EP1146887A1 - Antibiotiques a glycopeptide contenant un residu desmethylvancosamine, banques combinatoires et procedes de production associes - Google Patents

Antibiotiques a glycopeptide contenant un residu desmethylvancosamine, banques combinatoires et procedes de production associes

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Publication number
EP1146887A1
EP1146887A1 EP00903240A EP00903240A EP1146887A1 EP 1146887 A1 EP1146887 A1 EP 1146887A1 EP 00903240 A EP00903240 A EP 00903240A EP 00903240 A EP00903240 A EP 00903240A EP 1146887 A1 EP1146887 A1 EP 1146887A1
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European Patent Office
Prior art keywords
heterocyclic
group
alkyl
carbonyl
linked
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EP00903240A
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German (de)
English (en)
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EP1146887A4 (fr
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Daniel Kahne
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Princeton University
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Princeton University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to glycopeptide compounds bearing a desmethylvancosamine residue, libraries of such compounds and methods of generating those libraries. Substituent groups are substituted on the carbohydrate moieties of these compounds.
  • the libraries are generated using combinatorial chemical techniques that produce a diverse set of carbohydrate functionalities conjugated to an oligopeptide.
  • Glycopeptide antibiotics are characterized by having at least one saccharide group chemically bonded to a rigid peptide structure having a cavity or cleft which acts as a binding site for the substrate used in bacterial cell wall synthesis.
  • the glycopeptide antibiotics are further categorized into various subclasses depending on the identity and interconnections of the amino acids comprising the peptide backbone and the number and substitution pattern of the sugar residues in the molecule.
  • the glycopeptide antibiotics are generally active against Gram-positive bacteria but relatively ineffective against Gram-negative bacteria.
  • Vancomycin is produced by
  • Amycolatopsis orientalis and is often referred to as "the drug of last resort” because it is effective against most multi-drug-resistant gram positive bacteria.
  • vancomycin-resistant strains of some bacteria have emerged. [Cohen M., (1992): Neu H., (1992)]. It is estimated that 5-25% of enterococcal strains in hospitals are now resistant to vancomycin [Axelsen, P.H. et al. (1997)]. Most feared among the bacteria is Staphylococcus aureus, which can result in dangerous respiratory and blood infections. Vancomycin- resistant and vancomycin-insensitive strains of this bacterium have also been recently reported [Milewski (1996)].
  • vancomycin The structural formula of vancomycin is shown below and is characterized by a disaccharide moiety covalently linked to a heptapeptide structure. The structure of vancomycin places it in a class of molecules referred to as the "dalbaheptides.” [Malabarba A., et al. (1997a)]
  • Dalbaheptides in general are characterized by the presence of seven amino acids linked together by peptide bonds and held in a rigid conformation by cross-links through the aromatic substituent groups of at least five of the amino acid residues.
  • the aromatic side-chains of amino acids 2, 4, and 6 are fused together through ether linkages.
  • glycopeptide antibiotics are similar to vancomycin in that they have a glucose residue linked to the aromatic substituent on amino acid 4 through formation of a bond with a phenolic hydroxyl group. The glucose residue, in turn, is linked through its vicinal hydroxyl position to a unique amino sugar, L-vancosamine.
  • the sugars have been separately removed from glycopeptide antibiotics, and it has been found that the presence of both sugars enhances the pharmacokinetic properties of this class of antibiotics. [Nagarajan R. (1988), (1991), (1993]
  • glycopeptide antibiotic teicoplanin which contains an N-alkyl chain on one of the sugars. It is suggested that this N-alkyl chain increases the effective avidity of teicoplanin for surface-bound D-Ala- D-Ala ligands by interacting with the membrane, thus “anchoring" the teicoplanin molecule at the membrane surface.
  • N-alkyl chain increases the effective avidity of teicoplanin for surface-bound D-Ala- D-Ala ligands by interacting with the membrane, thus “anchoring" the teicoplanin molecule at the membrane surface.
  • vancomycin class of glycopeptide antibiotics include the ristocetins, the eremomycins, the avoparcins and teicoplanin. Several of these compounds are shown, together with vancomycin in Figure 1.
