EP1147118A1 - Disaccharides a liaison alpha non substitues - Google Patents

Disaccharides a liaison alpha non substitues

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Publication number
EP1147118A1
EP1147118A1 EP00906899A EP00906899A EP1147118A1 EP 1147118 A1 EP1147118 A1 EP 1147118A1 EP 00906899 A EP00906899 A EP 00906899A EP 00906899 A EP00906899 A EP 00906899A EP 1147118 A1 EP1147118 A1 EP 1147118A1
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European Patent Office
Prior art keywords
hydrogen
heterocyclic
alkyl
single bond
group
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EP00906899A
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German (de)
English (en)
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EP1147118A4 (fr
Inventor
Daniel Kahne
Min Ge
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Princeton University
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Princeton University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to substituted alpha-linked disaccharide compounds comprising two hexose residues. These compounds are useful as antibiotics, and are believed to function as transglycosylase inhibitors.
  • Peptidoglycan synthesis in bacteria is known to proceed in stages, the last of which involves transglycosylation of the disaccharide building blocks and cross-linking of the peptide chains attached thereto.
  • Compounds that inhibit transglycosylation are potentially very useful as antibiotics.
  • a disaccharide fragment of moenomycin inhibits transglycosylase activity with the same potency as moenomycin itself. This disaccharide, as shown below,
  • This invention is directed to a disaccharide compound comprising two hexose residues joined by an alpha glycosidic linkage.
  • the compound has the formula
  • R 2 Y 2 Y ⁇ is bonded to a ring carbon atom adjacent to the alpha glycosidic linkage;
  • and R 3 are independently hydrogen, alkyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl or heterocyclic-alkyl-carbonyl;
  • R 2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl, heterocyclic-alkyl-carbonyl or a peptide comprising 2-6 amino acid residues
  • Rj, R 2 and R 3 are not hydrogen or methyl; when p is 0, Xi is a single bond, and X 2 is NR 12 , then Ri is not benzoyl or methylbenzoyl; when X 2 is C(O)O, C(O)S, C(S)O, C(S)S or C(NR 12 )O, then Ri is not hydrogen; when Y 2 is C(O)O, C(O)S, C(S)O, C(S)S or C(NR 12 )O, then R 2 is not hydrogen; when Z 2 is C(O)O, C(O)S, C(S)O, C(S)S or C(NR 12 )O, then R 3 is not hydrogen; and when R 2 is a peptide comprising 2-6 amino acid residues, then Rj is not hydrogen or methyl.
  • This invention is also directed to a method for preparation of these compounds by allowing a first monosaccharide having the formula
  • R 2 Y 2 Y ⁇ is bonded to a ring carbon atom adjacent to a free hydroxyl group; and none of R 2 Y 2 Y ⁇ , W 1 R 4 , W 2 R5 and Z 1 Z 2 R3 is a free hydroxyl, amino or thiol group, or bears a free hydroxyl, amino or thiol group; to react with a second monosaccharide having the formula
  • Ar is an aryl group, and none of R 8 , R ⁇ W 3 , R 7 W 4 and X)X 2 R ⁇ is a free hydroxyl, amino or thiol group, or bears a free hydroxyl, amino or thiol group; and an activating agent; via a glycosylation reaction in which an alpha glycosidic linkage is formed between the first monosaccharide and the second monosaccharide.
