WO1995025113A1 - Composes synthetiques qui se fixent a h. pylori, et utilisations de ces composes - Google Patents

Composes synthetiques qui se fixent a h. pylori, et utilisations de ces composes Download PDF

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WO1995025113A1
WO1995025113A1 PCT/US1995/003273 US9503273W WO9525113A1 WO 1995025113 A1 WO1995025113 A1 WO 1995025113A1 US 9503273 W US9503273 W US 9503273W WO 9525113 A1 WO9525113 A1 WO 9525113A1
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compound
group
branched chain
linear
substituted
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PCT/US1995/003273
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English (en)
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Samuel J. Danishefsky
John T. Randolph
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Sloan-Kettering Institute For Cancer Research
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Priority to AU21005/95A priority Critical patent/AU2100595A/en
Publication of WO1995025113A1 publication Critical patent/WO1995025113A1/fr

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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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • 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
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids

Definitions

  • the carbohydrate domains of the blood group substances are distributed in erythrocytes, epithelial cells and in various secretions.
  • the early focus on these systems centered on their central role in determining blood group specificities.
  • it is recognized that such determinants are broadly implicated in cell adhesion and binding phenomena.
  • M.L. Phillips E. Nudelman
  • F.C.A. Gaeta, M. Perez, A.K. Singhal S. Hakomori, J.C.
  • the present invention provides new strategies and protocols for oligosaccharide synthesis.
  • the object is to simplify such constructions such that relatively complex domains can be assembled with high stereospecifity.
  • Major advances in glycoconjugate synthesis require the attainment of high degrees of convergence and relief from the burdens associated with the manipulation of blocking groups.
  • Another requirement is that of delivering the carbohydrate determinant with appropriate provision for conjugation to carrier proteins or lipids. (M.A. Bernstein, L.D. Hall, Carbohydr. Res . 1980, 78, Cl; R.U. Lemieux, Chem . Soc . Rev. 1978, 7, 423; R.U. Lemieux, D.R. Bundle, D.A. Baker, J . Am . Chem . Soc . 1975, 97, 4076) This is a critical condition if the synthetically derived carbohydrates are to be incorporated into carriers suitable for biological application.
  • the present invention shows how the use of glycals both as glycosyl donors and as glycosyl acceptors can be exploited to accomplish such ends in the context of a straightforward synthesis of the Le y (type II) system.
  • the Le y hapten was first isolated from a blood group glycoprotein in 1966 by Kabat and Lloyd. (K.O. Lloyd, E.A. Kabat, E.J. Layug, F. Gruezo, Biochem . 1966, 5 , 1489) Subsequently, Potapov and coworkers (M.I. Potapov, Probl. Hematol . Blood Transfus . (USSR) 1970, 15, 45) discovered an antibody to this carbohydrate antigen.
  • the method of synthesis disclosed herein provides for the determinant to be insulated from the conjugation device by a carbohydrate spacer module which can in principle be broadly varied. Through appropriate insulation, the likelihood that the protein or lipid carrier might distort the recognition property of the determinant is thus minimized.
  • the present invention provides a method of equipping the reducing end of the antigen with a suitable device for subsequent attachment to a carrier protein.
  • An intervening spacer element lactose is incorporated to insulate the recognition domain from the bioconjugation module.
  • the present invention provides a compound having the structure:
  • the present invention further provides a compound having the structure:
  • R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph, a linear or branched chain alkyl or acyl group, or an aryl group; wherein M has the structure:
  • n is an integer from 0 to 18, and where n is greater than 1, each M is independently the same or different; wherein R 2 , R 3 , R 5 and R 6 are independently the same or different and are H or OH, with the proviso that geminal R 2 and R 3 are not both OH, and geminal R 5 and R 6 are not both OH; wherein each wavy line between a carbon atom and an oxygen atom denotes an R or S configuration at. the carbon atom; and wherein R 7 is a substituted or unsubstituted allyl group.