  • the chemical structures of all of these compounds include a dalbaheptide structure as the aglycone core, with minor differences in the amino acids and in cross-linking, but differ from each other most distinctively in terms of the nature of the sugar residues as well as the number and points of attachment of sugar residues to the aglycone core.
  • This invention is directed to glycopeptide of the formula A ⁇ -A -A - -A 5 -A -A 7 . in which each dash represents a covalent bond; wherein the group Ai comprises a modified or unmodified ⁇ -amino acid residue, alkyl, aryl, aralkyl, alkanoyl, aroyl.
  • each of the groups A to A 7 comprises a modified or unmodified ⁇ -amino acid residue, whereby (i) the group Ai is linked to an amino group on the group A 2 , (ii) each of the groups A , A and A ⁇ bears an aromatic side chain, which aromatic side chains are cross-linked together by two or more covalent bonds, and (iii) the group A 7 bears a terminal carboxyl, ester, amide, or N- substituted amide group;
  • the groups A] to A 7 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 bears one or more substituents of the formula YXR in which the group Y is a single bond, O, NR, or S; the group X is O, NR,, S, SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR ⁇ )O, C(O)NR ⁇ , or halo (in which case Y and R are absent); and R is hydrogen, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic- alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; Ri is hydrogen, alkyl,
  • aralkanoyl heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and any pharmaceutically acceptable salts thereof; provided that: X and Y are not both O; X and Y are not S and O, or O and S, respectively; and if two or more of said substituents are present, they can be the same or different; and
  • A is linked to a glycosidic group comprising a glucose residue substituted only by hydroxyl and/or amino groups and by attachment via a glycosidic bond to
  • Z is a single bond, NR- t , SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR- O, or C(O)NR- 4 ;
  • Z 2 is a single bond, SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR 5 )O, or C(O)NR 5 ;
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and wherein R is as defined above; provided that when Z? is SO , C(O)O, C(O)S, C(S)O, C(S)S or C(NR 5 )O, then R 2 is not hydrogen.
  • This invention is further directed to a library of glycopeptide compounds.
  • a process for glycosylating a glycopeptide antibiotic, pseudoaglycone, or glycone comprising the steps of attaching at least one sugar bearing one or more desired substituent groups or at least one protected unsubstituted sugar to a nucleophilic group of a glycopeptide antibiotic, pseudoaglycone, or glycone under conditions that permit a glycosylation reaction to take place.
  • the glycosylation reaction involves nucleophilic attack of an activated group on the sugar by a nucleophile found in the glycopeptide antibiotic, pseudoaglycone, or glycone.
  • the activated group includes an activated anomeric sulfoxide.
  • the glycopeptide antibiotic is vancomycin
  • the pseudoaglycone is the pseudoaglycone of vancomycin
  • the aglycone is the aglycone of vancomycin.
  • the process is directed to the preparation of a carbohydrate-modified glycopeptide derivative
  • a sugar having an anomeric sulfoxide substituent with a pseudoglycone or aglycone under conditions that permit a sulfoxide glycosylation reaction to take place.
  • This reaction provides a glycopeptide having a modified carbohydrate group.
  • the sulfoxide glycosylation reaction is generally believed to involve a nucleophilic group of the pseuodoglycone or aglycone, which attacks an activated anomeric sulfoxide moiety of the sugar to form a glycosidic linkage.
  • conditions can be utilized to effect the sulfoxide glycosylation reaction, which can be permitted to take place in solution or over a solid phase.
  • the conditions include effective amounts of trifluoromethanesulfonic anhydride and 2,6-di-t-butylmethylpyridine.
  • the conditions include the presence of boron trifluoride.
  • the sugar comprises a monosaccharide bearing an anomeric sulfoxide substituent, for example.
  • the monosaccharide can then be allowed to come into contact with a pseudoaglycone or an agylcone, as the case may be.
  • the sugar may also comprise a disaccharide bearing an anomeric sulfoxide substituent.
  • the disaccharide is contacted with an aglycone, for instance.
  • the resulting glycosylated product when a monosaccharide is contacted with an aglycone, the resulting glycosylated product might be subjected to a second glycosylation reaction (e.g., a second sulfoxide glycosylation reaction) involving a second sugar.
