学上可接受的载体中，包含有效量的式I化合物（其取代基在此描述）或其立体异构体或其药学上可接受的盐，其抑制糖基转移酶结合底物的能力， 提供

    Desleucyl glycopeptide antibiotics and methods of making same
    3.
    发明授权
    Desleucyl glycopeptide antibiotics and methods of making same 失效
    赖氨酸糖肽抗生素及其制备方法

    公开(公告)号：US06518243B1

    公开(公告)日：2003-02-11

    申请号：US09540761

    申请日：2000-03-31

    申请人： Daniel Kahne ,  Suzanne Walker

    发明人： Daniel Kahne ,  Suzanne Walker

    IPC分类号： A61K3814

    CPC分类号： C07K9/008 ,  A61K38/00

    摘要： Compounds that are analogs of glycopeptide antibiotics are disclosed. The compounds have the formula A1-A2-A3-A4-A5-A6-A7 wherein each of the groups A2 to A7 is a modified or unmodified &agr;-amino acid residue, A1 is optional and, when present, is an organic group other than N-substituted leucine, and at least one of the groups A1 to A7 is linked via a glycosidic bond to one or more glycosidic groups each having one or more sugar residues, wherein at least one of said sugar residues is modified to bear at least one hydrophobic substituent. Methods of making these compounds, compositions including these compounds, and methods of using the compounds to treat infections in a host are also disclosed.

    摘要翻译： 公开了作为糖肽抗生素类似物的化合物。 化合物具有式A1-A2-A3-A4-A5-A6-A7，其中A2至A7组中的每一个为经修饰或未修饰的α-氨基酸残基，A1为任选的，并且当存在时为有机基团 并且A1至A7中的至少一个通过糖苷键与一个或多个各自具有一个或多个糖残基的糖苷基连接，其中至少一个所述糖残基被修饰以承载至少 一个疏水取代基。 还公开了制备这些化合物的方法，包括这些化合物的组合物，以及使用该化合物治疗宿主感染的方法。

    Glycosylation method
    4.
    发明授权
    Glycosylation method 失效
    糖基化方法

    公开(公告)号：US06388059B1

    公开(公告)日：2002-05-14

    申请号：US09353373

    申请日：1999-07-14

    申请人： Daniel Kahne ,  Jeff Gildersleeve ,  Christopher Thompson ,  Min Ge

    发明人： Daniel Kahne ,  Jeff Gildersleeve ,  Christopher Thompson ,  Min Ge

    IPC分类号： C07M100

    CPC分类号： C07H15/18 ,  C07H5/10 ,  C07H11/00 ,  C07H15/203

    摘要： A method for forming a glycosidic linkage by: (a) contacting a glycoside bearing an anomeric sulfoxide group with a compound bearing a free hydroxyl group in the presence of an organic acid anhydride and a scavenger of sulfenyl esters; and (b) allowing a glycosylation reaction to proceed under conditions effective to produce the glycosidic linkage. In a preferred embodiment of the invention, the glycoside bearing an anomeric sulfoxide group is added to a mixture of the other reactants. In another preferred embodiment of the invention, a Lewis acid is also present in the reaction mixture. This invention is further directed to a method for forming a glycosidic linkage by: (a) forming a solution comprising: a compound bearing a free hydroxyl group, and an organic acid anhydride; (b) adding to the solution a glycoside bearing an anomeric sulfoxide group; and (c) allowing a glycosylation reaction to proceed under conditions effective to produce the glycosidic linkage. In a preferred embodiment of the invention, a Lewis acid is present in the solution.

    摘要翻译： 通过以下步骤形成糖苷键的方法：（a）在有机酸酐和亚磺酰基酯的清除剂存在下，使含有异头亚烷基的糖苷与具有游离羟基的化合物接触; 和（b）允许糖基化反应在有效产生糖苷键的条件下进行。 在本发明的优选实施方案中，将含有异头亚烷基基团的糖苷加入到其它反应物的混合物中。 在本发明的另一个优选实施方案中，路易斯酸也存在于反应混合物中。本发明还涉及通过以下方法形成糖苷键的方法：（a）形成溶液，其包含：具有游离羟基的化合物， 和有机酸酐; （b）向溶液中加入带有异头亚烷基的糖苷; 和（c）允许糖基化反应在有效产生糖苷键的条件下进行。 在本发明的优选实施方案中，路易斯酸存在于溶液中。

    Glycopeptide antibiotics, combinatorial libraries of glycopeptide antibiotics and methods of producing same
    6.
    发明授权
    Glycopeptide antibiotics, combinatorial libraries of glycopeptide antibiotics and methods of producing same 失效
    糖肽抗生素，糖肽抗生素组合文库及其生产方法

    公开(公告)号：US07473671B2

    公开(公告)日：2009-01-06

    申请号：US10631883

    申请日：2003-07-31

    申请人： Daniel Kahne ,  Robert Kerns ,  Seketsu Fukuzawa ,  Min Ge ,  Christopher Thompson