  • This invention is also directed to a method for preparing a disaccharide compound comprising two hexose residues joined by an alpha glycosidic linkage; said compound having the formula
  • Ri and R 3 are independently hydrogen, alkyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl or heterocyclic-alkyl-carbonyl;
  • R 2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl, heterocyclic-alkyl-carbonyl or a peptide comprising 2-6 amino acid residues;
  • Ri is not hydrogen or methyl
  • Ri is not benzoyl or methylbenzoyl
  • X 2 is C(0)0, C(0)S, C(S)0, C(S)S or C(NR ⁇ 2 )0
  • R x is not hydrogen
  • Y 2 is C(0)0, C(0)S, C(S)0, C(S)S or C(NR, 2 )0, then
  • R 2 is not hydrogen; when Z 2 is C(0)0, C(0)S, C(S)0, C(S)S or C(NR ⁇ 2 )0, then R 3 is not hydrogen; and when R 2 is a peptide comprising 2-6 amino acid residues, then R] is not hydrogen or methyl;
  • said method comprising:
  • R 2 Y 2 1 is bonded to a ring carbon atom adjacent to a free hydroxyl group; and none of R 2 Y 2 Yj, W 1 R 4 , W 2 R 5 and Z ⁇ Z 2 R 3 is a free hydroxyl, amino or thiol group, or bears a free hydroxyl, amino or thiol group;
  • Ar is an aryl group, and none of R 8 , R ⁇ W 3 and R 7 W 4 is a free hydroxyl, amino or thiol group, or bears a free hydroxyl, amino or thiol group; and an activating agent; and
  • This invention is further directed to a chemical library comprising a plurality of these compounds, and to a method of treating bacterial infections in humans by administering an effective amount of the compound.
  • Figure 1 is a graph showing the effects on macromolecular synthesis in Bacillus megaterium MB410 of known antibiotics.
  • Figure 2 is a graph showing the effect of compound 6a on synthesis of RNA, DNA, protein and peptidoglycan in comparison with the effects of vancomycin and ampicillin.
  • Figures 3 A and 3B are graphs showing the activity of compound 6a in ether-treated bacteria, and the site of inhibition of peptidoglycan synthesis.
  • Figures 4 - 7 are tables presenting results obtained on several compounds of this invention, along with controls, for synthesis of RNA, DNA, protein and peptidoglycan, and for the site of inhibition of peptidoglycan synthesis in ether treated bacteria.
  • alkyl refers to an 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, trialkylammonium, alkylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, heterocyclic, CONH 2 , CONH-alkyl, CONH-aryl, CONH- aralkyl, CON(alkyl) 2 , COO-aralkyl, COO-aryl, COO-heterocyclic, COO-alkyl or phosphonium substituted by any combination of alkyl, aryl, aralkyl or heterocyclic.
  • 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, amino, hydrazino, alkylhydrazino, arylhydrazino, nitro, cyano, alkoxy, aryloxy, aralkyloxy, aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, COO-alkyl, COO-aralkyl
  • 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, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, COO-alkyl, COO-aralkyl, COO-aryl, COO-heterocyclic, CONH 2 , CONH- alkyl, CONH-aryl, CONH-aralkyl, CON(alkyl) 2 or phosphonium substituted by any combination of alkyl, aryl
  • 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.
  • hydroxyl protecting group refers to a group bonded to a hydroxyl group which is easily removed to regenerate the free hydroxyl group by treatment with acid or base, by reduction, or by exposure to light.
  • exemplary hydroxyl protecting groups include, without limitation, acetyl, chloroacetyl, pivaloyl, benzyl, benzoyl, p- nitrobenzoyl, tert-butyl-diphenylsilyl, allyloxycarbonyl and allyl.
  • amino protecting group and “thiol protecting group” refer to groups bonded to an amino or thiol group, respectively, which are easily removed to regenerate the free amino or thiol group, respectively, by treatment with acid or base, by reduction, or by exposure to light.
  • amino protecting groups include, without limitation, Fmoc, CBz, aloe and alkanoyl and alkoxycarbonyl groups.
  • thiol protecting groups include, without limitation, alkanoyl and aroyl groups.
  • a “glycopeptide” is a compound comprising a peptide linked to at least one carbohydrate.
  • An “aglycone” is the result of removing the carbohydrate residues from a glycopeptide, leaving only a peptide core.
  • 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. These 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., vancomycin and teicoplanin.
  • 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.
  • the disaccharide compound of the present invention comprises two hexose residues joined by an alpha glycosidic linkage. At least one of the hexose residues is substituted by a lipid group, i.e., an organic functional group having from 2-30 carbon atoms, preferably 2-20 carbon atoms and may also contain heteroatoms.
  • the lipid group may be linear, branched, or cyclic, and may include aliphatic, aromatic and/or heterocyclic groups.
