WO2020204691A1 - A functionalized glycolipid and an application thereof - Google Patents

A functionalized glycolipid and an application thereof Download PDF

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WO2020204691A1
WO2020204691A1 PCT/MY2020/050015 MY2020050015W WO2020204691A1 WO 2020204691 A1 WO2020204691 A1 WO 2020204691A1 MY 2020050015 W MY2020050015 W MY 2020050015W WO 2020204691 A1 WO2020204691 A1 WO 2020204691A1
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group
glycolipid
functionalized
formula
integer ranging
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PCT/MY2020/050015
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French (fr)
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Heidelberg THORSTEN
Rusnah Syahil Binti DUALI HUSSEN
Ean Wai GOH
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University Malaya
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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
    • 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
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to the field of pharmaceutics and nanotechnology, particularly a functionalized glycolipid and its use in a vesicular carrier for delivering medical drugs to specific target cells.
  • the vesicular carrier shields the drug from untimely interaction with body cells, whereas chemically bonded biological receptor antigens at the functionalized glycolipids direct the carrier to the targeted cells, particularly tumor cells and bacteria.
  • An efficient drug delivery system consists of a drug delivery carrier, which protects the drugs from reacting with unwanted cells while ensuring efficient delivery of the drugs to the targeted cells.
  • Vesicular assemblies of surfactants sometimes also termed as satisfactionliposomes ⁇ , have proven to be effective carriers for pharmaceutical active compounds. They enable encapsulation of both hydrophilic and hydrophobic compounds, thereby providing applicability for most drugs.
  • the particle size of the drug carriers must be sufficiently small to pass through small blood vessels.
  • an efficient use of the drug requires a narrow size distribution of the drug carriers to ensure an optimum concentration of the active compound at the target site.
  • a receptor-mediated targeted drug delivery for vesicles requires the incorporation of a recognition domain on the exterior interphase of the drug carrier. The binding of the receptor antigen must be strong to avoid loss of the targeting function.
  • a flexible anchor and an adjustable surface concentration are recommended.
  • Various types of drug delivery carriers have been developed in order to produce an enhanced drug delivery system with targeting properties for delivering the drugs to specific cells.
  • US 2011/0123520 A1 discloses a composition and method for site specific delivery of nucleic acids such as iRNA agent (e.g., an iRNA agent or siRNA agent) or other nucleic acid, by combining them with targeting ligands and endosomolytic components.
  • the endosomolytic component may be a polyanionic peptide or peptidomimetic, which shows pH-dependent membrane activity and fusogenicity.
  • the targeting ligand may be any moiety that, for example, alters the pharmacokinetics, biodistribution or cellular uptake of the modular composition of the invention.
  • US 20060002991A1 relates to a pH-sensitive cationic lipid with a general formula cation-spacer-Y-spacer-X-lipid, where Y and X represent linking groups. Further, liposomes are described which include optional cationic lipid. Also, the application relates to a pharmaceutical composition comprising at least one inventive lipid, at least one inventive liposome and/or one inventive nanocapsule, optionally together with a pharmaceutically tolerable carrier. The pharmaceutical composition can be used as a drug.
  • Another objective of the present invention is to provide an efficient drug delivery carrier, which is biodegradable by utilizing glycolipids for producing said carrier. It is also an objective of the present invention to provide an improved drug delivery carrier, which is cost effective while maintaining the efficiency in delivering drugs to specific targeted cells. Accordingly, these objectives may be achieved by following the teachings of the present invention.
  • the present invention provides a functionalized glycolipid and an application thereof.
  • the functionalized glycolipid having a formula (I):
  • Y is selected from a group consisting of O, NH and NAc
  • A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
  • a drug delivery carrier comprising a functionalized glycolipid for specific cells recognition, the functionalized glycolipid having a formula (I):
  • Y is selected from a group consisting of O, NH and NAc
  • A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
  • FIG. 1(b) illustrates structure of carrier formulation based on Click chemistry conjugation in accordance with an embodiment of the present invention.
  • Fig. 2 illustrates utilization of bonded biological recognition domains in selective interactions of the vesicular drug carrier with target cells in accordance with an embodiment of the present invention.
  • Fig. 3(a), (b) and (c) illustrate synthesis schemes of glycolipid anchors in accordance with an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • compositions or an element or a group of elements are preceded with the transitional phrase“comprising”, it is understood that we also contemplate the same composition, element or group of elements with transitional phrases“consisting of”,“consisting”,“selected from the group of consisting of,“including”, or“is” preceding the recitation of the composition, element or group of elements and vice versa.
  • Y is selected from a group consisting of O, NH and NAc
  • A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
  • L 0 is selected from a group consisting of (CH 2 ) i (where i is an integer ranging from 0 to 2), CO and CH(OH)CH 2 ;
  • Y 1 is selected from a group consisting of O, NH and NR (where R is a hydrocarbon chain);
  • R is selected from a group consisting of C n H 2n ⁇ 1 and CH 2 OC n H 2n ⁇ 1 ;
  • R ⁇ is selected from a group consisting of C m H 2m ⁇ 1 , OC m H 2m ⁇ 1 and CH 2 OC m H 2m ⁇ 1 ;
  • n is an integer ranging from 4 to 20; and
  • m is an integer ranging from 0 to 20; wherein m + n > 5;
  • B having a formula (IV):
  • L 2 is selected from a group consisting of C 2 H 4 and CH 2 CH(OH)CH 2
  • L 3 is selected from a group consisting of (C 2 H 4 O) k C 2 H 4 and [CH 2 CH(OH)CH 2 O] k CH 2 CH(OH)CH 2
  • k is an integer ranging from 1 to 10
  • X is selected from a group consisting of SH, N 3 and OCH 2 CoCH and OC 2 H 4 C oCH.
  • the functionalized glycolipid can be applied with any type of drugs or antigens carrier for treating any diseases or disorders without affecting its contents.
  • the functionalized glycolipid can be applied in the formulation of an encapsulating drug carrier, thereby enabling a mild and selective coupling of complementary functionalized biological recognition domains (receptor antigens) on the exterior surface of the drug carrier. This step can be done after finishing or completing the production of the drug carrier, including its loading with the active drug.
  • the functionalized glycolipid is made up of, but not limited to, a non-ionic surfactant base material.
  • the non-ionic surfactant base material contributes high assembly stability to the drug carriers, which minimize a non-specific release of active compound over time, Further, the non-ionic nature minimizes the response of the assembly to external stimuli, such as, but not limited to, variations of pH or ion concentrations, whereas the poly-hydroxy-core provides intermolecular cohesion between head groups, thereby further strengthening the surfactant assembly, which originates from hydrophobic interactions of the lipophilic domain.
  • high stability of the surfactant assembly constrains the control of the vesicle size and its distribution.
  • the selected base material or carbohydrate core is glycolipid.
  • Glycolipid is preferred due to its high assembly stability properties which minimize potential leakages during encapsulation of the drug.
  • A is a hydrophobic domain site of the glycolipid.
  • the type of glycolipid chosen is, but not limited to, a mono-antennary glycolipid formed by incorporating mono- antennary hydrophobic domain or a bi-antennary glycolipid formed by incorporating bi-antennary hydrophobic domain.
  • a glycoside-type or amide-type is chosen in order to ensure chemical stability of the base material, while maintaining the biodegradability of the same.
  • the bi-antennary hydrophobic domain is having a formula (II):
  • L 0 is selected from a group consisting of (CH 2 ) i (where i is an integer ranging from 0 to 2), CO and CH(OH)CH 2 ;
  • R is selected from a group consisting of C n H 2n ⁇ 1 and CH 2 OC n H 2n ⁇ 1 ; and where n is an integer ranging from 4 to 20.
  • Y 1 can be selected from a group containing heteroatom such as, but not limited to, O, NH and NR (where R is a hydrocarbon chain).
  • R is a linear or branched, saturated or unsaturated hydrocarbon chain, which may include one oxygen atom replacing a CH 2 group such as, but not limited to, C n H 2n ⁇ 1 and CH 2 OC n H 2n ⁇ 1 .
  • R ⁇ is a hydrogen atom or a linear or branched, saturated or unsaturated hydrocarbon chain, which may include one oxygen atom replacing a CH 2 group such as, but not limited to, C m H 2m ⁇ 1 , OC m H 2m ⁇ 1 and CH 2 OC m H 2m ⁇ 1 .
  • the functionalized glycolipid is incorporated with an ionic charge to increase molecular interactions between the glycolipid base material and an ionic dopant due to hydrogen bonding in order to avoid gradual loss of the dopant over time.
  • the glycolipid is attached with imidazolium ion which provides positive charge ion to the glycolipid.