  • a second glycosylation reaction e.g., a second sulfoxide glycosylation reaction
  • the second sugar can be an azido sugar.
  • Figure 1 contains structure diagrams of vancomycin and related glycopeptide antibiotics.
  • Figures 2A and 2B are graphs showing inhibition of peptidoglycan synthesis by compounds of this invention and controls.
  • a “glycoconjugate” comprises any molecule linked to at least one carbohydrate of any size.
  • the molecule can be a peptide or protein, a nucleic acid, a small molecule, a lipid, or another carbohydrate; it may be of natural or non-natural origin.
  • a “glycopeptide” is a glycoconjugate comprising a peptide linked to at least one carbohydrate.
  • a “glycopeptide antibiotic” is one of the naturally occurring glycopeptides with antibacterial activity, including, e.g., vancomycin, teicoplanin, ristocetin, chloroeremomycin and avoparicin.
  • aglycone is the result of removing the carbohydrate residues from a glycopeptide, leaving only a peptide core.
  • a “pseudoaglycone” is the result of removing only one of two sugar residues of a disaccharide residue linked to residue of a glycopeptide.
  • a pseudoaglycone comprises an aglycone in which A 4 is linked to a monosaccharide residue.
  • a “dalbaheptide” is a glycopeptide containing a heptapeptide moiety which is held in a rigid conformation by cross-links between the aromatic substituent groups of at least five of the seven ⁇ -amino acid residues, including a cross-link comprising a direct carbon-carbon bond between the aryl substituents of amino acid residues 5 and 7, and aryl ether cross-links between the substituents of amino acid residues 2 and 4, and 4 and 6.
  • Amino acid residues 2 and 4-7 in different dalbaheptides are those found in the naturally occurring glycopeptide antibiotics.
  • amino acid residues differ only in that residues 2 and 6 do not always have a chlorine substituent on their aromatic rings, and in that substitution on free hydroxyl or amino groups may be present.
  • Amino acid residues 1 and 3 may differ substantially in different dalbaheptides; if both bear aryl substituents, these may be cross-linked.
  • Molecules having a dalbaheptide structure include, e.g., the glycopeptide antibiotics mentioned above.
  • alkyl refers to a linear or branched acyclic or non-aromatic cyclic group having from one to twenty carbon atoms connected by single or multiple bonds.
  • An alkyl group may be substituted by one or more of halo, hydroxyl, protected hydroxyl, amino, nitro.
  • cyano alkoxy, aryloxy, aralkyloxy, COOH, aroyloxy, alkylamino, dialkylamino, trialkylarnrnoniurn, alkylthio, arylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, heterocyclic, CONH 2 , CONH-alkyl, CON(alkyl) 2 , COO-aralkyl, COO-aryl or
  • aryl refers to a group derived from a non-heterocyclic aromatic compound having from six to twenty carbon atoms and from one to four rings which may be fused or connected by single bonds.
  • An aryl group may be substituted by one or more of alkyl. aralkyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl, halo, hydroxyl, protected hydroxyl.
  • heterocyclic refers to a group derived from a heterocyclic compound having from one to four rings, which may be fused or connected by single bonds; said compound having from three to twenty ring atoms which may be carbon, nitrogen, oxygen, sulfur or phosphorus.
  • a heterocyclic group may be substituted by one or more of alkyl, aryl, aralkyl, halo, hydroxyl, protected hydroxyl, amino, hydrazino, alkylhydrazino, arylhydrazino, nitro, cyano, alkoxy, aryloxy, aralkyloxy, aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio, arylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, COO-alkyl, COO-aralkyl, COO-aryl, CONH 2 , CONH-alkyl or CON(alkyl) 2 .
  • alkoxy refers to groups derived from bonding an oxygen atom to an alkyl, aryl or aralkyl group, respectively.
  • alkanoyl refers to groups derived from bonding a carbonyl to an alkyl, aryl or aralkyl group, respectively.
  • heterocyclic-alkyl and “heterocyclic-carbonyl” refer to groups derived from bonding a heterocyclic group to an alkyl or a carbonyl group, respectively.
  • heterocyclic-alkyl-carbonyl refers to a group derived from bonding a heterocyclic-alkyl group to a carbonyl group.