  • the present invention further provides a compound having the structure:
  • n is an integer from 1 to 18; wherein R is H or a linear or branched chain acyl group; wherein R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph, a linear or branched chain alkyl or acyl group, or an aryl group; and wherein R 2 is a substituted or unsubstituted allyl group.
  • the present invention further provides a compound having the structure:
  • R is H or a linear or branched chain acyl group; wherein R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph, a linear or branched chain alkyl or acyl group, or an aryl group; wherein R 2 is a substituted or unsubstituted allyl group; and wherein n is an integer from 1 to 18.
  • the present invention provides a compound having the structure:
  • R is H or a linear or branched chain acyl group.
  • the present invention also provides a process for synthesizing a compound having the structure:
  • R is a substituted or substituted allyl group.
  • Figure 1 shows glycal assembly leading to neoglycoproteins.
  • Figure 3 shows the synthesis of 8a.
  • Reagents a) 9a, AgBF 4 , 4A mol. sieves, THF (75%); b) i. TBAF, THF; ii. Na/NH 3 ; iii Ac 2 O, pyr. c) i. 3,3-dimethioxirane; allyl alcohol, ZnCl 2 (72%); ii. NaOMe, MeOH (quant.).
  • Figure 4 shows a strategy for the solid-phase of oligosaccharides using the glycal assembly method.
  • Figure 5 shows the application of the solid-support method to the assembly of 1,2-branching patterns of complex carbohydrates.
  • Figure 6 shows the synthesis of a tetrasaccharide having H-type 2 blood group specificity.
  • Reagents (a) 1. 3,3-dimethyldioxirane, CH 2 Cl 2 ; 2. 8, ZnCl 2 , THF; (b) 10, Sn(OTf) 2 , di-tert-butylpyridine, THF; (c) TBAF, AcOH, THF; (d) TIPSC1, imidazole, DMF; (e) I (coll) 2 ClO 4 , PhSO 2 NH 2 , CH 2 Cl 2 ; (f) 15, AgBF 4 , 4A M.S., THF; (g) 1. TBAF, AcOH, THF; 2. Na/NH 3 ; 3. Ac 2 O, pyridine.
  • Figure 7a and 7b show the synthesis of a Le b hexasaccharide in bioconjugatable form.
  • Reagents (a) 1. 3, 3-dimethyldioxirane, CH 2 Cl 2 ; 2. 19, ZnCl 2 , THF; (b) 10, Sn(OTf) 2 di-tert-butylpyridine, THF; (c) TBAF, AcOH, THF; (d) TIPSC1, imidazole, DMF; (e) I (coll) 2 ClO 4 , PhSO 2 NH 2 , CH 2 Cl 2 ; (f) 24 AgBF 4 , 4AM.S., THF; (g) 1. TBAF, AcOH, THF; 2. Na/NH 3 ; 3. Ac 2 O, pyridine; (h) 1. 3,3-dimethyldioxirane, CH 2 Cl 2 ; 2. allyl alcohol, ZnCl 2 ; 3. NaOMe, MeOH.
  • the present invention provides a compound having the structure:
  • the present invention provides the compound disclosed hereinabove wherein A is lysine or a lysine residue.
  • the present invention provides the compound disclosed hereinabove wherein A is glutamic acid or a glutamic acid residue.
  • the present invention provides the compound disclosed hereinabove wherein A is aspartic acid or an aspartic acid residue.
  • the invention also provides the compound disclosed hereinabove wherein A is an amino acid residue of a globular protein.
  • the invention provides the compound wherein the globular protein is selected from the group consisting of bovine serum albumin and human serum albumin.
  • the invention provides the compound disclosed hereinabove wherein k is 1. In another embodiment, the invention provides the compound disclosed hereinabove wherein n and p are both equal to 0.
  • the invention provides a compound having the structure:
  • R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph, a linear or branched chain alkyl or acyl group, or an aryl group; wherein M has the structure:
  • n is an integer from 0 to 18, and where n is greater than 1, each M is independently the same or different; wherein R 1 , R 3 , R 5 and R 6 are independently the same or different and are H or OH, with the proviso that geminal R 2 and R 3 are not both OH, and geminal R 5 and R 6 are not both OH; wherein each wavy line between a carbon atom and an oxygen atom denotes an R or S configuration at the carbon atom; and wherein R 7 is a substituted or unsubstituted allyl group.
  • the invention also provides a compound having the structure:
  • n is an integer from 1 to 18; wherein R is H or a linear or branched chain acyl group; wherein R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph, a linear or branched chain alkyl or acyl group, or an aryl group; and wherein R 2 is a substituted or unsubstituted allyl group.
  • the invention provides the compound wherein n is 1.