  • a positive charge is introduced on the functionalized glycolipid in order to ensure optimum binding of the ionic co-surfactant within the vesicular carrier assembly.
  • B is attached at a hydrophilic domain site of the glycolipid. The carbohydrate part of the hydrophilic domain ensures hydrogen bonding with the surfactant matrix, which minimizes potential loss of the co-surfactant.
  • B is having a formula (IV):
  • L 2 is a linker which links the imidazolium ion to the glycolipid.
  • the functionalized glycolipid comprises a spacer, which links a clickable functional group via the imidazolium ion to the glycolipid.
  • the spacer is, but not limited to, a water-soluble oligomer spacer.
  • the spacer and clickable functional group is having a formula of:
  • the functionalized glycolipid utilizes Click chemistry based approach for effectively delivering drugs to the specific targeted cells.
  • the Click coupling ensures an efficient introduction of biological recognition functional group in aqueous environment under mild reaction conditions, which prevent potential damages on sensitive receptor antigens.
  • the functionalized glycolipid is having a formula (V):
  • R is selected from a group consisting of C n ⁇ H 2n ⁇ 1 , CHR 2 (where R is CH 2 OC n ⁇ H 2n ⁇ 1 ), CH 2 CHR 1 R 2 (where R 1 is C n ⁇ H 2n ⁇ 1 and R 2 is C m ⁇ H 2m ⁇ 1 ) and CH 2 CH(OR 2 )CH 2 OR 1 (where R 1 is C n ⁇ H 2n ⁇ 1 and R 2 is C m ⁇ H 2m ⁇ 1 ); Y is selected from a group consisting of O, NH and NAc; X is selected from a group consisting of CH 2 SH, CH 2 N 3 , CoCH and CH 2 CoCH; n is an integer ranging from 1 to 10; and n ⁇ and m ⁇ is an integer ranging from 1 to 20.
  • the central carbohydrate core can be based on either glucose or 2-amino-deoxyglucose.
  • R is a mono- or biantennary hydrocarbon domain which reflecting linear or branched hydrocarbon chains (C 8 -C 40 ), with or without unsaturation in which up to two oxygen atoms may be incorporated in ether linkages.
  • the functionalized glycolipid is having a formula (VI):
  • R is selected from a group consisting of C n ⁇ H 2n ⁇ 1 , CH(CH 2 OR a ) 2 (where R a is C n ⁇ H 2n ⁇ 1 ), CH 2 CHR a R b (where R a is C n ⁇ H 2n ⁇ 1 and R b is C m ⁇ H 2m ⁇ 1 ) or CH 2 CH(OR b )CH 2 OR a (where R a is OC n ⁇ H 2n ⁇ 1 and R b is C m ⁇ H 2m ⁇ 1 ); one of the R 2 , R 3 , R 4 or R 6 is having a formula (VIII),
  • Fig. 1(a) illustrates structure of carrier formulation based on direct conjugation in accordance with an embodiment of the present invention while, Fig. 1(b) illustrates structure of carrier formulation based on Click chemistry conjugation in accordance with an embodiment of the present invention.
  • Fig. 1(b) illustrates structure of carrier formulation based on Click chemistry conjugation in accordance with an embodiment of the present invention.
  • FIG. 1(a) illustrates the disadvantage of a direct state-of-art incorporation of biological recognition domains during the vesicle preparation, leading to loss of bio-recognition domains inside the drug carrier– a feature that can be avoided with the present invention as illustrated in Fig.1(b).
  • the structure as shown in Fig. 1(a) reflects the common structure of biological membranes, in which a surfactant bonded biological recognition domain is incorporated into the bilayer of a drug carrier.
  • the disadvantage of employing the direct conjugation approach is being shown in Fig. 1(a), where only half of the biological recognition functional group is being utilized, while the other half remain inactive inside the carrier.
  • Fig. 1(b) shows the structure of carrier formulation based on Click chemistry, in which all of the biological recognition functional group is utilized. Further, said figure illustrates an approach for the external surface bio- conjugation of the vesicular drug carriers.
  • the incorporation of functionalized anchor-glycolipid into the formulation enables the introduction of the biological recognition domain exclusively on the external surface of the vesicles without loss of precious receptor-antigens inside the drug carrier thus significantly reducing the cost. This concept enables addressing of various target cells solely by changing the applied receptor antigen.
  • Fig. 2 illustrates the utilization of bonded biological recognition domains in selective interactions of the vesicular drug carrier with target cells.
  • Click chemistry for the bio-conjugation ensures effective and selective coupling with low risk for loss of bio-recognition domains due to the covalent linkage.
  • Fig. 3(a), (b) and (c) illustrate synthesis schemes of glycolipid anchors in accordance with an embodiment of the present invention. The synthesis schemes are further discussed in the below examples. References
  • Azido-Ethoxylated 6-Imidazolium Glycolipid P1
  • Azido-terminated oligoethoxylated imidazole linker S2 A solution of imidazole (0.30 g, 4.4mmol) and sodium hydride (60% in paraffin oil; 0.32 g, 8.0 mmol) in THF (40 mL) was treated with 1,2-bis-(2-chloroethoxy)ethane S1 (2.8 mL, 18 mmol) under ice bath cooling and subsequently heated to reflux overnight. The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and insoluble solids were filtered off.
  • Functionalized glycolipid precursor G2 1 A solution of 2-hexyl-decyl b-D- glucopyranoside G1 2 (1.70 g, 4.2 mmol) and triphenylphosphine (2.21 g, 8.4 mmol) in DMF (12 mL), was cooled to 0°C and subsequently treated with N- bromosuccinimide (1.53 g, 8.4 mmol). The mixture was then heated to 70 °C for two hours, after which methanol (10 mL) was added to quench the reaction. After evaporation of the solvent, the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the organic phase was dried over magnesium sulfate and concentrated to furnish the crude 6-bromo-glycolipid, which was acetylated without further purification.
  • the crude 6-bromo-glycolipid treated with acetic anhydride (4 mL, 42 mmol) in pyridine (12 mL). The reaction was left at room temperature overnight and subsequently concentrated under reduced pressure. The residue was taken up in dichloromethane and washed with diluted hydrochloric acid and water.
  • Anchor glycolipid P1 A mixture of S2 (0.11 g, 0.4 mmol) and G2 (0.20 g, 0.4 mmol) in xylene (1 mL) was heated to 130 °C. The reaction was monitored by TLC. Upon completion the solvent was evaporated to furnish spectroscopic clean P1 i , which was deacetylated without further purification. P1 i was dissolved in methanol (3 mL) and treated with a catalytic amount of sodium methoxide. The reaction was kept at room temperature overnight, after which the catalyst was removed by treatment with acidic ion exchanging resin Amberlite IR-120. Evaporation of the solvent furnished P1 (0.22 g, quant.) as yellow syrup. IR [neat] n/cm -1 : 3354 (OH), 2824, 2856 (CH), 2104 (N 3 ). [a] 25
  • Oligoethoxylated-Imidazolium on Branched Chain Alkyl Glycoside This example demonstrates the synthetic scheme for a Click-chemistry suitable anchor glycolipid involving a terminal alkyne.
  • the preparation involves several steps.
  • Alkyne-terminated oligoethoxylated linker S3 A solution of diethylene glycol (15 mL, 160 mmol) in anhydrous THF (60 mL) was treated with sodium hydride (60% in paraffin oil, 1.6 g, 40 mmol) and the mixture was stirred for 1 h at room temperature. Propargyl bromide (3.3 mL, 37 mmol) was added gradually at 0 °C and the reaction was subsequently stirred at room temperature overnight.
  • the solvent was evaporated and the residue taken up in dichloromethane and washed twice with water. After drying over magnesium sulphate the solvent was evaporated and the tosylate purified by chromatography (hexane / ethyl acetate 7:1) to provide a yellow liquid (3.4 g, 87%).
  • the intermediate (3.0 g, 10 mmol) was dissolved in acetone (40 mL) and treated with sodium iodide (3.0 g, 20 mmol). After stirring at room temperature overnight, the solvent was evaporated and the residue taken up in dichloromethane and water. The organic phase was washed with aqueous sodium thiosulfate solution and water and dried over magnesium sulfate.
  • Anchor glycolipid P2 A mixture of S3 (0.20 g, 0.8 mmol) and G7 (0.50 g, 0.8 mmol) in toluene (3 mL) was heated to reflux. The reaction was monitored by TLC. Upon completion the solvent was evaporated to furnish spectroscopic clean P2 i , which was deacetylated without further purification. P2 i was dissolved in methanol (5 mL) and treated with a catalytic amount of sodium methoxide. The reaction was kept at room temperature overnight, after which the catalyst was removed by treatment with acidic ion exchanging resin Amberlite IR-120. Evaporation of the solvent furnished P2 (0.40 g, quant.) as brown syrup. IR [neat] n/cm -1 : 3407 (OH), 2924, 2855 (CH), 2114 (CoC). [a] 25
  • the above-mentioned functionalized glycolipid utilizes Click chemistry based approach, which produces a drug delivery carrier capable of interacting with specific targeted cells and reducing side effect to the host. Further, the functionalized glycolipid ensures the biodegradability of drug carrier, while maintaining the efficiency of the same.