  • protected hydroxyl refers to a hydroxyl group bonded to a group which is easily removed to regenerate the free hydroxyl group by treatment with acid or base, by reduction, or by exposure to light.
  • Lewis acid refers to any substance that can accept an electron pair from a base, with the exception of the mineral acids and organic carboxylic acids.
  • organic solvent refers to non-aqueous solvents, preferably to ketones, halogenated solvents, ethers, esters and non-heterocyclic aromatic solvents.
  • a “chemical library” is a synthesized set of compounds having different structures. The chemical library may be screened for biological activity to identify individual active compounds of interest.
  • a "glycosyl donor” is a sugar or glycosidic residue that bears an anomeric leaving group, preferably a sulfoxide, which may be activated to render the anomeric carbon susceptible to reaction with a nucleophile to displace the activated group, thereby forming a glycosidic bond.
  • leaving group is a group easily displaced from a sulfonyl group by a nucleophile.
  • Examples of leaving groups are halo, alkoxy, aryloxy, alkanoyloxy and arylsulfonyloxy.
  • DMF N-N-dimethylformamide
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • THF trifluoroacetic acid
  • EtOAc ethyl acetate
  • MeOH methanol
  • MeCN refers to acetonitrile
  • Tf ' refers to the trifluoroacetyl group
  • DMSO dimethyl sulfoxide
  • DIEA diisopropylethylamine
  • All in structural formulas refers to the allyl group
  • Fmoc refers to 9-fluorenylmethyloxycarbonyl
  • HOBt 1- hydroxybenzotriazole and “OBt” to the 1 -oxybenzotriazolyl group
  • PyBOP refers to benzotriazol-1-yl-oxytripyrrolidine-phosphonium hexafluorophosphate
  • Su refers to the succinimidyl group
  • HBTU refers to O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • aloe refers to allyloxycarbony
  • glycopeptide compositions of this invention have the formula A ⁇ -A 2 -A 3 -A -A 5 -A 6 -A 7 , in which each dash represents a covalent bond; wherein the group Ai comprises a modified or unmodified ⁇ -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 the groups A 2 to A 7 comprises a modified or unmodified ⁇ -amino acid residue, whereby (i) the group Ai is linked to an amino group on the group A 2 , (ii) each of the groups A 2 , A and A bears an aromatic side chain, which aromatic side chains
  • one or more of the groups A, to A 7 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 bears one or more substituents of the formula YXR in which the group Y is a single bond, O, NR, or S; the group X is O, NR,, S, SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR,)O, C(O)NR ⁇ , or halo (in which case Y and R are absent); and R and R, are independently hydrogen, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and any
  • a 4 is linked to a glycosidic group comprising a glucose residue substituted only by hydroxyl and/or amino groups and by attachment via a glycosidic bond to
  • Z is a single bond, NIL,, SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR- O, or C(O)NR-,;
  • Z 2 is a single bond, SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR 5 )O, or C(O)NR 5 ;
  • R 2 , R3, R4 and R 5 are independently hydrogen, alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and wherein R is as defined above; provided that when Z 2 is SO 2 , C(O)O,
  • R 2 is not hydrogen.
  • the substitution on the glucose residue, other than the desmethylvancosamine residue is not limited to hydroxyl and/or amino groups as described above.
  • the glycopeptide has the formula A 1 -A 2 -A 3 -A -A 5 -
  • each dash represents a covalent bond; wherein the group Ai comprises a modified or unmodified ⁇ -amino acid residue, alkyl, aryl, aralkyl, alkanoyl. aroyl.
  • each of the groups A 2 to A 7 comprises a modified or unmodified ⁇ -amino acid residue, whereby (i) the group A, is linked to an amino group on the group A 2 , (ii) each of the groups A 2 , A 4 and A 6 bears an aromatic side chain, which aromatic side chains are cross-linked together by two or more covalent bonds, and (iii) the group A 7 bears a terminal carboxyl, ester, amide, or N- substituted amide group;
  • one or more of the groups A, to A 7 is linked via a glycosidic bond to one or more glycosidic groups each having one or more substituted or unsubstituted sugar residues, provided that A is linked to a glycosidic group comprising a glucose residue substituted only by hydroxyl and/or amino groups and by attachment via a glycosidic bond to
  • Z is a single bond, NR 4 , SO 2 , C(O)O, C(O)S, C(S)0. C(S)S, C(NR4)O, or C(O)NR 4 ;
  • Z 2 is a single bond, SO 2 , C(O)O, C(O)S, C(S)O, C(S)S, C(NR 5 )O, or C(O)NR 5 ;
  • R, R 2 , R 3 , R 4 and R 5 are independently hydrogen, alkyl, aryl, aralkyl.