    发明人： Daniel Kahne ,  Robert Kerns ,  Seketsu Fukuzawa ,  Min Ge ,  Christopher Thompson

    IPC分类号： C40B40/14

    CPC分类号： C07K9/008

    摘要： A glycopeptide of the formula A1-A2-A3-A4-A5-A6-A7, in which each dash represents a covalent bond; wherein A1 comprises a modified or unmodified α-amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl; wherein each of A2 to A7 comprises a modified or unmodified α-amino acid residue, whereby (i) A1 is linked to an amino group on A2, (ii) each of A2, A4 and A6 bears an aromatic side chain, which aromatic side chains are cross-linked together by two or more covalent bonds, and (iii) A7 bears a terminal carboxyl, ester, amide, or N-substituted amide group; and wherein one or more of A1 to A7 is linked via a glycosidic bond to one or more glycosidic groups each having one or more sugar residues, at least one of the sugar residues bearing one or more substituents of the formula YXR, N+(R1)=CR2R3, N=PR1R2R3, N+R1R2R3 or P+R1R2R3 in which Y is a single bond, O, NR, or S; X is O, NR1, S, SO2, C(O)O, C(O)S, C(S)O, C(S)S, C(NR1)O, C(O)NR1, or halo (in which case Y and R are absent). A chemical library comprising a plurality of the glycopeptides of the invention.A method for preparing a glycopeptide by glycosylation of an aglycone derived from a glycopeptide antibiotic.A method for preparing a glycopeptide by preparing a pseudoaglycone from a glycopeptide antibiotic and glycosylating the pseudoaglycone.

    摘要翻译： 式A1-A2-A3-A4-A5-A6-A7的糖肽，其中每个短划线代表共价键; 其中A1包含经修饰或未修饰的α-氨基酸残基，烷基，芳基，芳烷基，烷酰基，芳酰基，芳烷酰基，杂环，杂环羰基，杂环烷基，杂环 - 烷基 - 羰基，烷基磺酰基，芳基磺酰基，胍基，氨基甲酰基或 呫吨 其中A2至A7各自包含经修饰或未修饰的α-氨基酸残基，由此（i）A1与A2上的氨基连接，（ii）每个A2，A4和A6均带有芳香侧链，该芳族侧 链通过两个或更多个共价键交联在一起，和（iii）A7具有末端羧基，酯，酰胺或N-取代的酰胺基; 并且其中A1至A7中的一个或多个通过糖苷键与一个或多个各自具有一个或多个糖残基的糖苷基连接，至少一个具有一个或多个式YXR，N +（R1）的取代基的糖残基， = CR2R3，N = PR1R2R3，N + R1R2R3或P + R1R2R3，其中Y为单键，O，NR或S; X是O，NR1，S，SO2，C（O）O，C（O）S，C（S）O，C（S）S，C（NR1）O，C（O）NR1或卤素 哪种情况下Y和R不存在）。 包含本发明多种糖肽的化学文库。 通过糖衍生自糖肽抗生素的糖苷配基制备糖肽的方法。 一种通过从糖肽抗生素制备假糖苷配基并糖基化假糖苷配基来制备糖肽的方法。

    Glycopeptide antibiotics, combinatorial libraries of glycopeptide antibiotics and methods of producing same
    7.
    发明申请
    Glycopeptide antibiotics, combinatorial libraries of glycopeptide antibiotics and methods of producing same 失效
    糖肽抗生素，糖肽抗生素组合文库及其生产方法

    公开(公告)号：US20050075483A1

    公开(公告)日：2005-04-07

    申请号：US10676391

    申请日：2003-10-01

    申请人： Daniel Kahne ,  Robert Kerns ,  Seketsu Fukuzawa ,  Min Ge ,  Christopher Thompson

    发明人： Daniel Kahne ,  Robert Kerns ,  Seketsu Fukuzawa ,  Min Ge ,  Christopher Thompson

    IPC分类号： A61K38/00 ,  A61K38/14 ,  A61K38/16 ,  A61P31/04 ,  C07K1/00 ,  C07K1/04 ,  C07K7/50 ,  C07K9/00 ,  C07K14/00 ,  C07K17/00