Abstract

The present invention discloses a functionalized glycolipid having a formula (I): (I) where Y is selected from a group consisting of O, NH and NAc; wherein A is selected from a group of bi-antennary hydrophobic domain having a formula (II): (II) and mono-antennary hydrophobic domain having a formula (III): (III) wherein B having a formula (IV): (IV). Further, the present invention discloses an application of the functionalized glycolipid having the formula (I) thereof. The functionalized glycolipid is usable with a drug delivery carrier for binding biological recognition domain for the cells specific recognition of the carrier via click chemistry.

Description

A FUNCTIONALIZED GLYCOLIPID AND AN APPLICATION THEREOF TECHNICAL FIELD
The present invention relates to the field of pharmaceutics and nanotechnology, particularly a functionalized glycolipid and its use in a vesicular carrier for delivering medical drugs to specific target cells. The vesicular carrier shields the drug from untimely interaction with body cells, whereas chemically bonded biological receptor antigens at the functionalized glycolipids direct the carrier to the targeted cells, particularly tumor cells and bacteria. BACKGROUND ART
Nowadays, due to unwanted side effects of pharmaceutics, increasing effort is placed to a selective delivery of biologically active material to target cells. A potential selection process can apply specific interactions of antigens to cell-bound receptors. In view of the highly specific receptor structures on cells, which distinguish different species and tissues within an organism, higher possibility for cell-differentiation can be achieved compared with drugs targeting on specific cellular processes. An efficient drug delivery system consists of a drug delivery carrier, which protects the drugs from reacting with unwanted cells while ensuring efficient delivery of the drugs to the targeted cells. Vesicular assemblies of surfactants, sometimes also termed as„liposomes‟, have proven to be effective carriers for pharmaceutical active compounds. They enable encapsulation of both hydrophilic and hydrophobic compounds, thereby providing applicability for most drugs. In order to ensure a reliable drug delivery throughout the body, the particle size of the drug carriers must be sufficiently small to pass through small blood vessels. Moreover, an efficient use of the drug requires a narrow size distribution of the drug carriers to ensure an optimum concentration of the active compound at the target site. A receptor-mediated targeted drug delivery for vesicles requires the incorporation of a recognition domain on the exterior interphase of the drug carrier. The binding of the receptor antigen must be strong to avoid loss of the targeting function. In order to ensure an efficient receptor binding and avoid blocking of recognition domains, a flexible anchor and an adjustable surface concentration are recommended. Various types of drug delivery carriers have been developed in order to produce an enhanced drug delivery system with targeting properties for delivering the drugs to specific cells. Currently, there are a number of solutions developed for producing said drug carrier and few of them have been discussed in following prior arts. US 2011/0123520 A1 discloses a composition and method for site specific delivery of nucleic acids such as iRNA agent (e.g., an iRNA agent or siRNA agent) or other nucleic acid, by combining them with targeting ligands and endosomolytic components. The endosomolytic component may be a polyanionic peptide or peptidomimetic, which shows pH-dependent membrane activity and fusogenicity. Further, the targeting ligand may be any moiety that, for example, alters the pharmacokinetics, biodistribution or cellular uptake of the modular composition of the invention. US 20060002991A1 relates to a pH-sensitive cationic lipid with a general formula cation-spacer-Y-spacer-X-lipid, where Y and X represent linking groups. Further, liposomes are described which include optional cationic lipid. Also, the application relates to a pharmaceutical composition comprising at least one inventive lipid, at least one inventive liposome and/or one inventive nanocapsule, optionally together with a pharmaceutically tolerable carrier. The pharmaceutical composition can be used as a drug. The aforesaid documents and other similar solutions may strive to provide an improved drug delivery carrier; however, they still have a number of limitations and shortcomings, such as, but not limited to, the drug delivery carrier or composition disclosed in the aforesaid prior art tend to couple with unwanted cells, which reduces the efficiency and causing side effect to the host. Further, none of the above-mentioned prior arts disclose a drug delivery carrier which utilizes a functionalized glycolipid for exhibiting biological recognition features or targeting features on the delivery carrier. Accordingly, there remains a need in the prior art to have an improved vesicular drug delivery carrier which utilizes a functionalized glycolipid for exhibiting biological recognition features or targeting features on the delivery carrier, which overcomes the aforesaid problems and shortcomings. SUMMARY OF THE INVENTION
An objective of the present invention is to provide a functionalized glycolipid that enables a mild and selective coupling of biological recognition domains. It is also an objective of the present invention to provide a drug delivery carrier, which utilizes the functionalized glycolipid for exhibiting biological recognition features or targeting features on the delivery carrier to effectively delivering the drugs to selected cell types expressing specific surface receptor patterns. It is an objective of the present invention to provide a drug delivery carrier which utilizes a functionalized glycolipid for exhibiting biological recognition features or targeting features on the delivery carrier, in which synthetic or biological derived antigens can be applied. A further objective of the present invention is to provide an improved drug delivery carrier by employing Click-chemistry to couple vesicular surfactant assemblies with biological recognition domains for efficient delivering of drugs to specific targeted cells. Another objective of the present invention is to provide an efficient drug delivery carrier, which is biodegradable by utilizing glycolipids for producing said carrier. It is also an objective of the present invention to provide an improved drug delivery carrier, which is cost effective while maintaining the efficiency in delivering drugs to specific targeted cells. Accordingly, these objectives may be achieved by following the teachings of the present invention. The present invention provides a functionalized glycolipid and an application thereof. The functionalized glycolipid having a formula (I):
Figure imgf000006_0001
where Y is selected from a group consisting of O, NH and NAc;
wherein A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
Figure imgf000006_0002
and mono-antennary hydrophobic domain having a formula (III):
Figure imgf000006_0003
wherein B having a formula (IV):
Figure imgf000007_0001
A drug delivery carrier comprising a functionalized glycolipid for specific cells recognition, the functionalized glycolipid having a formula (I):
Figure imgf000007_0002
where Y is selected from a group consisting of O, NH and NAc;
wherein A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
Figure imgf000007_0003
and mono-antennary hydrophobic domain having a formula (III):
Figure imgf000007_0004
wherein B having a formula (IV):
Figure imgf000007_0005
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may have been referred by embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawing illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments. These and other features, benefits, and advantages of the present invention will become apparent by reference to the following text figure, with like reference numbers referring to like structures across the views, wherein: Fig. 1(a) illustrates structure of carrier formulation based on direct conjugation in accordance with an embodiment of the present invention. Fig. 1(b) illustrates structure of carrier formulation based on Click chemistry conjugation in accordance with an embodiment of the present invention. Fig. 2 illustrates utilization of bonded biological recognition domains in selective interactions of the vesicular drug carrier with target cells in accordance with an embodiment of the present invention. Fig. 3(a), (b) and (c) illustrate synthesis schemes of glycolipid anchors in accordance with an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