  • alkanoyl aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic-alkyl-carbonyl, alkylsulfonyl or arylsulfonyl; and any pharmaceutically acceptable salts thereof; provided that when Z 2 is SO 2 , C(O)O, C(O)S, C(S)O, C(S)S or C(NR 5 )O, then R 2 is not hydrogen.
  • Modified amino acid residues include amino acid residues whose aromatic groups have been substituted by halo, alkyl, alkoxy, alkanoyl, or other groups easily introduced by electrophilic substitution reactions or by reaction of phenolic hydroxyl groups with alkylating or acylating agents; and amino acid residues which have protecting groups or other easily introduced substituents on their hydroxyl or amino groups, including, but not limited to alkyl, alkanoyl, aroyl, aralkyl, aralkanoyl, carbamoyl, alkyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclic, heterocyclic-alkyl or heterocyclic- carbonyl substituents.
  • Examples of preferred protecting groups include acetyl, allyloxycarbonyl (aloe), CBz, allyl, benzyl, p-methoxybenzyl and methyl. Modifications of hydroxyl groups occur on phenolic hydroxyl groups, benzylic hydroxyl groups, or aliphatic hydroxyl groups. Other amino acid residues, in addition to A 2 , A 4 and A 6 , may be cross- linked through their aromatic substituent groups.
  • residues A 2 to A 7 of the glycopeptide are linked sequentially by peptide bonds and are cross-linked as in a dalbaheptide, as defined hereinabove.
  • the preferred glycopeptides thus have a peptide core in which the residues are linked as in the natural glycopeptide antibiotics, as shown in Figure 1. Substitution of different amino acids at A is permitted, as are modified amino acid residues at all positions, as described hereinabove.
  • residue A is an ⁇ -amino acid, which may be substituted on the terminal amino group by alkyl, aryl, aralkyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-carbonyl, heterocyclic alkyl, alkylsulfonyl, arylsulfonyl, guanidinyl, carbamoyl, or xanthyl, and the structures and interconnections of A, to A 7 are those of vancomycin, i.e., the glycopeptide has the heptapeptide core of vancomycin, subject to the amino acid modifications and substitutions on A, and A described hereinabove.
  • glycopeptides of this invention contain at least one glycosidic group attached through a glycosidic bond to the residues A, to A 7 .
  • a glycosidic group is linked to residue A-j; this glycosidic group comprises a glucose residue that is attached directly to A .
  • the glucose residue is in turn linked through a glycosidic bond to a desmethylvancosamine residue.
  • the glucose residue is substituted only by hydroxyl groups, amino groups, or a combination thereof, in addition to the desmethylvancosamine residue, and more preferably, the glucose residue is not substituted by any amino groups.
  • the desmethylvancosamine residue lacks the methyl group which is geminal to the amino group in the naturally occurring vancosamines.
  • the glycosidic group attached to A4 is a disaccharide consisting only of a glucose residue and a desmethylvancosamine residue. It is further preferred that no other position on the glycopeptide is substituted by a glycosidic group.
  • Z 2 is a single bond and R 2 is hydrogen, alkyl, alkanoyl, aroyl or aralkanoyl. It is further preferred that R 3 is hydrogen and Z, is a single bond, and still more preferred that R is alkyl, aralkyl, alkanoyl, aroyl or aralkanoyl.
  • R is aralkyl (4-(4-chlorophenyl)benzyl)
  • R 3 is hydrogen and Z, is a single bond.
  • the compounds are prepared by glycosylation of a pseudoaglycone with a glycosylating agent derived from a desmethylvancosamine.
  • the glycosylating agent is a desmethylvancosamine bearing an anomeric sulfoxide group.