  • the invention further provides a compound having the structure:
  • R is H or a linear or branched chain acyl group; wherein R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph , a linear or branched chain alkyl or acyl group, or an aryl group; and wherein R 2 is a substituted or unsubstituted allyl group.
  • the invention also provides a compound having the structure:
  • R is H or a linear or branched chain acyl group; wherein R 1 is H, OH, NH 2 or NHR 4 , where R 4 is SO 2 Ph, a linear or branched chain alkyl or acyl group, or an aryl group; wherein R 2 is a substituted or unsubstituted allyl group; and wherein n is an integer from 1 to 18.
  • the invention provides the compound wherein n is l.
  • the invention also provides a compound having the structure:
  • R is H or a linear or branched chain acyl group.
  • the invention also provides a process for synthesizing a compound having the structure:
  • R is a substituted or substituted allyl group, which comprises the steps of (a) synthesizing a compound having the structure:
  • R is a trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl or triaarylsilyl group; (b) reacting the compound of step (a) with a compound having structure:
  • R is a trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl or triaarylsilyl group; (c) reacting the compound formed in step (b) with a compound having the structure:
  • R is a trialkylsilyl, aryldialkylsilyl, alkyldiarylsilyl or triaarylsilyl group; (d) deprotecting and re-protecting the compound formed in step (c) under suitable conditions to form a compound having the structure:
  • R is TIPS; (e) iodosulfonamidating the compound formed in step (d) under suitable conditions to form a compound having the structure:
  • step (f) reacting the compound formed in step (e) with a compound having the structure:
  • R is H; (g) deprotecting and peracetylating the compound formed in step (f) under suitable conditions to form a compound having the structure: (h) epoxidizing the compound formed in step (g) under suitable conditions to form an epoxide thereof and reacting the epoxide under suitable conditions to form a compound having the structure:
  • R is a substituted or unsubstituted allyl group
  • R is a substituted or unsubstituted allyl group.
  • suitable conditions necessary for the various reactions and treatments may be found in the Experimental Details section which follows hereinafter. However, it is within the confines of the present invention that the specific reagents and solvents provided as well as the specific conditions necessary for reaction or treatment may be substituted with other suitable reactants, solvents and conditions well known to those skilled in the art.
  • the allyl compound may be conjugated to a peptide or protein via amine or carboxylic acid side chain.
  • a bioconjugate is prepared according to the protocol of Bernstein and Hall (Carbohydr. Res. 1980, 78, Cl).
  • the allyl group is ozonolyzed to form either an aldehyde or carboxylic acid, which is condensed to a terminal amine to form, respectively, an imine or an amide.
  • the imine is reduced with sodium borohydride to the amine.
  • the aldehyde is reductively aminated using procedures known in the art to form an amine which is reacted with a side-chain terminal carboxylic acid to form an amide conjugate.
  • the invention provides a pharmaceutical composition which comprises a therapeutically effective amount of the compound disclosed hereinabove and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.01-0.1M and preferably 0.05M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • Preserva-tives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • the invention further provides a method for treating a subject afflicted with a disorder caused by Helicobacter pylori which comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed hereinabove so as to treat the subject afflicted with the disorder.
  • the invention provides a method of treating a subject afflicted with gastric or duodenal ulcer.
  • the invention provides a method of treating a subject afflicted with gastric adenocarcinoma.
  • the invention provides a method for inhibiting the adhesion of Helicobacter pylori to gastric epithelium in a subject which comprises administering to the subject an amount of the compound disclosed hereinabove effective to inhibit the adhesion of Helicobacter pylori to gastric epithelium in the subject.