While the present invention is described herein by way of example using embodiments and illustrative drawings, those skilled in the art will recognize that the invention is not limited to the embodiments of drawing or drawings described, and are not intended to represent the scale of the various components. Further, some components that may form a part of the invention may not be illustrated in certain figures, for ease of illustration, and such omissions do not limit the embodiments outlined in any way. It should be understood that the drawings and detailed description thereto are not intended to limit the invention to the particular form disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the scope of the present invention as defined by the appended claim. As used throughout this description, the word "may" is used in a permissive sense (i.e. meaning having the potential to), rather than the mandatory sense, (i.e. meaning must). Further, the words "a" or "an" mean "at least one” and the word “plurality” means“one or more” unless otherwise mentioned. Furthermore, the terminology and phraseology used herein is solely used for descriptive purposes and should not be construed as limiting in scope. Language such as "including," "comprising," "having," "containing," or "involving," and variations thereof, is intended to be broad and encompass the subject matter listed thereafter, equivalents, and additional subject matter not recited, and is not intended to exclude other additives, components, integers or steps. Likewise, the term "comprising" is considered synonymous with the terms "including" or "containing" for applicable legal purposes. Any discussion of documents, acts, materials, devices, articles and the like is included in the specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention. In this disclosure, whenever a composition or an element or a group of elements is preceded with the transitional phrase“comprising”, it is understood that we also contemplate the same composition, element or group of elements with transitional phrases“consisting of”,“consisting”,“selected from the group of consisting of,“including”, or“is” preceding the recitation of the composition, element or group of elements and vice versa. The present invention is described hereinafter by various embodiments with reference to the accompanying drawing, wherein reference numerals used in the accompanying drawing correspond to the like elements throughout the description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiment set forth herein. Rather, the embodiment is provided so that this disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art. In the following detailed description, numeric values and ranges are provided for various aspects of the implementations described. These values and ranges are to be treated as examples only, and are not intended to limit the scope of the claims. In addition, a number of materials are identified as suitable for various facets of the implementations. These materials are to be treated as exemplary, and are not intended to limit the scope of the invention. Referring to the drawings, the invention will now be described in more detail. The functionalized glycolipid having a formula (I):
Figure imgf000010_0001
where Y is selected from a group consisting of O, NH and NAc;
wherein A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
Figure imgf000010_0002
and mono-antennary hydrophobic domain having a formula (III):
Figure imgf000010_0003
where L0 is selected from a group consisting of (CH2)i (where i is an integer ranging from 0 to 2), CO and CH(OH)CH2; Y1 is selected from a group consisting of O, NH and NR (where R is a hydrocarbon chain); L1 is selected from a group consisting of CO and (CH2) with i=0,1; R is selected from a group consisting of CnH2n±1 and CH2OCnH2n±1; R‟ is selected from a group consisting of CmH2m±1, OCmH2m±1 and CH2OCmH2m±1; n is an integer ranging from 4 to 20; and m is an integer ranging from 0 to 20; wherein m + n > 5; wherein B having a formula (IV):
Figure imgf000011_0001
where L2 is selected from a group consisting of C2H4 and CH2CH(OH)CH2; L3 is selected from a group consisting of (C2H4O)kC2H4 and [CH2CH(OH)CH2O]kCH2CH(OH)CH2; k is an integer ranging from 1 to 10; and X is selected from a group consisting of SH, N3 and OCH2CºCH and OC2H4C ºCH. In accordance with an embodiment of the present invention, the functionalized glycolipid can be applied with any type of drugs or antigens carrier for treating any diseases or disorders without affecting its contents. In a preferred embodiment, the functionalized glycolipid can be applied in the formulation of an encapsulating drug carrier, thereby enabling a mild and selective coupling of complementary functionalized biological recognition domains (receptor antigens) on the exterior surface of the drug carrier. This step can be done after finishing or completing the production of the drug carrier, including its loading with the active drug. In accordance with an embodiment of the present invention, the functionalized glycolipid is made up of, but not limited to, a non-ionic surfactant base material. The non-ionic surfactant base material, particularly carbohydrate-based surfactants, contributes high assembly stability to the drug carriers, which minimize a non-specific release of active compound over time, Further, the non-ionic nature minimizes the response of the assembly to external stimuli, such as, but not limited to, variations of pH or ion concentrations, whereas the poly-hydroxy-core provides intermolecular cohesion between head groups, thereby further strengthening the surfactant assembly, which originates from hydrophobic interactions of the lipophilic domain. However, high stability of the surfactant assembly constrains the control of the vesicle size and its distribution. Therefore, a small portion of an ionic co-surfactant is incorporated to mediate the distribution of surfactants during the assembly formulation and producing uniformly small nanoparticles. Intermolecular repulsion of the ionic head groups prevents the aggregation of the ionic co-surfactants within the assembly, while a positive head group ensures a suitable surface charge for attractive interactions of the drug carrier with typical anionic dominated surfaces of target cells. Preferably, the selected base material or carbohydrate core is glycolipid. Glycolipid is preferred due to its high assembly stability properties which minimize potential leakages during encapsulation of the drug. In accordance with an embodiment of the present invention, A is a hydrophobic domain site of the glycolipid. In a preferred embodiment, the type of glycolipid chosen is, but not limited to, a mono-antennary glycolipid formed by incorporating mono- antennary hydrophobic domain or a bi-antennary glycolipid formed by incorporating bi-antennary hydrophobic domain. Particularly, a glycoside-type or amide-type is chosen in order to ensure chemical stability of the base material, while maintaining the biodegradability of the same. Preferably, the bi-antennary hydrophobic domain is having a formula (II):
Figure imgf000013_0001
and mono-antennary hydrophobic domain having a formula (III):
Figure imgf000013_0002
where L0 is selected from a group consisting of (CH2)i (where i is an integer ranging from 0 to 2), CO and CH(OH)CH2; Y1 is selected from a group consisting of O, NH and NR (where R is a hydrocarbon chain); L1 is selected from a group consisting of CO and (CH2)i with i=0,1; R is selected from a group consisting of CnH2n±1 and CH2OCnH2n±1; and where n is an integer ranging from 4 to 20. In a preferred embodiment, Y1 can be selected from a group containing heteroatom such as, but not limited to, O, NH and NR (where R is a hydrocarbon chain). In a preferred embodiment, R is a linear or branched, saturated or unsaturated hydrocarbon chain, which may include one oxygen atom replacing a CH2 group such as, but not limited to, CnH2n±1 and CH2OCnH2n±1. Further, R‟ is a hydrogen atom or a linear or branched, saturated or unsaturated hydrocarbon chain, which may include one oxygen atom replacing a CH2 group such as, but not limited to, CmH2m±1, OCmH2m±1 and CH2OCmH2m±1. In accordance with an embodiment of the present invention, the functionalized glycolipid is incorporated with an ionic charge to increase molecular interactions between the glycolipid base material and an ionic dopant due to hydrogen bonding in order to avoid gradual loss of the dopant over time. The glycolipid is attached with imidazolium ion which provides positive charge ion to the glycolipid. In accordance with an embodiment of the present invention, a positive charge is introduced on the functionalized glycolipid in order to ensure optimum binding of the ionic co-surfactant within the vesicular carrier assembly. In accordance with an embodiment of the present invention, B is attached at a hydrophilic domain site of the glycolipid. The carbohydrate part of the hydrophilic domain ensures hydrogen bonding with the surfactant matrix, which minimizes potential loss of the co-surfactant. In accordance with an embodiment of the present invention, B is having a formula (IV):