  • a number of substituents can also be present on the hexose rings, in particular the ring not bearing the lipid group. However, the substituents exclude peptidic moieties having demonstrable transpeptidase inhibitory activity.
  • the disaccharide of the invention exhibits anti-infective, preferably antibiotic activity. Most preferably, the compound of the invention exhibits transglycosylase inhibitory activity.
  • the disaccharide compound has the formula (I)
  • R 2 Y 2 Y ⁇ is bonded to a ring carbon atom adjacent to the alpha glycosidic linkage;
  • R) and R 3 are independently hydrogen, alkyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl or heterocyclic-alkyl-carbonyl;
  • R 2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkanoyl, aroyl, aralkanoyl, heterocyclic, heterocyclic-alkyl, heterocyclic-carbonyl, heterocyclic-alkyl-carbonyl or a peptide comprising 2-6 amino acid
  • Rj, R 2 and R 3 are not hydrogen or methyl; when p is 0, X, is a single bond, and X 2 is NRn, then Ri is not benzoyl or methy lbenzoyl; when X 2 is C(0)0, C(0)S, C(S)0, C(S)S or C(NR, 2 )0, then Ri is not hydrogen; when Y 2 is C(0)0, C(0)S, C(S)0, C(S)S or C(NR 12 )0, then
  • R 2 is not hydrogen; when Z 2 is C(0)0, C(0)S, C(S)0, C(S)S or C(NR, 2 )0, then R 3 is not hydrogen; and when R 2 is a peptide comprising 2-6 amino acid residues, then Rj is not hydrogen or methyl.
  • the alpha glycosidic linkage results in a very different relative spatial presentation of the hydroxyls and other functional groups on the two sugars than would be observed for any other linkage.
  • the transglycosylase activity displayed by the compounds of this invention could not have been predicted based on the activity of moenomycin and its derivatives, which have beta glycosidic linkages.
  • Another consequence of the unique shape of the disaccharide compounds of this invention is that a great variety of substituents may be introduced without destroying the antibiotic activity of this compound.
  • R 2 is a peptide comprising 2-6 amino acid residues
  • R is any natural or synthetic peptide in the stated size range. It is preferred that R 2 has the formula A 2 -A 3 -A 4 -A 5 -A 6 -A 7 , in which each dash represents a covalent bond; wherein each of the groups A 2 to A 7 comprises a modified or unmodified ⁇ -amino acid residue, whereby (i) 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 (ii) the group A bears a terminal carboxyl, ester, amide, or N-substituted amide group.
  • R 2 is one of the dalbaheptide aglycones of the natural vancomycin family of antibiotics from which the leucine residue has been removed completely, thereby producing a hexapeptide. It is not intended that R 2 is a glycopeptide.
  • 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 , may be cross-linked through their, aromatic substituent groups.
  • R 2 Y 2 Y ⁇ group is attached to the anomeric position of a monosaccharide and the alpha glycosidic linkage is attached to the 2-position of the same monosaccharide. It is further preferred
  • Wi, W 2 and W 3 are O. It is also preferred that at least one of Ri, R 2 and R 3 is not acetyl, benzyl or benzoyl. It is also preferred that at least two substituents on the disaccharide are not hydroxyl, amino, protected hydroxyl or protected amino. In one embodiment of the invention, it is preferred that R 8 is hydrogen and p is 0, further preferred that k is 1 and m is 0, still further preferred that r is 1, and most preferred that X] is a single bond and X 2 is NR ⁇ 2 .
  • Zj is a single bond
  • Z 2 is O, S or NRj 4
  • Rj, R5 and Rs are hydrogen
  • X) is a single bond
  • X 2 is NR ⁇ 2
  • Yi is a single bond
  • Y 2 is O.
  • X]X 2 Ri and a CH 3 group are both attached to the 3-position of a monosaccharide.
  • the disaccharide is derived from the disaccharide component of vancomycin, which has a glucose residue attached through its 2-position to a vancosamine residue.
  • Examples of such disaccharides are shown below in Scheme 1.