  • Melting points (mp) were uncorrected and performed in soft glass capillary tubes using an Electrothermal series IA9100 digital melting point apparatus.
  • HRMS high resolution mass spectral
  • MS mass spectra
  • El electron impact ionization
  • CI chemical ionization
  • a carrier gas ammonia or methane
  • GCMS gas chromatography/mass spectra
  • a DB-5 fused capillary column (30 m, 0.25mm thickness) was used with helium as the carrier gas.
  • Typical conditions used a temperature program from 60-250°C at 40°C/min.
  • Thin layer chromatography was performed using precoated glass plates (silica gel 60, 0.25 mm thickness). Visualization was done by illumination with a 254 nm UV lamp, or by immersion in anisaldehyde stain (9.2 mL p-anisaldehyde in 3.5 mL acetic acid, 12.5 mL cone, sulfuric acid and 338 mL 95% ethanol (EtOH)) and heating to colorization.
  • Flash silica gel chromatography was carried out according to the standard protocol. Unless otherwise noted, all solvents and reagents were commercial grade and were used as received, except as indicated hereinbelow, where solvents were distilled under argon using the drying methods listed in paretheses: CH 2 Cl 2 (CaH 2 ); benzene (CaH 2 ); THF (Na/ketyl); Et 2 O (Na/ketyl); diisopropylamine (CaH 2 ).
  • Polymer-bound galactal 7 (500 mg; S.J. Danishefsky, et al., J. Am. Chem. Soc. 1992, 8331) was placed in a 100 mL polymer flask and dried in vacuo. On cooling to 0°C under N 2 , dry CH 2 Cl 2 (20 mL) and freshly prepared Murray solution (30 mL; R.W. Murray and R. Jeyaraman, J. Org Chem. 1985, 2847) was added. After stirring at 0°C for -90 min., solubles were filtered using N 2 pressure. The oxidation procedure was repeated. The resulting epoxide of 7 kept on a vacuum line for -3 h to dry.
  • the polymer-bound tetrasaccharide 20 (50 mg) was stirred in 2 mL THF, and treated with 0.2 mL each of 1.0 M solutions of TBAF and AcOH in THF. The mixture was stirred at 40°C overnight. The polymer was washed with 3 ⁇ 5 mL THF. The combined rinsings were concentrated and column-chromatographed on silica (2:1 EtOAc:hex), providing tetrasaccharide glycal 21 as a colorless gum. Yield: 9.0 mg. EXAMPLE 2
  • Galactal 7' (0.100 g, 0.304 mmol) in 5 mL dry CH 2 Cl 2 at 0°C under a N 2 atmosphere was treated with 10 mL Murray solution (freshly prepared) and stirred at 0°C for 40 min. TLC (1:1 EtOAc:hex) showed no trace of 7'. Solvents were evaporated using a dry N 2 stream. The residual epoxide of 7' was kept on a vac. line ⁇ 2h. To the epoxide under a N 2 atmosphere was added a solution of glucal derivative 3' (0.150 g, 0.496 mmol) in 3 mL dry THF.
  • Tetrasaccharide 22 Diol 18' (86 mg, 0.133 mmol) and fucosyl donor 10 (0.290 g, 0.665 mmol) were azeotropically dried using benzene.
  • Tetrasaccharide glycal 22 120 mg, 81.1 mmol
  • PhSO 2 NH 2 (20 mg, 0.13 mmol) were azeotropically dried using benzene.
  • Added (glove bag) 4 A MS (0.2 g).
  • dry CH 2 Cl 2 1.0 mL was added.
  • the mixture was treated with a solution of I(coll) 2 ClO 4 (prepared from 100 mg Ag(coll) 2 ClO 4 , 5 mL collidine, and 60 mg I 2 in 1 mL dry CH 2 Cl 2 ) via canula through a plug of flame-dried celite and 4 A MS.
  • the mixture was stirred at 0°C for 40 min.
  • Tetrasaccharide glycal 22 200 mg, 0.135 mmol
  • PhSO 2 NH 2 42 mg, 0.27 mmol
  • 200 mg powdered 4 A MS in 2.0 mL dry CH 2 Cl 2 at 0°C under a N 2 atmosphere was treated with I(coll) 2 ClO 4 (prepared from 120 mg Ag(coll) 2 ClO 4 and 67 mg I 2 in 1 ml dry CH 2 Cl 2 ). The mixture was stirred at 0°C (protected from light using foil) for 30 min. TLC (1:2 EtOAc:hex) showed mainly iodosulfonamide with some glycal.
  • Iodosulfonamide 23 (60 mg, 34 mmol) in a 35 mL r.b. was treated with 200 mg powdered 4 A MS (glove bag). To this flask under N 2 was added a solution of protected lactal 24 in THF (1.5 mL). On cooling the mixture to -78°C, a solution of AgBF 4 (40 mg, 0.206 mmol) was added in 0.25 mL dry THF. The mixture was stirred and slowly warmed to r.t. overnight. The mixture was warmed to 45°C and stirred ⁇ 36 h. TLC showed only a trace of iodosulfonamide. Saturated aq.
  • Hexasaccharide 25 (55 mg, 24.4 mmol) in ⁇ 1.5 mL THF was treated at 0°C with TBAF (0.25 mL, 1.0 M solution in THF, 0.25 mmol), and stirred at r.t. overnight.
  • TLC (1:9 MeOH:CH 2 Cl 2 ) showed a 3:1 mixture of 25a vs. a less polar substance. Additional 1.0 M TBAF (0.10 mL) was added, and the mixture was stirred overnight at r.t. TLC showed that the reaction was complete. Solvents were removed using a N 2 stream. Column chromatography on silica (1:19 MeOH:CH 2 Cl 2 )