Figure imgf000014_0001
The positive charge ion of said formula efficiently promotes an interaction between the carrier and targeted cells having negative-charge surfaces for accurate delivering of drugs or antigens. In accordance with an embodiment of the present invention, L2 is a linker which links the imidazolium ion to the glycolipid. In accordance with an embodiment of the present invention, the functionalized glycolipid comprises a spacer, which links a clickable functional group via the imidazolium ion to the glycolipid. Preferable, the spacer is, but not limited to, a water-soluble oligomer spacer. In a preferred embodiment, the spacer and clickable functional group is having a formula of:
where L3 is the spacer and X is the clickable functional group. Preferably, the spacer is based on oligo-ethyleneoxide or oligo-glycerol. In accordance with an embodiment of the present invention, the functionalized glycolipid utilizes Click chemistry based approach for effectively delivering drugs to the specific targeted cells. The Click coupling ensures an efficient introduction of biological recognition functional group in aqueous environment under mild reaction conditions, which prevent potential damages on sensitive receptor antigens. In a preferred embodiment, the functionalized glycolipid is having a formula (V):
Figure imgf000015_0001
where R is selected from a group consisting of Cn‟H2n‟±1, CHR2 (where R is CH2OCn‟H2n‟±1), CH2CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1) and CH2CH(OR2)CH2OR1 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1); Y is selected from a group consisting of O, NH and NAc; X is selected from a group consisting of CH2SH, CH2N3, CºCH and CH2CºCH; n is an integer ranging from 1 to 10; and n‟ and m‟ is an integer ranging from 1 to 20. Preferably, the central carbohydrate core can be based on either glucose or 2-amino-deoxyglucose. Also, R is a mono- or biantennary hydrocarbon domain which reflecting linear or branched hydrocarbon chains (C8-C40), with or without unsaturation in which up to two oxygen atoms may be incorporated in ether linkages. In another preferred embodiment, the functionalized glycolipid is having a formula (VI):
Figure imgf000016_0001
where Y6 is selected from a group consisting of CH2OH, CH2NCOR, C2H4NCOR and CONRR‟ (where R is a linear or branched hydrocarbon chain selected from a group consisting of Cn‟H2n‟±1, and CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1) and R‟=H; or R is a linear or branched hydrocarbon chain (where R is Cn‟H2n‟±1, CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1); Y2 is selected from a group consisting of O, NH and NCOR (where R is a linear or branched hydrocarbon chain selected from a group consisting of Cn‟H2n‟±1, and CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1); X is selected from the group consisting of CH2SH, CH2N3, CºCH and CH2CºCH; n is an integer ranging from 1 to 10; and n‟ and m‟ is an integer ranging from 1 to 20. In another preferred embodiment, the functionalized glycolipid is having a formula (VII):
Figure imgf000016_0002
where R is selected from a group consisting of Cn‟H2n‟±1, CH(CH2ORa)2 (where Ra is Cn‟H2n‟±1), CH2CHRaRb (where Ra is Cn‟H2n‟±1 and Rb is Cm‟H2m‟±1) or CH2CH(ORb)CH2ORa (where Ra is OCn‟H2n‟±1 and Rb is Cm‟H2m‟±1); one of the R2, R3, R4 or R6 is having a formula (VIII),
Figure imgf000017_0001
and the remaining three are H; where X is selected from a group consisting of CH2SH, CH2N3, CºCH and CH2CºCH; and n is an integer ranging from 1 to 10; and n‟ and m‟ is an integer ranging from 1 to 20. Fig. 1(a) illustrates structure of carrier formulation based on direct conjugation in accordance with an embodiment of the present invention while, Fig. 1(b) illustrates structure of carrier formulation based on Click chemistry conjugation in accordance with an embodiment of the present invention. Fig. 1(a) illustrates the disadvantage of a direct state-of-art incorporation of biological recognition domains during the vesicle preparation, leading to loss of bio-recognition domains inside the drug carrier– a feature that can be avoided with the present invention as illustrated in Fig.1(b). The structure as shown in Fig. 1(a) reflects the common structure of biological membranes, in which a surfactant bonded biological recognition domain is incorporated into the bilayer of a drug carrier. The disadvantage of employing the direct conjugation approach is being shown in Fig. 1(a), where only half of the biological recognition functional group is being utilized, while the other half remain inactive inside the carrier. This is caused by difficulty in arranging the selective direction of antenna towards the extracellular water phase as the internal and external water phase exhibit similar environment. Alternatively, Fig. 1(b) shows the structure of carrier formulation based on Click chemistry, in which all of the biological recognition functional group is utilized. Further, said figure illustrates an approach for the external surface bio- conjugation of the vesicular drug carriers. The incorporation of functionalized anchor-glycolipid into the formulation enables the introduction of the biological recognition domain exclusively on the external surface of the vesicles without loss of precious receptor-antigens inside the drug carrier thus significantly reducing the cost. This concept enables addressing of various target cells solely by changing the applied receptor antigen. Further, the coupling functionality on the ionic co-surfactant prevents a clustering of biological recognition domains, thereby ensuring their accessibility for interactions of the drug carrier with target cells. Fig. 2 illustrates the utilization of bonded biological recognition domains in selective interactions of the vesicular drug carrier with target cells. The application of Click chemistry for the bio-conjugation ensures effective and selective coupling with low risk for loss of bio-recognition domains due to the covalent linkage. Hereinafter, examples of the present invention will be provided for more detailed explanation. It will be understood that the examples described below are not intended to limit the scope of the present invention. Example
Fig. 3(a), (b) and (c) illustrate synthesis schemes of glycolipid anchors in accordance with an embodiment of the present invention. The synthesis schemes are further discussed in the below examples. References
1S. Hanessian et al., Carbohydr. Res.24 (1972) 45-56;
2R. Hashim et al., Thin Solid Films 509 (2007) 27-35;
3M. Tabandeh et al., Carhohydr. Res.469 (2018) 14-22;
4K. Sabah et al., Carbohydr. Res.346 (2011) 891-896; 5S. Hanessian et al., Carbohydr. Res.63 (1978) 265-269;
6S. Combemale et al., Molecules 19 (2014) 1120-1149;
7O.W. Mak et al., J. Surf. Det.18 (2015) 973-980; and
8T. Heidelberg et al., Mal. J. Sci.28 Spec. Ed. (2009) 105-114. Example 1
Synthesis of Azido-Ethoxylated 6-Imidazolium Glycolipid (P1) Azido-terminated oligoethoxylated imidazole linker S2: A solution of imidazole (0.30 g, 4.4mmol) and sodium hydride (60% in paraffin oil; 0.32 g, 8.0 mmol) in THF (40 mL) was treated with 1,2-bis-(2-chloroethoxy)ethane S1 (2.8 mL, 18 mmol) under ice bath cooling and subsequently heated to reflux overnight. The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and insoluble solids were filtered off. Purification by column chromatography (ethyl acetate / acetone 8:1) provided 1-(8-chloro-3,6-dioxa- octyl)-imidazole as a yellow liquid (0.58 g, 60 %). The intermediate (0.54 g, 2.5 mmol) was dissolved in DMF (10 mL) and treated with sodium azide (0.40 g, 6.2 mmol) followed by heating to 80°C overnight. The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and salts were removed by filtration. Evaporation of the solvent furnished spectroscopic pure 1-(2-azido-ethoxy-ethoxyethyl)-imidazole S2 as yellow liquid (0.51 g, 91%). IR [neat] n/cm-1: 2872 (CH), 2102 (N3). 1H NMR (400 MHz, CDCl3): d 7.46 (s, 1H), 6.95-6.92 (m, 2H), 4.06-4.02 (m, 2H), 3.70-3.66 (m, 2H), 3.56-3.53 (m, 6H), 3.30-3.28 (m, 2H); 13C NMR (100 MHz, CDCl3): d 137.43, 129.04, 119.31, 70.60, 70.54, 70.50, 69.99, 50.57, 46.97. Functionalized glycolipid precursor G2:1 A solution of 2-hexyl-decyl b-D- glucopyranoside G12 (1.70 g, 4.2 mmol) and triphenylphosphine (2.21 g, 8.4 mmol) in DMF (12 mL), was cooled to 0°C and subsequently treated with N- bromosuccinimide (1.53 g, 8.4 mmol). The mixture was then heated to 70 °C for two hours, after which methanol (10 mL) was added to quench the reaction. After evaporation of the solvent, the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated to furnish the crude 6-bromo-glycolipid, which was acetylated without further purification. The crude 6-bromo-glycolipid treated with acetic anhydride (4 mL, 42 mmol) in pyridine (12 mL). The reaction was left at room temperature overnight and subsequently concentrated under reduced pressure. The residue was taken up in dichloromethane and washed with diluted hydrochloric acid and water. After drying over magnesium sulfate the organic solution was concentrated and the product purified by column chromatography (hexane / ethyl acetate 9:1) to provide 2-hexyl-decyl 6-bromo-6-deoxy-2,3,4-tri-O-acetyl- b-D-glucopyranoside G2 (1.30 g, 52%) as yellow syrup. [a] 25