  • the vancosamine residue may lack the methyl group geminal to the amine, as in compound 11.
  • Compounds 1 1 , 6a and 6c are substituted with an N-4-(4-chlorophenyl)benzyl substituent on the vancosamine nitrogen, while compound 6b has an n-decyl substituent on the vancosamine nitrogen.
  • Compounds 1 1, 6a and 6b have an equatorial 2,6- dimethoxyphenyl substituent on the glucose anomeric hydroxyl, while compound 6c has an axial methoxy substituent.
  • the compounds of formula (I) are prepared by allowing a first monosaccharide having the formula
  • R 2 Y 2 Y] is bonded to a ring carbon atom adjacent to a free hydroxyl group; and none of R 2 Y 2 Y ⁇ , W 1 R 4 , W 2 R5 and Z]Z 2 R 3 is a free hydroxyl, amino or thiol group, or bears a free hydroxyl, amino or thiol group; to react with a second monosaccharide having the formula
  • Ar is an aryl group, and none of Rg, 6W3, R 7 W 4 and X ⁇ X 2 Rj is a free hydroxyl, amino or thiol group, or bears a free hydroxyl, amino or thiol group; and an activating agent; via a glycosylation reaction in which an alpha glycosidic linkage is formed between the first monosaccharide and the second monosaccharide.
  • XjX 2 R] substituent after deprotection is an amino or alkylamino group, i.e., when Xi is a single bond, X 2 is NR ⁇ 2 and Rj is hydrogen
  • the disaccharide is contacted with an alkylating agent capable of reacting with the amino or alkylamino group to produce an alkylated substituent.
  • suitable alkylating agents include, without limitation, alkyl halides, alkyl sulfonate esters, and aldehydes or ketones under reactive amination conditions.
  • the X ⁇ X 2 R] substituent is replaced by an azido group, i.e., the second monosaccharide bears a group (CH 2 ) P N 3 .
  • the azido group preferably is reduced to an amino group using one of the suitable reducing agents that are well known in the art. This method is exemplified in Scheme 3.
  • the anomeric aryl sulfoxide group is activated by contacting it with an organic acid anhydride which will react with the sulfoxide.
  • the organic acid anhydride may be an anhydride of a sulfonic acid, of two different sulfonic acids or of a sulfonic acid and a carboxylic acid.
  • the preferred organic acid anhydride is trifluoromethanesulfonic anhydride (triflic anhydride, Tf 2 0).
  • a non-nucleophilic mild base is also added to the reaction mixture.
  • Suitable non-nucleophilic mild bases include, but are not limited to, porphyrins, 2,6-dialkylanilines, acetamides, 2,6-dialkylpyridines and co-solvents such as ethyl acetate or ethers.
  • the preferred base is 2,6-di-tert-butyl-4-methylpyridine (DTBMP).
  • a partially protected glucose, la or lb, having one free hydroxyl group is allowed glycosylated product 3a or 3b, respectively.
  • the ⁇ -thiophenoxy substituent in 3b is converted to an ⁇ - methoxy substituent by treatment with mercury(II) trifluoroacetate and DTBMP to give 3c.
  • Treatment of 3a or 3c with hydrazine gives the partially deprotected product 4a or 4b, respectively.
  • Hydrogenation of 4a or 4b gives completely deprotected product 5a or 5b, respectively.
  • chlorobiphenyl aldehyde 4-(4- chlorophenyl)benzaldehyde
  • 1 -decanal under conditions effective for reductive amination gives products 6a-6c, as shown.
  • This approach may be used to introduce a variety of XiX 2 Ri and R 2 Y 2 Y ⁇ substituent groups at the vancosamine nitrogen and at the glucose anomeric carbon.
  • Scheme 3 shows the reaction of a partially protected glucose la with a hexose bearing an anomeric sulfoxide substituent 7.
  • compound 7 is a desmethyl vancosamine derivative.
  • the same sequence of reactions carried out in Scheme 2 produces compound 11, a desmethyl derivative of compound 6a.