  • Hexasaccharide 25a (36 mg) in 0.25 mL dry THF was added via canula to ⁇ 8 mL bright blue Na/NH 3 solution at -78°C (dry ice bath) under N 2 atm. After removing the dry ice bath, the mixture was stirred in refluxing NH 3 (dry ice condenser) for 15 min. After adding 2 mL dry MeOH (slowlyl), the resulting mixture was stirred while blowing off NH 3 with a N 2 stream. The MeOH solution was treated with Dowex 50 ⁇ 8 [H + ] until pH -8-9, and then filtered. The resin was washed with MeOH. The residue was concentrated and kept on a vacuum line to dry.
  • Hexasaccharide 17 Hexasaccharide 26 (10.0 mg, 6.3 mmol) under N 2 at 0°C was treated with 0.5 mL dry CH 2 Cl 2 . Dioxirane solution (0.20 mL) was added, and the mixture was stirred at 0°C ⁇ 40 min. TLC (EtOAc) showed no trace of 26. Solvents were evaporated with a N 2 stream. The epoxide was dried on a vacuum line for ⁇ 2 h. The epoxide was treated under a N 2 atmosphere with 0.5 mL allyl alcohol (passed through basic alumina to dry) and 0.5 mL dry THF.
  • Le y determinant commences with lactal (la) (W.N. Haworth, E.L. Hirst, M.M.T. Plant, R.J.W. Reynolds, J. Chem . Soc . 1930, 2644) as shown in Figure 2. Capping both primary hydroxyl groups as their TBDPS ethers under standard conditions was followed by simple engagement of the 3' and 4' hydroxyl functions as a cyclic carbonate 2a. The stereospecific introduction of two ⁇ -linked fucose residues gave tetrasaccharide glycal 3a in 51% yield in a single step. The donor used was the known fluorosugar 5a (S.J. Danishefsky, J. Gervay, J.M.
  • the assembly of the Le b (type 1) domain is a relatively more difficult undertaking than was the Le y (type 2) target, wherein lactal was used as a convenient starting material. In the case of the type 1 determinant, lactal is not a useful starting material.
  • the synthesis of the Le b system offered an opportunity to apply the polymer-based oligosaccharide construction method. (S.J. Danishefsky, K.F. McCLure, J.T. Randolph, R.B. Ruggeri, Science 1993, 260, 1307)
  • the strategy is summarized in Figure 4, wherein polymer-bound glycal 1 is activated for glycosyl donation via direct formation of a 1,2-anhydro derivative 2. Reaction of 2 with acceptor glycal 3 furnishes 4.
  • Reiteration is achieved by means of direct epoxidation and reaction with acceptor 3.
  • acceptor 3 The self-policing nature of the method and the simple "one time” purification at the end of the synthesis are useful features.
  • the present invention discloses an important additional dimension of the polymer-bound method.
  • the logic is captured by inspection of Figure 5.
  • Each glycosylation event generates a unique C 2 hydroxyl. In principle (and in fact, see infra) this hydroxyl can function as a glycosyl acceptor upon reaction with a solution based donor.
  • the glycal linkage of 5, still housed on the support, can be further elongated. In this way, branching at C 2 is accomplished while minimizing the requirement for protecting group machinations.
  • this branching can be implemented at any site in a growing chain.
  • the polymer-bound oligosaccharide can serve as either donor or acceptor, wherever appropriate.
  • Iodosulfonamide 23 obtained from 22 using I(coll) 2 ClO 4 and PhSO 2 NH 2 , reacted with lactal derivative 24 in the presence of AgBF 4 to provide hexasaccharide glycal 25 in 55% yield.
  • Deprotection of 25 was accomplished in two stages (TBAF to remove the silyl ethers, followed by Na/NH 3 reduction to remove the aromatic protecting groups), and the crude product was peracetylated to give 26 in a 51% overall yield.
  • the present invention extends the solid-support glycal assembly method for complex carbohydrate domain synthesis to include the branching patterns critical for biorecognition.
  • the determinant for the binding of H. pylori to human gastric epithelium has been stereospecifically fashioned, with simplicity, in a way which provides significant relief from some of the complexities of protecting group manipulations.
  • This material was once again placed under N 2 before being treated with 19 (-10 molar equivalents as a 0.5 M solution in THF).
  • the suspension was cooled to -40 °C, and treated with ZnCl 2 ( ⁇ 2 molar equivalents as a 1.0 M solution in THF).
  • the reaction mixture was allowed to slowly warm to rt (over ca. 2 h), and then stirred an additional 3-4 h. Solubles were removed by filtration. and polymer 18 was washed several times with THF and then dried in vacuo.