D = -4 (c 0.20, CHCl3). 1H NMR (400 MHz, CDCl3): d 5.21 (dd~t, H-3), 5.01-4.94 (m, 2H, H-4, H-2), 4.49 (d, H-1), 3.84 (dd, a-CH2A), 3.71-3.66 (m, H-5), 3.46 (dd, H-6a), 3.41-3.33 (m, 2H, H-6b, a-CH2B), 2.06, 2.03, 2.01 (3 s, 9H, Ac), 1.56 (mc, b- CH), 1.26 (mc, 24H, bulk-CH2), 0.89 (t, 6H, CH3); 3J1,2=8.0, 3J2,3=10.0, 3J3,4=10.0, 3J4,5=10.0, 3J5,6a=3.0, 3J5,6b=6.0, 2J6=11.0 Hz; 13C NMR (100 MHz, CDCl3): d 170.28, 169.50, 169.13, 100.84, 73.30, 72.92, 72.66, 71.44, 71.24, 37.93, 31.87/ 31.84, 31.11, 30.90, 30.71, 30.04 / 30.02, 29.69 / 29.67, 29.59, 29.32, 26.76 / 26.71, 26.61 / 26.56, 22.65, 20.65, 20.60, 20.57, 14.08. Anchor glycolipid P1: A mixture of S2 (0.11 g, 0.4 mmol) and G2 (0.20 g, 0.4 mmol) in xylene (1 mL) was heated to 130 °C. The reaction was monitored by TLC. Upon completion the solvent was evaporated to furnish spectroscopic clean P1i, which was deacetylated without further purification. P1i was dissolved in methanol (3 mL) and treated with a catalytic amount of sodium methoxide. The reaction was kept at room temperature overnight, after which the catalyst was removed by treatment with acidic ion exchanging resin Amberlite IR-120. Evaporation of the solvent furnished P1 (0.22 g, quant.) as yellow syrup. IR [neat] n/cm-1: 3354 (OH), 2824, 2856 (CH), 2104 (N3). [a] 25
D = -13 (c 0.14, MeOH).1H NMR (400 MHz, CD3OD): d 7.70, 7.59 (2 s, 2H, imidazole), 4.65 (dd~d, H-6a), 4.46-4.41 (3H, m, NCH2, H-6b), 4.25 (d, H-1), 3.88 (t, 2H, EG), 3.67-3.61 (m, 8H, EG, a-CH2, H-5), 3.41-3.35 (m, 4H, -CH2N3, a-CH2, H-4), 3.15 (dd~t, H-2), 3.06 (dd~t, H-3), 1.59 (mc, b-CH), 1.42-1.30 (m 24H, bulk-CH2), 0.90 (t, 6H, CH3); 3J1,2=8.0, 3J2,3=9.5, 3J3,4=9.5 Hz; 13C NMR (100 MHz, CD3OD): d 138.66,124.69, 124.10, 105.02, 77.74, 75.09, 74.90, 74.33, 72.45, 71.59, 71.58, 71.22, 69.98, 51.94, 51.87, 51.10, 39.64, 33.21, 32.34 / 32.33, 32.28 / 32.26, 31.30 / 31.29, 30.98, 30.88 / 30.86, 30.62, 28.02, 28.01, 27.96, 27.95, 23.89, 14.60. HRMS (ESI): Calcd. for [M-Br]+ [C31H58N5O7]+ 612.4337 (100%), 613.4370 (34%), 614.4404 (5%); found 612.4337 (100%), 613.4354 (40%), 614.4410 (12%). Example 2
Synthesis of Ethyleneoxide-Bridged Propargyl-Terminated
Oligoethoxylated-Imidazolium on Branched Chain Alkyl Glycoside (P2) This example demonstrates the synthetic scheme for a Click-chemistry suitable anchor glycolipid involving a terminal alkyne. The preparation involves several steps. Alkyne-terminated oligoethoxylated linker S3: A solution of diethylene glycol (15 mL, 160 mmol) in anhydrous THF (60 mL) was treated with sodium hydride (60% in paraffin oil, 1.6 g, 40 mmol) and the mixture was stirred for 1 h at room temperature. Propargyl bromide (3.3 mL, 37 mmol) was added gradually at 0 °C and the reaction was subsequently stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was taken up in dichloromethane and washed twice with water. The organic phase was dried over magnesium sulfate and concentrated. Pure mono-propargylated diethylene glycol S3i (3.8 g, 72%) was obtained by column chromatography (hexane : ethyl acetate 3:1) as light yellow liquid. A solution of S3i (1.9 g, 13 mmol) in THF (30 mL) was treated with powdered sodium hydroxide (0.68 g, 17 mmol) at 0 °C and toluene sulfonyl chloride (2.7 g, 14 mmol) was added. The reaction mixture was stirred allowing it to warm to room temperature overnight. The solvent was evaporated and the residue taken up in dichloromethane and washed twice with water. After drying over magnesium sulphate the solvent was evaporated and the tosylate purified by chromatography (hexane / ethyl acetate 7:1) to provide a yellow liquid (3.4 g, 87%). The intermediate (3.0 g, 10 mmol) was dissolved in acetone (40 mL) and treated with sodium iodide (3.0 g, 20 mmol). After stirring at room temperature overnight, the solvent was evaporated and the residue taken up in dichloromethane and water. The organic phase was washed with aqueous sodium thiosulfate solution and water and dried over magnesium sulfate. Concentration furnished 9-iodo-4,7-dioxa-nonyne S3 (2.2 g, 88%) as colourless liquid. 1H NMR (400 MHz, CDCl3): d 4.23 (s, 2H), 3.77 (t, 2H), 3.71 (bs, 4H), 3.28 (t, 2H), 2.45 (bs, 1H); 13C NMR (100 MHz, CDCl3): d 79.51, 74.61, 71.98, 70.00, 69.05, 58.47, 2.67. Functionalized glycolipid precursor G7: The synthesis of intermediate G4i followed a literature reported procedure for the C12-homologue,3 whereas the introduction of the hydroxyethyl-linker in G5i followed another literature known procedure.4 A solution of G4i (2.90 g, 4.3 mmol in toluene (60 mL) was treated with aqueous sodium hydroxide (50 %, 40 mL) and tetrabutyl ammonium bromide (1.40 g, 4.3 mmol). The reaction mixture was stirred vigorously and subsequently cooled 0 °C, before tert. butyl-bromoacetate (1.3 mL, 8.7 mmol) was gradually added. Stirring was continued until TLC indicated complete conversion. Remaining bromide was then destroyed with methanol (10 mL). The organic phase was isolated and concentrated to furnish crude G4, which was dissolved in THF (70 mL) and cooled with an ice bath, before slow addition of lithium aluminum hydride (0.4 g, 11 mmol). The reaction mixture was allowed to warm to room temperature and stirred until TLC indicated complete conversion. Excess of the hydride was carefully destroyed with water. Upon addition of sodium hydroxide (15%, 2 mL) aluminum hydroxide precipitated and was removed by filtration. The solution was concentrated under reduced pressure and taken up in dichloromethane and water. The organic phase was dried over magnesium sulfate concentrated to provide crude G5i, which was dissolved in toluene (50 mL) and treated with iodine (1.7 g, 6.7 mmol), triphenyl phosphine (1.6 g, 6.1 mmol) and imidazole (0.90 g, 13 mmol). The reaction mixture was heated to 50 °C until TLC indicated complete conversion. The reaction was cooled to room temperature and methanol (50 mL) was added to destroy remaining reagents. The solvents were evaporated and the residue was dissolved in dichloromethane and washed with aqueous sodium thiosulfate solution and water. After drying over magnesium sulphate the solvent was evaporated and the crude product purified by column chromatography (hexane / ethyl acetate 12:1) to provide G5 (2.1 g, 59%) as light yellow syrup. To a mixture of imidazole (0.30 g, 4.4 mmol) and sodium hydride (50 % in paraffin oil; 0.20 g, 5.0 mmol) in THF (25 mL), G5 (1.90 g, 2.3 mmol) was added under ice bath cooling, before the reaction was refluxed overnight. The solvent was evaporated and the residue was treated with dichloromethane. Insoluble salts were filtered off. Evaporation of the solvent was followed by column chromatography (hexane / ethyl acetate 3:2) to provide G6 as light yellow syrup. A solution of G6 (1.0 g, 1.3 mmol) in methanol was treated with hydrochloric acid (37%; 1 mL) and palladium on charcoal (10%; 30 mg). The reaction mixture was stirred overnight under hydrogen atmosphere, when TLC indicated complete conversion. The catalyst was removed by membrane filtration (0.2 µm pores) and the solution neutralized with solid sodium bicarbonate. Solid salts were removed by filtration and the solution was concentrated to provide crude G7i. It was dissolved in pyridine (30 mL), treated with acetic anhydride (1.5 mL, 16 mmol) and kept at room temperature overnight. Pyridine was evaporated at reduced pressure and the residue was dissolved in dichloromethane and washed with diluted hydrochlorid acid and water. The organic phase was dried over magnesium sulfate and concentrated. Column chromatography of the crude product (ethyl acetate / acetone 8:1) provided G7 (600 mg, 74%) as yellow syrup. [a] 25
D = -24 (c = 0.24, CHCl3); 1H NMR (400 MHz, CDCl3): d 8.27 (s, <1H), 7.16, 7.02 (2 s, 2H), 5.16 (dd~t, H-3), 4.85 (dd~t, H-2), 4.41 (d, H-1), 4.29-4.21 (m, 3H, H-6a, CH2N), 4.07 (m, H-6b), 3.90-3.75 (m, 3H, CH2O, a-CH2A), 3.51-3.49 (m, 2H, H-4, H-5), 3.27 (dd, a- CH2B), 2.10, 2.01, 1.97 (3 s, 9H, Ac), 1.53 (mc, b-CH), 1.25-1.23 (m, 24H, bulk- CH2), 0.88 (t, 6H, CH 3