  • Particular preferred compounds of this invention are those derived from the desmethyl vancomycin disaccharide and substituted on the C-6 position of the glucose residue, as well as on the vancosamine nitrogen.
  • Derivatives at the C-6 position are produced from intermediates having a mesitylenesulfonyl group at the C-6 position and a protected vancosamine nitrogen.
  • a method for functionalizing the C-6 position is described in copending application Serial No. 09/115,667, titled “Glycopeptide Antibiotics, Combinatorial Libraries of Glycopeptide Antibiotics and Methods of Producing Same," filed July 14, 1998, and which is incorporated herein by reference.
  • a variety of Z]Z 2 R 3 substituent groups are introduced at the glucose-6 position by using common methods for nucleophilic displacement of primary arylsulfonyl groups directly, or by further synthetic modification of initial displacement products, including azido and iodo groups.
  • the iodo group is displaced by a variety of nucleophiles to produce additional C ⁇ -derivatives.
  • a preferred nucleophile is a thiol compound, especially a heterocyclic thiol.
  • Modification of an azido group at the 6-position is performed, e.g., by reducing the azido group to an amino group, which in turn is functionalized by means of reductive alkylation, nucleophilic substitution, or other amino-group reactions well known to those skilled in the art.
  • the substituent R 2 Y 2 Y ⁇ is a peptide having from 2-6 amino acid residues and linked through an oxygen atom to the anomeric carbon atom of the saccharide ring, i.e., Yi is a single bond, Y 2 is O, and R 2 is a peptide having from 2-6 amino acid residues.
  • Yi is a single bond
  • Y 2 is O
  • R 2 is a peptide having from 2-6 amino acid residues.
  • An example of a compound in this embodiment is compound 12, whose preparation and structure are shown below in Scheme 4: Scheme 4
  • the chemical library of compounds of this invention is prepared to explore the effects on biological activity of introducing a large number of different substituents on disaccharides having an alpha glycosidic linkage.
  • at least two steps are performed, each of which introduces a substituent group.
  • a combinatorial format is established in which many different predetermined substituent groups are introduced independently at each of at least two positions on an alpha-linked disaccharide, resulting in a library containing a large number of substituted alpha-linked disaccharides, wherein each possible combination of the predetermined substituent groups is represented.
  • At least two of the X ⁇ X 2 R ⁇ , R 2 Y 2 Y ⁇ and Z)Z 2 R 3 substituent groups are introduced in a combinatorial format, choosing each substituent from a group of possible substituents, thereby generating a chemical library.
  • the methods used to introduce these substituents are those presented in Scheme 2 for introduction of the and R 2 Y 2 Y ⁇ substituent groups, and the method outlined hereinabove for functionalization of the glucose C-6 position with a Z ⁇ R substituent by means of a C-6 mesitylenesulfonyl group.
  • EXAMPLE 1 3-(N-benzyloxy-carbonyloxy)-4-0-acetyl-2,3,6-trideoxy-3-C-methyl- ⁇ -L-lyxo- hexopyranosyl-(l— »2)-3,4,6-tri-0-benzyl- ⁇ -glucopyranoyl 2,6-dimethoxyphenol (3a).
  • the compound la (20 mg, 0.0315 mmol) and DTBMP (32 mg, 0.158 mmol) are azeotroped with toluene 3 times and then dissolved in 2 mL Et 2 0.
  • the reaction solution is cooled to -78 C and 0.5 mL toluene is added.
  • Triflic anhydride (6 ⁇ L, 0.0347 mmol) is added to the reaction solution, and the sulfoxide 2 (28 mg, 0.0629 mmol) in 1 mL Et 0 is added dropwise over 10 minutes.
  • the reaction is warmed up to 0°C in 1 hour and then quenched with 3 mL of saturated aqueous NaHC0 3 solution.
  • EXAMPLE 2 Phenyl 2-(3-N-Cbz-4-0-acetyl-2,3,6-trideoxy-3-C-methyl- ⁇ -L-lyxo-hexopyranosyl)-3,4,6- -tri-O-benzyl- 1 -thio- ⁇ -D-glucopyranoside (3b).