    CPC分类号： C07K1/047 ,  A61K38/00 ,  C07K9/008 ,  Y10S930/19

    摘要： A glycopeptide of the formula A1-A2-A3-A4-A5-A6-A7, in which each dash represents a covalent bond; wherein A1 comprises a modified or unmodified α-amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl; wherein each of A2 to A7 comprises a modified or unmodified α-amino acid residue, whereby (i) A1 is linked to an amino group on A2, (ii) each of A2, A4 and A6 bears an aromatic side chain, which aromatic side chains are cross-linked together by two or more covalent bonds, and (iii) A7 bears a terminal carboxyl, ester, amide, or N-substituted amide group; and wherein one or more of A1 to A7 is linked via a glycosidic bond to one or more glycosidic groups each having one or more sugar residues, at least one of the sugar residues bearing one or more substituents of the formula YXR, N+(R1)═CR2R3, N═PR1R2R3, N+R1R2R3 or P+R1R2R3 in which Y is a single bond, O, NR1 or S; X is O, NR1, S, SO2, C(O)O, C(O)S, C(S)O, C(S)S, C(NR1)O, C(O)NR1, or halo (in which case Y and R are absent). A chemical library comprising a plurality of the glycopeptides of the invention. A method for preparing a glycopeptide by glycosylation of an aglycone derived from a glycopeptide antibiotic. A method for preparing a glycopeptide by preparing a pseudoaglycone from a glycopeptide antibiotic and glycosylating the pseudoaglycone.

    摘要翻译： 式A1-A2-A3-A4-A5-A6-A7的糖肽，其中每个短划线代表共价键; 其中A1包含经修饰或未修饰的α-氨基酸残基，烷基，芳基，芳烷基，烷酰基，芳酰基，芳烷酰基，杂环，杂环羰基，杂环烷基，杂环 - 烷基 - 羰基，烷基磺酰基，芳基磺酰基，胍基，氨基甲酰基或 呫吨 其中A2至A7各自包含经修饰或未修饰的α-氨基酸残基，由此（i）A1与A2上的氨基连接，（ii）每个A2，A4和A6均带有芳香侧链，该芳族侧 链通过两个或更多个共价键交联在一起，和（iii）A7具有末端羧基，酯，酰胺或N-取代的酰胺基; 并且其中A1至A7中的一个或多个通过糖苷键连接至每个具有一个或多个糖残基的一个或多个糖苷基，至少一个含有一个或多个式YXR，N + （R1）= CR2R3，N = PR1R2R3，N + R1R2R3或P + R1R2R3，其中Y为单键，O，NR1或S; X是O，NR1，S，SO2，C（O）O，C（O）S，C（S）O，C（S）S，C（NR1）O，C（O）NR1或卤素 哪种情况下Y和R不存在）。 包含本发明多种糖肽的化学文库。 通过糖衍生自糖肽抗生素的糖苷配基制备糖肽的方法。 一种通过从糖肽抗生素制备假糖苷配基并糖基化假糖苷配基来制备糖肽的方法。

    Glycopeptide antibiotics, combinational libraries of glycopeptide antibiotics and methods of producing same
    9.
    发明授权
    Glycopeptide antibiotics, combinational libraries of glycopeptide antibiotics and methods of producing same 失效
    糖肽抗生素，糖肽抗生素组合文库及其生产方法

    公开(公告)号：US07331920B2

    公开(公告)日：2008-02-19

    申请号：US10676391

    申请日：2003-10-01

    申请人： Daniel Kahne ,  Robert Kerns ,  Seketsu Fukuzawa ,  Min Ge ,  Christopher Thompson

    发明人： Daniel Kahne ,  Robert Kerns ,  Seketsu Fukuzawa ,  Min Ge ,  Christopher Thompson

    IPC分类号： C40B50/00

    CPC分类号： C07K1/047 ,  A61K38/00 ,  C07K9/008 ,  Y10S930/19

    摘要： Methods for preparing a glycopeptide are disclosed. The methods comprise the steps of selecting a protected glycopeptide of the formula A1-A2-A3-A4-A5-A6-A7, wherein the groups A1 to A7 comprise the heptapeptide structure of naturally occurring vancomycin; at least A4 is linked to a glycosidic group which has a hexose residue linked to A4; and the protected glycopeptide has no free amino or carboxyl groups and has a free primary hydroxyl group only at the 6-position of said hexose residue. The protected glycopeptide is contacted with a compound of the formula ArSO2G where Ar is an aryl group and G is a leaving group under conditions effective to allow reaction of said free primary hydroxyl group to form a glycopeptide sulfonate ester; and the glycopeptide sulfonate ester is contacted with a nucleophile under conditions effective to allow displacement of a sulfonate group to produce a substituted glycopeptide.

    摘要翻译： 公开了制备糖肽的方法。 所述方法包括以下步骤：选择式A 1 -A 2 -A 3 -S 3 -A 4的保护的糖肽， 基团A 1〜A 5 - - - - - - - - - - - - - - - - - 7包含天然存在的万古霉素的七肽结构; 至少A 4连接于具有与A 4连接的己糖残基的糖苷基; 并且保护的糖肽不具有游离氨基或羧基，并且仅在所述己糖残基的6-位具有游离的伯羟基。 保护的糖肽与式ArSO 2 G的化合物接触，其中Ar是芳基，G是离去基团，条件是有效使所述游离伯羟基反应形成糖肽磺酸盐 酯; 并且糖肽磺酸酯在有效使得磺酸酯基取代以产生取代的糖肽的条件下与亲核试剂接触。