3); J1,2=8.0, 3J2,3=9.0, 3J3,4=9.0, 2J6=12.5 Hz; 13C NMR (100 MHz, CDCl3): d 170.52, 169.97, 169.46, 136.98, 127.07, 119.70, 100.82, 76.42, 74.49, 73.06, 72.44, 71.79, 71.31, 62.26, 47.66, 37.91, 31.82, 31.78, 31.02, 30.80, 30.01, 29.97, 29.65 / 29.62, 29.53, 29.28 / 29.26, 26.73 / 13 26.67, 26.54 / 26.49, 22.60, 20.79, 20.73, 20.54, 14.04. Anchor glycolipid P2: A mixture of S3 (0.20 g, 0.8 mmol) and G7 (0.50 g, 0.8 mmol) in toluene (3 mL) was heated to reflux. The reaction was monitored by TLC. Upon completion the solvent was evaporated to furnish spectroscopic clean P2i, which was deacetylated without further purification. P2i was dissolved in methanol (5 mL) and treated with a catalytic amount of sodium methoxide. The reaction was kept at room temperature overnight, after which the catalyst was removed by treatment with acidic ion exchanging resin Amberlite IR-120. Evaporation of the solvent furnished P2 (0.40 g, quant.) as brown syrup. IR [neat] n/cm-1: 3407 (OH), 2924, 2855 (CH), 2114 (CºC). [a] 25
D = -10 (c = 0.41, MeOH); 1H NMR (400 MHz, CD3OD): d 8.60 (s, 1H), 7.73 (s, 2H), 4.55-4.45 (m, 4H, CH2N), 4.28-4.25 (m, 4H, H-1, EG, CH2Cº C), 4.09 (mc, OCH2A), 3.94 (m, 2H, m, EG), 3.84 (dd, a-CH2A), 3.75-3.73 (m, 5H, H-6a, EG), 3.59-3.51 (m, 2H, H-6b, H-3), 3.46-3.42 (dd, a-CH2B), 3.40-3.32 (m, 2H, H-4, H-5), 3.24 (dd~t, H-2), 2.96 (s, CºCH), 1.65 (mc, b-CH), 1.46-1.35 (m, 24H, bulk-CH2), 0.96 (t, 6H, CH3); 3J1, 2
2=9.0, 3J2,3=9.0, J6=13.0 Hz; 13C NMR (100 MHz, CD3OD): d 138.34, 124.08, 123.98, 104.74, 80.71, 79.65, 77.92, 76.66, 76.43, 75.51, 74.17, 71.22, 71.16, 70.15, 69.85, 62.06, 59.21, 51.49, 50.93, 39.58, 33.13, 32.28, 31.21, 30.91, 30.78, 30.52, 27.90, 23.81, 14.61. HRMS (ESI): Calcd. for [M-I]+ [C34H61N2O8]+ 625.4428 (100%), 626.4462 (37%), 627.4496 (7%); found 625.4429 (100%), 626.4459 (40%), 627.4490 (5%). Example 3
Synthesis of an Amide-Linked Anchor Glycolipid with Glycoside-Linked Azido-Ethoxylated Imidazolium Ion (P3) This example describes the synthesis of an anchor glycolipid, in which the functionlized linker is introduced at the reducing center of an amide-based glycolipid. The preparation required several steps. Azido-terminated oligoethoxylated imidazole linker S2: see example 1. Functionalized glycolipid precursor G11: The synthesis of glycolipid precursor G8 followed a literature reported protocol based on commercial available methyl glucoside.1, 5 Acetolysis6 and subsequent ester hydrolysis provided the reducing precursor G9, which was reacted with chloroethanol in a Fischer glycosylation. Coupling of the resulting azido-sugar G10 with palmitoyl chloride in a Staudinger reaction, followed by Finkelstein halide exchange provided the glycolipid precursor G11. A solution of G96
i (0.80 g, 2.1 mmol) was dissolved in methanol and treated with a catalytic amount of sodium methoxide. The reaction was kept at room temperature overnight, after which the catalyst was removed by treatment with acidic ion exchanging resin Amberlite IR-120. Evaporation of the solvent furnished G9 (0.40 g, 90%) as light yellow syrup. It (0.40 g, 1.9 mmol) was treated with 2-chloroethanol (10 mL) and acidic cation exchanging resin Amberlite IR-120 (1.0 g) and the mixture was heated to 80 °C for 5 h. The resin was removed by filtration and remaining reagent evaporated at reduced pressure. The crude intermediate was subsequently acetylated in pyridine and acetic anhydride. Excess reagents were evaporated at reduced pressure and the residue was dissolved in dichloromethane and washed subsequently with dilute hydrochloric acid and water. The organic phase was dried over magnesium sulphate and concentrated. Chromatographic purification hexane / ethyl acetate 4:1) provided yellow syrupy G10 as anomeric mixture. To a solution of G10 (0.80 g, 4.0 mmol) and triphenylphosphine (0.80 g, 3.1 mmol) in dichloromethane (10 mL) was added a solution of palmitoyl chloride (1.2 mL, 1.6 mmol) in dichloromethane dropwise at 0 °C. The reaction mixture was stirred overnight allowing it to warm to room temperature and subsequently washed with saturated aqueous sodium bicarbonate solution and and water. The organic phase was dried over magnesium sulphate and concentrated. Chromatographic purification (hexane / ethyl acetate 1:1) furnished anomeric pure G11i (0.50 g, 41 %) as yellow syrup. The intermediate (0.40 g, 0.6 mmol) was dissolved in acetone (30 mL) and treated with sodium iodide (0.20 g, 1.3 mmol) followed by refluxing for 30 hours. The solid was filtered off and acetone was evaporated at reduced pressure. The residue was taken up in dichloromethane and water. The organic layer was dried over magnesium sulfate and concentrated to furnish G11 (0.40 g, 84 %) as yellow syrup. [a] 25
D = +72 (c 0.09, CHCl 1
3); H NMR (400 MHz, CDCl3): d 5.83 (dd~t, NH), 5.48 (dd~t, H-3), 5.11 (d, H-1), 4.86 (dd~t, H-4), 4.79(dd, H-2), 4.01 (ddd, H-5), 3.91 (dt,-OCH2A), 3.74 (dt, OCH2B), 3.59 (mc, H-6A), 3.34 (mc, H-6b), 3.27 (t, 2H, CH2I), 2.21-2.17 (m, 2H, a-CH2), 2.08, 2.06, 2.01 (3 s, 9H, Ac), 1.62 (mc, 2H, b-CH2), 1.29-1.25 (m, 26H, bulk-CH2), 0.88 (t, 3H, CH3); 3J1,2=4.0, 3J2,3 =10.0, 3J3,4=10.0, 3J4,5=10.0, 3J5,6A=2.5, 3J5,6B=6.0, 3J6A,NH=6.0, 3J6B,NH=6.0, 2J6=12.0, 3JOCH2,CH2Cl=7.0, 2JOCH2=11.5 Hz; 13C NMR (100 MHz, CDCl3): d 173.27, 170.31, 170.01, 169.95, 95.59, 70.90, 69.71, 69.26, 69.23, 68.44, 38.75, 36.69, 31.87, 29.64, 29.61, 29.47, 29.31, 29.29, 25.60, 22.64, 20.76, 20.64, 14.07, 1.62. Anchor glycolipid P3: A mixture of S2 (0.10 g, 0.4 mmol) and G11 (0.30 g, 0.4 mmol) in toluene (5 mL) was heated to reflux. The reaction was monitored by TLC. Upon completion the solvent was evaporated to furnish spectroscopic clean P3i, which was deacetylated without further purification. P3i was dissolved in methanol (10 mL) and treated with a catalytic amount of sodium methoxide. The reaction was kept at room temperature overnight, after which the catalyst was removed by treatment with acidic ion exchanging resin Amberlite IR-120. Evaporation of the solvent furnished P3 (0.20 g, quant.) as yellow syrup. IR [neat] n/cm-1: 3376 (OH), 2923, 2853 (CH), 2106 (N3), 1639 (C=O). [a] 25
D = +14 (c = 0.03, MeOH); 1H NMR (400 MHz, CD3OD): d 9.11 (s, 1H), 8.44 (bs, NH), 7.75, 7.70 (2 s, 2H), 4.84 (mc, H-1), 4.53-4.45 (m, 4H, CH2N), 4.07 (m, OCH2A), 3.93 (t, 2H, EG), 3.83 (m, OCH2B), 3.73-3.66 (m, 6H, EG), 3.60 (mc, H-3), 3.52 (1H, dd, H-6A), 3.48-3.38 (m, 4H, H-6B, CH2N3, H-2), 3.30 (mc, H-5), 3.16-3.11 (dd~t, H-4), 2.26 (t, 2H, a-CH2), 1.64 (mc, 2H, b-CH2), 1.32 (mc, 26H, bulk-CH2), 0.93 (t, 3H, CH3); 3J3,4= 9.5, 3J4,5= 9.5, 3J5,6A= 3.0, 3J5,6B= 4.0, 2J6= 14.0 Hz; 13C NMR (100 MHz, CD3OD): d 177.14, 138.64, 124.39, 124.12, 100.41, 74.57, 73.36, 73.00, 72.35, 71.58, 71.20, 70.00, 66.88, 51.95, 51.13, 50.74, 41.45, 37.19, 33.22, 30.94, 30.82, 30.61, 30.55, 27.29, 23.88, 14.61. HRMS (ESI): Calcd. for [M-I]+ [C33H61N6O8]+ 669.4551(100%), 670.4585 (36%), 671.4618 (6%); found 669.4554 (100%), 670.4579 (41%), 671.4605 (7%). Example 4
Formulation of Vesicles Comprising Anchor Glycolipid P1 This example describes the preparation of vesicles with CLICK-anchors based on a formulation comprising of non-ionic biantennary alkyl lactoside as main surfactant in combination with azido-terminated ethoxylated imidazolium glycosides as functional dopant. The vesicle preparation applied the alcoholic injection method following a literature reported protocol.7 A solution of 2-hexyl-decyl lactoside LacC10C 2
6 ,8 (a / b ~ 1:3; 47 mg, 83 µmol) and P1 (3 mg, 4 µmol) in ethanol (2 mL) was rapidly injected into bulk water (40 mL) through a 25 Ga bevel tip needle and the resulting dispersion was stirred for 10 min at room temperature. Dynamic light scattering measurements indicated the formation of vesicles with narrow size distribution, while zeta-potential measurements proofed the incorporation of the anchor glycolipid P1 into the vesicles, according to Table 1. Table 1: Vesicle size and surface charge
Figure imgf000028_0001
The above-mentioned functionalized glycolipid utilizes Click chemistry based approach, which produces a drug delivery carrier capable of interacting with specific targeted cells and reducing side effect to the host. Further, the functionalized glycolipid ensures the biodegradability of drug carrier, while maintaining the efficiency of the same. Various modifications to these embodiments are apparent to those skilled in the art from the description and the accompanying drawings. The principles associated with the various embodiments described herein may be applied to other embodiments. Therefore, the description is not intended to be limited to the embodiments shown along with the accompanying drawings but is to be providing broadest scope of consistent with the principles and the novel and inventive features disclosed or suggested herein. Accordingly, the invention is anticipated to hold on to all other such alternatives, modifications, and variations that fall within the scope of the present invention and appended claim.

