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WO2025163383A1 - Chirurgie moléculaire : technique de réaction cister (cut-insert-stitch editing reaction) - Google Patents

Chirurgie moléculaire : technique de réaction cister (cut-insert-stitch editing reaction)

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Publication number
WO2025163383A1
WO2025163383A1 PCT/IB2024/062990 IB2024062990W WO2025163383A1 WO 2025163383 A1 WO2025163383 A1 WO 2025163383A1 IB 2024062990 W IB2024062990 W IB 2024062990W WO 2025163383 A1 WO2025163383 A1 WO 2025163383A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzoyl
tri
benzyl
tetra
arabinofuranosyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/062990
Other languages
English (en)
Inventor
Srinivas HOTHA
Sumit Sen
Suman Kundu
Sandip Pasari
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Indian Institute of Science Education and Research Pune
Original Assignee
Indian Institute of Science Education and Research Pune
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Indian Institute of Science Education and Research Pune filed Critical Indian Institute of Science Education and Research Pune
Publication of WO2025163383A1 publication Critical patent/WO2025163383A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides

Definitions

  • the present invention generally relates to the field of organic synthesis chemistry. Particularly, the present invention relates to a cut-insert-stitch editing reaction (CIStER) process to stereo- and regioselectively synthesize complex and branched glycoconjugates and other molecules.
  • CIStER cut-insert-stitch editing reaction
  • the present invention also relates to a process of one pot-three step chemical approach to synthesize lipoarabinomannan analogs present in the cell wall of Mycobacterium tuberculosis.
  • Nucleic acids, proteins, carbohydrates, and lipids exist among the numerous biomolecules produced by living organisms, and occur in myriad sizes and structures. These biomolecules perform several biological functions, and have been extensively investigated. Additionally, nucleic acid chemistry has matured because of the development of excellent molecular biology tools, such as recombinant DNA technology, polymerase chain reaction, DNA amplification, CRISPR-editing, and prime editing. The tools have had an oblique impact on the synthesis of proteins as a direct consequence of the central dogma. Genomic editing techniques play a pivotal role in many fields, such as, agriculture, the discovery of pharmaceuticals and diagnostic tools, production of biofuels, and enable a better understanding of disease biology.
  • Carbohydrates are ubiquitous and impart several biological effects, including signal transduction, cell-cell communication, and development.
  • Carbohydrates exist as conjugates of glycans and aglycons, wherein the aglycon can be a protein, as in glycoproteins; a lipid, as in glycolipids; or a steroid, as in saponins.
  • the isolation of carbohydrates from natural systems is complicated because natural systems are innately microheterogeneous, and postsynthetic correction, amplification, and modification of synthetic or natural glycans are still nascent.
  • MOE cells are cultured with a monosaccharide containing a reporter moiety (e.g., alkyne/azide), theorizing that the conjugate of the reporter moiety and monosaccharide is incorporated into its cellular processes; the incorporated moiety can guide the investigation of biological pathways, including cell imaging by using bioorthogonal chemistry as shown in the figure below.
  • a reporter moiety e.g., alkyne/azide
  • EAG exploits the site-specific cleavage of glycosidic bonds by designer glycosidases, and the resulting hydrolyzed glycans are further subjected to glycosyl transferases as post-synthetic modifications to attach new glycans/probes as shown in the figure below.
  • glycosyl transferases as post-synthetic modifications to attach new glycans/probes as shown in the figure below.
  • glycosidation in which a glycosyl donor and aglycon are condensed to form a glycosidic bond.
  • Glycosyl donors often contain an appendage at the anomeric carbon (Cl), that can be activated by the addition of promoters to obtain a highly reactive oxocarbenium ion intermediate; the oxocarbenium ion intermediate can be attacked by an aglycon to afford a glycoside.
  • glycosyl donor chemistry Many pioneering efforts have culminated in the development of glycosyl donor chemistry. Moreover, previously reported glycosyl donors have been revived by modem reagents using either stoichiometric or catalytic amounts of the reagent(s). In addition to these developments, linear and convergent strategies have been formulated for glycan assembly using latent, iterative, catalytic, or orthogonal activation protocols. [0006] Synthesis of carbohydrates is still a challenging task in spite of the first glycoside synthesis about a century ago by Emil Fischer.
  • the main objective of the present invention is to develop a process of one pot-three step chemical approach for stereo- and regio-selectively synthesize complex and branched glycoconjugates.