  • An example of such a glycosylation reaction between a partially protected vancomycin pseudoaglycone and a protected desmethylvancosamine bearing an anomeric phenyl sulfoxide substituent is shown in Scheme 2.
  • the compounds of this invention are also accessible via glycosylation of an aglycone with a glycosylating agent comprising a glucose residue and a desmethylvancosamine residue.
  • the chemical library of compounds of this invention is prepared to explore the effects of introducing a large number of different substituents on glycopeptides on biological activity, especially substitutions on the sugar residues.
  • at least two steps are performed, each of which introduces a substituent group on the glycopeptide.
  • a combinatorial format is established in which many different predetermined substituent groups are introduced independently at each of at least two positions, resulting in a library containing a large number of glycopeptides, wherein each possible combination of the predetermined substituent groups is represented.
  • Substituents are introduced on the glycopeptide library compounds of this invention in two ways: (1) by using glycosylation reactions to attach sugars bearing desired substituent groups to hydroxyl groups on various positions of glycopeptide antibiotics, aglycones, or pseudoaglycones, as described in detail hereinbelow; and (2) by using glycosylation reactions to attach protected unsubstituted sugars, followed by partial deprotection of the sugar and introduction of a substituent on a deprotected amino, hydroxyl or thiol group via known reactions, e.g., alkylation, reductive amination, esterification.
  • at least two steps are carried out in a combinatorial format. These steps are selected independently from the two reaction schemes outlined hereinabove, such that a library is constructed using either scheme exclusively or a combination of the two.
  • a modified sulfoxide glycosylation of the aglycone phenolic hydroxyl group may be accomplished using an acetate or other unhindered ester at C-2 of the sugar as a neighboring group.
  • the leaving group at the anomeric center is a sulfoxide moiety which is activated by trifiuoromethanesulfonic anhydride (Tf 2 O) in the presence of 2,6-di-t-butylmethylpyridine.
  • Tf 2 O trifiuoromethanesulfonic anhydride
  • BF 3 prevents formation of the undesired ortho-ester side product which is unstable in the presence of acid.
  • Use of the modified procedure leads to the desired ⁇ glycosidic linkage.
  • the use of BF 3 is an improvement because previously the presence of a very bulky ester at C-2 (e.g., pivalate) was required to prevent formation of the undesired ortho-ester during formation of a ⁇ glycosidic linkage by the sulfoxide method using neighboring group participation. These bulky esters can be very difficult to remove, except under strongly basic conditions.
  • a suitable resin is a cross-linked polymer insoluble in the reaction solvent which is suitably functionalized for attachment, e.g., SASRIN (Wang's resin).
  • this hydroxyl group is freed before attachment to the resin, since the hydroxyl group does not interfere with the coupling reaction.
  • the free hydroxyl group then serves as the nucleophile in a second glycosylation reaction.
  • the hydroxyl is glycosylated, preferably in a solid phase reaction, with a variety of azido sugars.
  • the azido groups are reduced and the resulting amino groups are then derivatized.
  • the solid phase portion of the library construction can be carried out using a parallel synthesis or a mix and split strategy.
  • the carbohydrate-modified glycopeptide derivatives would then be deprotected and cleaved from the resin. This set of compounds would then be assayed for peptide binding and antibacterial activity.
  • protecting groups When it is desired to remove protecting groups from any of the compounds of this invention, their removal is accomplished using methods well known to those skilled in the art.
  • the preferred method for removal of protecting groups is as follows. Aloe groups on amines, and allyl esters or allyl ethers are removed by using Pd(0) mediated reactions, e.g., [Ph 3 P] 2 Pd(II)Cl 2 and Bu 3 SnH in 1 :1 acetic acid:DMF. Acetate protecting groups are removed using hydrazine in THF/methanol.
  • the pseudoaglycone 5 (214 mg, 0J22 mmol) is azeotroped with toluene three times (1 mL each), dissolved in 6 mL CH 2 C1 2 and then cooled to -78°C.
  • BF 3 OEt 2 (30 ⁇ L, 0.244 mmol) is added followed by triflic anhydride (20.5 ⁇ L, 0J22 mmol).