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Abstract

Cette invention concerne un composé ayant la structure (I), où: A est choisi dans le groupe constitué (i) par un acide aminé portant un groupe φ-amino ou un groupe φ-(C=O)-, (ii) par un résidu acide aminé d'un peptide, ce résidu portant un groupe φ-amino ou un groupe φ-(C=O)-, et (iii) par un résidu acide aminé d'une protéine, ce résidu portant un groupe φ-amino ou un groupe φ-(C=O)-; R1 représente H, OH, NH2 ou NHR4, où R4 représente SO2Ph, un groupe alkyle ou acyle à chaîne linéaire ou ramifiée, ou un groupe aryle; M représente un saccharide, où n est égal à un nombre entier compris entre 0 et 18, et, lorsque n est supérieur à 1, chaque M est séparément identique ou différent; p est égal à 0 ou à 1; R2, R3, R5 et R6 sont indépendamment identiques ou différents et représentent H ou OH, à condition que les éléments jumeaux R2 et R3 ne représentent pas tous les deux OH et les éléments jumeaux R5 et R6 ne représentent pas tous les deux OH; X et Y sont indépendamment identiques et différents et représentent H2 ou O; et k est égal à un nombre entier supérieur ou égal à 1, à condition que, lorsque A représente un acide aminé portant un groupe φ-amino ou un groupe φ-(C=O)-, alors k est égal à 1.
PCT/US1995/003273 1994-03-15 1995-03-15 Composes synthetiques qui se fixent a h. pylori, et utilisations de ces composes WO1995025113A1 (fr)

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AU21005/95A AU2100595A (en) 1994-03-15 1995-03-15 Synthetic compounds which bind to (h. pylori), and uses thereof

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0854878A1 (fr) * 1995-07-24 1998-07-29 Sloan-Kettering Institute For Cancer Research Synthese de glycoconjugues de l'epitope y de lewis et leurs utilisations
WO1998036757A1 (fr) * 1997-02-21 1998-08-27 Nippon Shinyaku Co., Ltd. Remede contre l'ulcere gastro-duodenal
AU732287B2 (en) * 1996-04-26 2001-04-12 Basf Aktiengesellschaft Fungicidal mixtures

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6351396A (ja) * 1986-08-20 1988-03-04 Rikagaku Kenkyusho ルイスｂ型糖脂質及びその製造法
WO1993005803A1 (fr) * 1991-09-25 1993-04-01 Genetics Institute, Inc. Agents anti-inflammatoires inhibiteurs de selectines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6351396A (ja) * 1986-08-20 1988-03-04 Rikagaku Kenkyusho ルイスｂ型糖脂質及びその製造法
WO1993005803A1 (fr) * 1991-09-25 1993-04-01 Genetics Institute, Inc. Agents anti-inflammatoires inhibiteurs de selectines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 109, Number 15, issued 10 October 1988, OGAWA et al., "Glycosphingolipids Bearing a Lewis b Type Antigenic Determinant and a Process for Their Preparation", page 752, Abstract No. 129595w; & JP,A,63 051 396. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0854878A1 (fr) * 1995-07-24 1998-07-29 Sloan-Kettering Institute For Cancer Research Synthese de glycoconjugues de l'epitope y de lewis et leurs utilisations
EP0854878A4 (fr) * 1995-07-24 2004-03-24 Sloan Kettering Inst Cancer Synthese de glycoconjugues de l'epitope y de lewis et leurs utilisations
AU732287B2 (en) * 1996-04-26 2001-04-12 Basf Aktiengesellschaft Fungicidal mixtures
WO1998036757A1 (fr) * 1997-02-21 1998-08-27 Nippon Shinyaku Co., Ltd. Remede contre l'ulcere gastro-duodenal

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