  • Another objective of the present invention is to develop a process of one pot-three step chemical approach for stereo- and regioselectively synthesize complex and branched glycoconjugates using a cut-insert stitch-editing reaction (CIStER).
  • CIStER cut-insert stitch-editing reaction
  • Another objective of the present invention is to provide a process of preparing glycohybrids using CIStER technique.
  • Another objective of the present invention is to provide a gram scale synthesis of 6- galactosyl lactose from lactose using CIStER technique.
  • Another objective of the present invention is to provide a process of preparation of linear and branched oligosaccharides using CIStER technique.
  • Another objective of the present invention is to synthesize lipoarabinomannan analogs present in Mycobacterium tuberculosis using a cut-insert stitch-editing reaction (CIStER).
  • CIStER cut-insert stitch-editing reaction
  • the present invention relates to a cut-insert stitch-editing reaction (CIStER) process to stereo- and region-selectively synthesize complex and branched glycoconjugates.
  • the present invention also relates to a process of one pot-three step chemical approach to synthesize lipoarabinomannan analogs present in Mycobacterium tuberculosis.
  • the present invention provides one pot-three step chemical approach to stereo- and regioselectively synthesize complex and branched glycoconjugates.
  • Inventors have used a cut-insert stitch-editing reaction (CIStER) technique to surgically edit branched and linear glycans.
  • the reaction comprises three steps and cutting an interglycosidic bond in a regiospecific manner, inserting a foreign glycan, and stitching the glycosidic bond to obtain a hybrid glycan.
  • the CISTER is successfully used to synthesize lipoarabinomannan analogs present in Mycobacterium tuberculosis.
  • the present invention makes a significant contribution to the literature because lipoarabinomannan is a strong antigenic epitope present in the cell wall of Mycobacterium tuberculosis (Mtb) and is being considered as a target for the development of vaccines and diagnostic tools.
  • the present invention relates to a process for synthesis of the glycoconjugates using a cut-insert stitch-editing reaction (CIStER) comprising the steps of:
  • step (c) stitching the janus-saccharides compound obtained in step (b) with monosaccharide in presence of [Au]/[Ag] catalyst and solvent to obtain stitched product, glycoconjugates.
  • the present invention relates to a process for synthesis of the glycoconjugates using a cut-insert stitch-editing reaction (CIStER) comprising the steps of:
  • step (c) stitching the trisaccharides compound (8) obtained in step (b) with monosaccharide (7) in presence of [Au]/[Ag] catalyst and solvent to obtain stitched product, tetra- and pentasaccharide, glycoconjugates (11).
  • the trisaccharide compound (5) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the thiotolyl gentiobiose (10) and monosaccharide (7) is [0020]
  • the Janus glycosyl acceptor donor compounds (6) is:
  • the trisaccharides compound (8) is: [0022]
  • the stitched product, tetra- and pentasaccharide, glycoconjugates is selected from the group consisting of: BRIEF DESCRIPTION OF THE FIGURES
  • Figure 1 represents the liquid chromatographs of CIStER reaction products 1 la-1 If.
  • Figure 2 represents the liquid chromatographs of CIStER reaction products 13-16.
  • Figure 3 represents the liquid chromatographs of CIStER reaction products 23-27.
  • the present invention relates to a process for synthesis of the glycoconjugates using a cut-insert stitch-editing reaction (CIStER) comprising the steps of:
  • step (c) stitching the janus-saccharides compound obtained in step (b) with monosaccharide in presence of [Au]/[Ag] catalyst and solvent to obtain stitched product, glycoconjugates.
  • the solvent used in the step (a) dichloromethane, CH 3 CN, CHC1 3 , Toluene, THF, and the like.
  • the solvent used in the step (b) dichloromethane, CH 3 CN, CHC1 3 , Toluene, THF, and the like.
  • the solvent used in the step (c) dichloromethane, CHCl , Toluene, THF, and the like.
  • the Ag/Au catalyst is chloro[tris(2,4- ditbutylphenyljphosphite] gold(I)/silver trifluoromethanesulfonate.
  • CIStER cutinsert stitch-editing reaction
  • the present invention provides a process of cutting of the interglycosidic bonds in naturally occurring disaccharides, as per scheme 2 below.
  • the present invention provides a process of preparing glycohybrids using CIStER technique as per Scheme -3 below.
  • the present invention provides a gram scale synthesis of 6- galactosyl lactose from lactose using CIStER technique as shown in the Scheme-4 below.
  • the present invention provides synthesis of linear and branched oligosaccharides using CIStER technique as shown in the Scheme-5 below.
  • the present invention relates to a process for synthesis of the glycoconjugates using a cut-insert stitch-editing reaction (CIStER), wherein the process comprises the steps of:
  • step (c) stitching the trisaccharides compound (8) obtained in step (b) with monosaccharide (7) in presence of [Au]/[Ag] catalyst and solvent to obtain tetra- and pentasaccharide, glycoconjugates (11).