  • a solution of sulfoxide 4 (93 mg, 0.244 mmol) in 0.3 mL Et 2 ⁇ is added dropwise over 15 minutes. The reaction is allowed to warm up to -10°C in 1 hour and then quenched with a mixture of 200 ⁇ L methanol and 200 ⁇ L DIEA.
  • the compound 7 (8J mg, 0.0046 mmol) is dissolved in 0.5 mL DMF/0.5 mL acetic acid.
  • tributyltin hydride in 100 ⁇ L portions every 5 minutes until the starting material and all intermediates disappear by TLC.
  • the crude reaction mixture is precipitated with 30 mL acetone in a 50 mL centrifuge tube. The mixture is centrifuged and decanted to give a white solid. This white solid is dissolved in 5 mL water and kept at 4°C overnight.
  • the suspension is filtered through a disposable 13 mm syringe filter (Whatman Inc.) and the resulting filtrate is concentrated and purified by reverse-phase HPLC using a PHENOMENEX LUNA C18 column (21.2x250mm), 5 ⁇ m particle, eluted with 0.1% trifluoroacetic acid (TFA) in water for 2 minutes and then a 30 min. linear gradient of 0.1% TFA in water to 20% acetonitrile/0J% TFA in water; flow rate of 7.5 mL/min. and ultraviolet (UN) detection at 285 nm. The fractions containing the product are combined and lyophilized to give 5.6 mg (79%) of 8 as its TFA salt as a white solid.
  • TFA trifluoroacetic acid
  • the reaction is stirred at 65°C for 2.5h, then cooled down to room temperature and poured into 10 mL of ether.
  • the precipitate is purified by reverse-phase HPLC using a PHENOMENEX LUNA C18 column (21.2x250mm), 5 ⁇ m particle, eluted with a 30 min. linear gradient of 10% acetonitrile/0J% acetic acid in water to
  • Vancomycin hydrochloride (3.0 g, 2 mmol) is dissolved in 25 mL water and 25 mL dioxane.
  • NaHCO (554 mg, 6.6 mmol) in 10 mL water is added to the reaction solution followed by N-(allyloxy carbonyloxy) succinimide (2 g, 8 mmol) in 10 mL dioxane.
  • the reaction is stirred at room temperature for 3 hours and then poured into 1000 mL acetone.
  • the white suspension is divided into 4 centrifuge tubes and centrifuged at 4000 rps for 5 minutes. The precipitate is collected and combined to give 3.8 g of vancomycin dialloc as white solid. Part of this white solid (2.7g) is subjected to next reaction without further purification.
  • Tf 2 O 200 ⁇ L, 335 mg, 1.19 mmol
  • pyridine 100 ⁇ L, 97.8 mg, 1.24 mmol
  • the reaction mixture is poured into saturated NaHCO 3 solution (10 mL).
  • the organic and aqueous layers are separated, and the aqueous layer is extracted with CH 2 C1 2 (3 x 5 mL).
  • the organic layers are combined and washed with IN HC1 (10 mL) and saturated NaHCO 3 (10 mL), dried over Na 2 SO 4 , filtered, and concentrated. Purification is accomplished by flash chromatography (7%
  • the ⁇ anomer of this product is prepared in exactly the same way; spectroscopic data for this compound are identical to those given for lb.
  • Lipid intermediate I consists of bactoprenol MurNAc- pentapeptide.
  • Lipid intermediate II consists of bactoprenol-GlcNAc-MurNAc-pentapeptide.
  • HAWP membrane filters from the reaction run in the absence of penicillin G Since peptidoglycan synthesis occurs sequentially, the site of inhibition can be determined by the pattern of inhibition, as shown in the following table:
  • ramoplanin is an inhibitor of the transferase step in stage II.
  • the compound inhibits incorporation into all three fractions.
  • Bambermycin is the only known inhibitor of the transglycosylase step and it inhibits incorporation into the material retained by the PVDF filters and into the fraction that is insoluble in hot SDS but not into the butanol-soluble fractions.
  • Cefoxitin inhibits transpeptidation. It only inhibits incorporation of [ rl I 4 4 ,C]GlcNAc into the hot SDS-insoluble fraction.