  • EXAMPLE 3 Methyl 2-(3-N-Cbz-4-0-acetyl-2,3,6-trideoxy-3-C-methyl- ⁇ -L-lyxo-hexopyranosyl)-3,4,6- -tri-O-benzyl- ⁇ -D-glucopyranoside (3c).
  • the combined filtrate is concentrated and the residue is purified by reverse-phase HPLC using a PHENOMENEX LUNA Ci8 column (21.2x250 mm), 5 ⁇ m particle, eluting with a 40 minute linear gradient of 0% acetonitrile/0.1% acetic acid in water to 70% acetonitrile/0.1% acetic acid in water; flow rate of 8 mL/min. and UV detection at 270 nm.
  • the fractions containing the pure product are combined and evaporated to give 7 mg (73%) of compound 5a as a white solid.
  • the solution is cooled back to room temperature, concentrated and purified by reverse-phase HPLC using a PHENOMENEX LUNA Ci8 column (21.2x250 mm), 5 ⁇ m particle, eluting with a 30 min. linear gradient of 20% acetonitrile/0.1% acetic acid in water to 70% acetonitrile/0.1% acetic acid in water; flow rate of 8 mL/min. and UV detection at 270 nm.
  • the fractions containing the pure products are combined and evaporated to give 8 mg (90%) of compound 6a as white solid.
  • the combined filtrate is concentrated and the residue is purified by reverse-phase HPLC using a PHENOMENEX LUNA C]8 column (21.2x250 mm), 5 ⁇ m particle, eluting with a 40 minute linear gradient of 0% acetonitrile/0.1% acetic acid in water to 70% acetonitrile/0.1% acetic acid in water; flow rate of 8 mL/min. and UV detection at 270 nm.
  • the fractions containing the pure product are combined and evaporated to give 15 mg (73%) of compound 10 as a white solid.
  • the clear solution is purified by reverse-phase HPLC using a PHENOMENEX LUNA C18 column (21.2 x 250 mm), 5 ⁇ m particle size, eluting with a 30 minute linear gradient of 0.1% acetic acid in water to 60% acetonitrile/0.1% acetic acid in water; flow rate of 8 mL/min. and ultraviolet (UV) detection at 285 nm to give 8 mg of the desired product. Retention time: 23 minutes.
  • ESI-MS calc. for C 72 H 72 N 8 0 23 Cl3 [M+H * ]: 1522.5, found: 1522.5.
  • Compound 6a selectively inhibited peptidoglycan synthesis and RNA synthesis.
  • the inhibition of RNA synthesis is likely not to be a secondary effect of the inhibition of peptidoglycan synthesis because ampicillin had no effect on RNA synthesis.
  • Rifampicin did not inhibit peptidoglycan synthesis.
  • Vancomycin inhibited peptidoglycan synthesis and RNA synthesis.
  • Lipid intermediate I consists of bactoprenol MurNAc-pentapeptide.
  • Lipid intermediate II consists of bactoprenol-GlcNAc-MurNAc-pentapeptide.
  • 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 [ 14 C]GlcNAc into the hot SDS-insoluble fraction.
  • Compound 6a is tested for activity in ether-treated bacteria (ETB) prepared from E. coli VC8 and from E. coli Wl. In the test against the ETB prepared from strain VC8, it is not possible to confirm that inhibition of stage II steps would have been observed. The separation scheme that was designed with strain W7 did operate in the same way with ETB from strain VC8. However, there is good evidence for the inhibition of the transglycosylase step by compound 6a, as shown in Figure 3A.
  • ETB ether-treated bacteria
  • Compound 6a is re-tested with ETB prepared from strain W7. The selectivity test with the known antibiotics confirmed that inhibition of stage II steps is observable with this strain. Again, compound 6a displays a pattern of inhibition that suggests inhibition of the transglycosylase step, as shown in Figure 3B.