  • the glycoconjugates are selected from the group consisting of:
  • Methyl-2 3, 6-tri-O-benzoyl-4-O-(2, 3, 4-tri-O-benzyl-6-O-(2, 3, 4-tri-O-benzyl-6-O-(2, 3,4,6- tetra-O-benzoyl-P-D-glucopyranosyl)-a-D-mannopyranosyl)-a/p-D-glucopyranosyl)-a-D- glucopyranoside (11b); Methyl-2, 3, 6-tri-O-benzoyl-4-O-(2, 3, -di-O-benzoyl-5-O-(2, 3, 4-tri-O-benzyl-6-O-(2, 3,4,6- tetra-O-benzoyl-P-D-glucopyranosyl)-a/p-D-mannopyranosyl)-a-D-arabinofuranosyl)-a-D- glucopyranoside (11c);
  • the glycans can be surgically edited using CIStER.
  • CIStER processes require thorough planning of the guide glycan and subtle stereoelectronic factors, leading to alterations in their interglycosidic bonds that undergo hydrolysis.
  • CIStER is based on the activation of glycosyl donors by trapping the oxocarbenium ion intermediate with a nucleophile (pTolSH) that can be orthogonally activated in the presence of an aglycon equipped with another leaving group (ethynylcyclohexyl carbonate) to afford a new glycoside.
  • pTolSH nucleophile
  • the reactions were monitored by analytical thin layer chromatography (TLC) performed on 0.25 mm Merck silica gel plates (60F254) under 254 nm UV lamp and stained by anisaldehyde stain. Removal of solvent in vacuo refers to distillation using a rotary evaporator attached to an efficient vacuum pump. Column chromatography of the crude compounds was performed on silica gel of 100-200 mesh (75-150 pm). Products obtained as solids or syrups were dried under high vacuum. Optical rotations were measured on digital polarimeter at 25 °C in CHC13 solution. IR spectra were recorded on a FT-IR spectrometer.
  • NIS 1.5 eq, 66 mg
  • AgOTf 1.5 eq, 10 mg
  • the reaction mixture was stirred for 15 min at 0 °C and gradually warmed to 25 °C and stirred for 45 min.
  • chloro [tris(2, 4- ditbutylphenyl)phosphite]gold(I) 0.08 eq, 13 mg
  • AgOTf 0.1 eq, 5 mg
  • the trisaccharide 23 (300 mg, 0.266 mmol) was dissolved in 3mL of anhydrous CH2C12.
  • the reaction vessel was cooled to 0 °C and BF3 «OEt2 (98.7 pL, 0.799 mmol) was added.
  • the reaction mixture was refluxed at 50 °C for 30 min, brought to 25 °C and external glycan acceptor (1 eq. for 24 0.5 eq. for 26) [24 (674 mg,) or 26 (323 mg)] were added to the reaction mixture and the reaction vessel was stirred at 0 °C.
  • freshly activated 4A MS powder (80 mg) was added at 0 °C under nitrogen atmosphere and kept for vigorous stirring for another 15 min.
  • NIS 1.5 eq., 89 mg
  • AgOTf 0.2 eq., 13 mg
  • chloro [tris(2, 4 dir-butylphenyl)phosphite] gold(I) 0.08 eq., 14 mg
  • AgOTf 0.1 eq., 5 mg
  • FIG. 3 depicts the Profile of CIStER of compounds 23-27. Progress of the one-pot CIStERs was monitored by using semi-preparative HPLC system equipped with a normal phase silica gel diol column. Initially, mobile phase conditions were optimized by injecting the four standards samples 23, S27, 24, and 26 so that the peaks are well resolved for identification purpose. Subsequently, aliquots of CIStER reaction (14,16) were injected under above optimized mobile phase conditions. Products 25&27 and intermediates during the CIStER were collected and characterized.
  • This compound was synthesized according to above mentioned one pot glycan editing procedure. (45% overall yield, white solid).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention relève d'une manière générale du domaine de la synthèse organique. En particulier, la présente invention concerne un procédé de réaction CIStER (cut-insert stitch-editing reaction) pour une synthèse stéréo- et régiosélective de glycoconjugués complexes et ramifiés. La présente invention concerne également un procédé d'une approche chimique en trois étapes en un seul pot pour synthétiser des analogues de lipoarabinomannane présents dans mycobacterium tuberculosis.
PCT/IB2024/062990 2024-02-01 2024-12-20 Chirurgie moléculaire : technique de réaction cister (cut-insert-stitch editing reaction) Pending WO2025163383A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202421006807 2024-02-01
IN202421006807 2024-02-01

Publications (1)

Publication Number Publication Date
WO2025163383A1 true WO2025163383A1 (fr) 2025-08-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/062990 Pending WO2025163383A1 (fr) 2024-02-01 2024-12-20 Chirurgie moléculaire : technique de réaction cister (cut-insert-stitch editing reaction)

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WO (1) WO2025163383A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5262312A (en) * 1990-04-25 1993-11-16 Hoechst Aktiengesellschaft Process for the glycosidase-catalyzed synthesis of glyco conjugates
WO2000053614A1 (fr) * 1999-03-06 2000-09-14 Bayer Aktiengesellschaft Procede de production de glycoconjugues de 20(s)-camptothecine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5262312A (en) * 1990-04-25 1993-11-16 Hoechst Aktiengesellschaft Process for the glycosidase-catalyzed synthesis of glyco conjugates
WO2000053614A1 (fr) * 1999-03-06 2000-09-14 Bayer Aktiengesellschaft Procede de production de glycoconjugues de 20(s)-camptothecine

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