  • Compound 9 is tested for activity in ether-treated bacteria (ETB) prepared from E. coli W7. Vancomycin, N-4-(4-chlorophenyl)benzylvancosamine vancomycin, and compound 8 are also tested for activity. The results are presented in Figures 2 A and 2B. Compounds 8 and 9 display inhibition of peptidoglycan synthesis. Compound 9 displays inhibition at lower levels than vancomycin. Moreover, compound 9 appears to function as a direct transglycosylase inhibitor, unlike vancomycin.
  • ETB ether-treated bacteria

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Abstract

La présente invention concerne un glycopeptide de formule A1-A2-A3-A4-A5-A6-A7, dans laquelle chaque tiret représente une liaison covalente, et dans laquelle le groupe A1 comprend un reste acide α-aminé modifié ou non modifié, un groupe alkyle, aryle, aralkyle, alcanoyle, aroyle, aralcanoyle, un groupe hétérocyclique, carbonyle hétérocyclique, alkyle hétérocyclique, alkyl-carbonylehétérocyclique, akylsulfonyle, arylsulfonyle, guanidinyle, carbamoyle, ou xanthyle; chacun des groupes A2 à A7 comprend un reste acide α-aminé modifié ou non modifié, (i) A1 étant lié à un groupe amino sur A2, (ii) A2, A4 et A6 portant chacun une chaîne latérale aromatique, lesquelles chaînes latérales aromatiques étant réticulées ensemble par au moins deux liaisons covalentes, et (iii) A7 portant un groupe terminal carboxyle, ester, amide, ou un groupe amide N-substitué. Dans cette formule, un ou plusieurs groupes parmi les groupes A1 à A7 sont liés via une liaison glycosidique à un ou plusieurs groupes glycosidiques comportant chacun un ou plusieurs restes sucres, l'un des restes sucres au moins portant un ou plusieurs substituants de formule YXR, pourvu que A4 soit lié à un groupe glycosidique portant un reste glucose substitué seulement par des groupes hydroxyles et/ou amino, et à la formule (II) par attachement via une liaison glycosidique.
EP00903240A 1999-01-12 2000-01-12 Antibiotiques a glycopeptide contenant un residu desmethylvancosamine, banques combinatoires et procedes de production associes Withdrawn EP1146887A4 (fr)

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WO2000004044A1 (fr) * 1998-07-14 2000-01-27 Princeton University Antibiotiques glycopeptidiques, bibliotheques combinatoires d'antibiotiques glycopeptidiques, et procedes de production correspondants
WO2000069892A1 (fr) * 1999-05-19 2000-11-23 Princeton University Antibiotiques de glycopeptide, bibliotheques de combinaisons d'antibiotiques de glycopeptides et procedes de production de ces derniers
BRPI0821947A2 (pt) * 2007-12-26 2015-09-22 Shionogi & Co derivados de antibiótico de glicopetídeo glicosilatado
HUE063288T2 (hu) * 2015-01-16 2024-01-28 Zoetis Services Llc Száj és körömfájás betegség vakcina

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US4742045A (en) * 1986-07-30 1988-05-03 Smithkline Beckman Corporation Glycopeptide antibiotics
US4882313A (en) * 1987-07-31 1989-11-21 Smithkline Beckman Corporation Carboxamide derivatives of glycopeptides
DE4013077A1 (de) * 1990-04-25 1991-10-31 Hoechst Ag Verfahren zur glycosidasekatalysierten synthese von glycokonjugaten

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Title
MALABARBA A ET AL: "STRUCTURAL MODIFICATIONS OF GLYCOPEPTIDE ANTIBIOTICS" MEDICINAL RESEARCH REVIEWS, NEW YORK, NY, US, vol. 17, no. 1, 1997, pages 69-137, XP000985926 ISSN: 0198-6325 *
MALABARBA A NICAS TI CIABATTI R: "Glycopeptide resistance in multiple antibiotic-resistant Gram-positive bacteria: a current challenge for novel semi-synthetic glycopeptide derivatives" EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 32, no. 6, 1 June 1997 (1997-06-01), pages 459-478, XP004088458 ISSN: 0223-5234 *
See also references of WO0041710A1 *

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