Claims

Claims: 1. A functionalized glycolipid having a formula (I):
Figure imgf000029_0001
where Y is selected from a group consisting of O, NH and NAc;
wherein A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
Figure imgf000029_0002
and mono-antennary hydrophobic domain having a formula (III):
Figure imgf000029_0003
where L0 is selected from a group consisting of (CH2)i (where i is an integer ranging from 0 to 2), CO and CH(OH)CH2;
where Y1 is selected from a group consisting of O, NH and NR (where R is a hydrocarbon chain);
where L1 is selected from a group consisting of CO and (CH2)I with i=0,1; where R is selected from a group consisting of CnH2n±1 and CH2OCnH2n±1;
where R‟ is selected from a group consisting of CmH2m±1, OCmH2m±1 and CH2OCmH2m±1; and
where n is an integer ranging from 4 to 20 and m is an integer ranging from 0 to 20; wherein m + n > 5; wherein B having a formula (IV):
Figure imgf000030_0001
where L2 is selected from a group consisting of C2H4 and CH2CH(OH)CH2;
where L3 is selected from a group consisting of (C2H4O)kC2H4 and [CH2CH(OH)CH2O]kCH2CH(OH)CH2;
where k is an integer ranging from 1 to 10; and
where X is selected from a group consisting of SH, N3 and OCH2CºCH and OC2H4CºCH. 2. The functionalized glycolipid as claimed in claim 1, wherein A is a hydrophobic domain site of the glycolipid. 3. The functionalized glycolipid as claimed in claim 1, wherein B is attached at a hydrophilic domain site of the glycolipid. 4. The functionalized glycolipid as claimed in claim 1, wherein B comprises a spacer which links a clickable functional group via an imidazolium ion to the glycolipid. 5. The functionalized glycolipid as claimed in claim 1, wherein the spacer is a water-soluble oligomer spacer. 6. The functionalized glycolipid as claimed in claim 1, wherein the functionalized glycolipid comprising formula (V):
Figure imgf000031_0001
where R is selected from a group consisting of Cn‟H2n‟±1, CHR2 (where R is CH2OCn‟H2n‟±1), CH2CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1) and CH2CH(OR2)CH2OR1 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1);
where Y is selected from a group consisting of O, NH and NAc;
where X is selected from a group consisting of CH2SH, CH2N3, CºCH and CH2CºCH;
where n is an integer ranging from 1 to 10; and
where n‟ and m‟ is an integer ranging from 1 to 20. 7. The functionalized glycolipid as claimed in claim 1, wherein the functionalized glycolipid comprising a formula (VI):
Figure imgf000031_0002
where Y6 is selected from a group consisting of CH2OH, CH2NCOR, C2H4NCOR and CONRR‟ (where R is a linear or branched hydrocarbon chain selected from a group consisting of Cn‟H2n‟±1, and CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1) and R‟=H; or R is a linear or branched hydrocarbon chain (where R is Cn‟H2n‟±1, CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1); where Y2 is selected from a group consisting of O, NH and NCOR (where R is a linear or branched hydrocarbon chain selected from a group consisting of Cn‟H2n‟±1, and CHR1R2 (where R1 is Cn‟H2n‟±1 and R2 is Cm‟H2m‟±1); where X is selected from the group consisting of CH2SH, CH2N3, CºCH and CH2CºCH;
where n is an integer ranging from 1 to 10; and
where n‟ and m‟ is an integer ranging from 1 to 20. 8. The functionalized glycolipid as claimed in claim 1, the functionalized glycolipid comprising a formula (VII):
Figure imgf000032_0001
where R is selected from a group consisting of Cn‟H2n‟±1, CH(CH2ORa)2 (where Ra is Cn‟H2n‟±1), CH2CHRaRb (where Ra is Cn‟H2n‟±1 and Rb is Cm‟H2m‟±1) or CH2CH(ORb)CH2ORa (where Ra is OCn‟H2n‟±1 and Rb is Cm‟H2m‟±1);
where one of the R2, R3, R4 or R6 is having a formula (VIII),
Figure imgf000032_0002
( )
and the remaining three are H;
where X is selected from a group consisting of CH2SH, CH2N3, CºCH and CH2CºCH;
where n is an integer ranging from 1 to 10; and
where n‟ and m‟ is an integer ranging from 1 to 20. 9. A drug delivery carrier comprising a functionalized glycolipid for specific cells recognition, the functionalized glycolipid having a formula (I):
Figure imgf000033_0001
where Y is selected from a group consisting of O, NH and NAc;
wherein A is selected from a group of bi-antennary hydrophobic domain having a formula (II):
Figure imgf000033_0002
and mono-antennary hydrophobic domain having a formula (III):
Figure imgf000033_0003
where L0 is selected from a group consisting of (CH2)i (where i is an integer ranging from 0 to 2), CO and CH(OH)CH2;
where Y1 is selected from a group consisting of O, NH and NR (where R is a hydrocarbon chain);
where L1 is selected from a group consisting of CO and (CH2)i with i=0,1; where R is selected from a group consisting of CnH2n±1 and CH2OCnH2n±1;
where R‟ is selected from a group consisting of CmH2m±1, OCmH2m±1 and CH2OCmH2m±1; and
where n is an integer ranging from 4 to 20 and m is an integer ranging from 0 to 20; wherein m + n > 5; wherein B having a formula (IV):
Figure imgf000034_0001
where L2 is selected from a group consisting of C2H4 and CH2CH(OH)CH2;
where L3 is selected from a group consisting of (C2H4O)kC2H4 and [CH2CH(OH)CH2O]kCH2CH(OH)CH2;
where k is an integer ranging from 1 to 10; and
where X is selected from a group consisting of SH, N3 and OCH2CºCH and OC2H4CºCH.
PCT/MY2020/050015 2019-04-05 2020-03-18 A functionalized glycolipid and an application thereof WO2020204691A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140220135A1 (en) * 2013-02-05 2014-08-07 Midatech Limited Permeation enhanced active-carrying nanoparticles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140220135A1 (en) * 2013-02-05 2014-08-07 Midatech Limited Permeation enhanced active-carrying nanoparticles

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GOH, E. W. ET AL.: "Imidazolium-linked azido-functionalized guerbet glycosides: multifunctional surfactants for biofunctionalization of vesicles", ACS OMEGA, vol. 4, 30 September 2019 (2019-09-30), pages 17039 - 17047, XP055739351 *
HAN, N. S. ET AL.,: "Spacer effect on triazole-linked sugar-based surfactants", JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY, vol. 38, no. 1, 2017, pages 105 - 109, XP055739349 *
SALMAN, A. A. ET AL: "Alkyl-imidazolium glycosides: non-ionic-cationic hybrid surfactants from renewable resources", CARBOHYDRATE RESEARCH, vol. 412, 2015, pages 28 - 33, XP055739347 *
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