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Abstract

L'invention concerne un composé de disaccharide présentant la formule (I); selon laquelle R2Y2Y1 est lié à un atome de carbone de chaîne adjacent à la liaison glycosidique alpha; W1, W2, W3 et W4 représentent chacun O, NH ou S; R8 représente hydrogène, hydroxyle ou un groupe protecteur hydroxyle; k, m, n, p et r sont indépendamment égaux à 0 ou 1; X1 représente une simple liaison, O, NR9 ou S; X2 représente O, NR12, S, C(O)O, C(O)S, C(S)O, C(S)S, C(NR12)O ou C(O)NR12; Y1 représente une simple liaison, O, NR10 ou S; Y2 représente O, NR13, S, C(O)O, C(O)S, C(S)O, C(S)S, C(NR13)O ou C(O)NR13; Z1 représente une simple liaison, O, NR11 ou S; Z2 représente O, NR14 S,C(O)O, C(O)S, C(S)O, C(S)S, C(NR14)O ou C(O)NR14. L'invention concerne en outre un procédé de préparation d'un composé de disaccharide à l'aide d'une réaction de glycosylation de sulfoxyde anomère activé. L'invention a aussi pour objet une bibliothèque chimique comprenant les composés selon l'invention. Enfin, l'invention traite d'un procédé permettant de traiter les infections bactériennes à l'aide de ce procédé.
EP00906899A 1999-01-12 2000-01-12 Disaccharides a liaison alpha non substitues Withdrawn EP1147118A4 (fr)

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US6518243B1 (en) * 1999-04-02 2003-02-11 Trustees Of Princeton University Desleucyl glycopeptide antibiotics and methods of making same
US6699836B2 (en) 1999-04-02 2004-03-02 The Trustees Of Princeton University Vancomycin analogs

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0578112A2 (fr) * 1992-07-03 1994-01-12 The Nisshin Oil Mills, Ltd. Dérivés de desaccharides et procédé pour leur préparation
US5635612A (en) * 1993-02-23 1997-06-03 The Trustees Of Princeton University Method of forming multiple glycosidic linkages in a single step
WO1998000153A1 (fr) * 1996-06-28 1998-01-08 Eli Lilly And Company Amides

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EP0578112A2 (fr) * 1992-07-03 1994-01-12 The Nisshin Oil Mills, Ltd. Dérivés de desaccharides et procédé pour leur préparation
US5635612A (en) * 1993-02-23 1997-06-03 The Trustees Of Princeton University Method of forming multiple glycosidic linkages in a single step
WO1998000153A1 (fr) * 1996-06-28 1998-01-08 Eli Lilly And Company Amides

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Title
GE ET AL: "Vancomycin Derivatives that Inhibit Peptidoglycan Biosynthesis without Binding D-Ala-D-Ala" SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE,, US, vol. 284, no. 5413, 16 April 1999 (1999-04-16), pages 507-511, XP002189915 ISSN: 0036-8075 *
HUTNY J ET AL: "ASSAY OF ALPHA-1,4-TRANSGLYCOSYLASE ACTIVITY WITH P-NITROPHENYL-N-MALTOSIDE AS SUBSTRATE" ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, POLISH ACADEMY OF SCIENCES, WROCLAW, PL, vol. 16, no. 4, 1968, pages 670-675, XP001062180 ISSN: 0004-069X *
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 *
NICOLAOU, K. C. ET AL: "Expeditious routes to evernitrose and vancosamine derivatives and synthesis of a model vancomycin aryl glycoside" ANGEWANDTE CHEMIE, INTERNATIONAL EDITION ( 1998 ), 37(13/14), 1871-1874 , 1998, XP002261776 *
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ZEHAVI U ET AL: "ENZYMIC SYNTHESIS OF OLIGOSACCHARIDES ON A POLYMER SUPPORT LIGHT-SENSITIVE, SUBSTITUTED POLYACRYLAMIDE BEADS" CARBOHYDRATE RESEARCH, ELSEVIER SCIENTIFIC PUBLISHING COMPANY. AMSTERDAM, NL, vol. 124, no. 1, 1983, pages 23-34, XP000565754 ISSN: 0008-6215 *

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EP1147118A4 (fr) 2004-01-28
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