Novel glycoconjugates, glycoamino acids, intermediates thereto, and uses thereof

A multi-antigenic glycopeptide comprising a peptidic backbone made up of two or more amino acids, wherein one or more of said amino acids is/are independently substituted with a glycosidic moiety having the structure:

• 164
• wherein
• L1 is a substituted or unsubstituted aliphatic or heteroaliphatic moiety;
• each occurrence of A is independently a carbohydrate determinant having the structure:
• 165
• wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent furanose or pyranose moieties and the sum of b and c is 1 or 2, the sum of d and f is 1 or 2, and the sum of g and i is 1 or 2, and with the proviso that x, y and z are not simultaneously 0;
• wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:
• 166
• wherein
• Y and Z are independently NH or O;
• wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2;
• with the proviso that the v and w bracketed structures represent furanose or pyranose moieties and the sum of l and k is 1 or 2, and the sum of s and u is 1 or 2, and with the proviso that v and w are not simultaneously 0;
• wherein R′0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group;
• wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group;
• wherein at least one occurrence of A is a carbohydrate domain having the structure:
• 167
• wherein each occurrence of Rx is independently hydrogen or a protecting group.

A glycopeptide having the structure:

• 186
• wherein
• q is 0 or 1;
• m is an integer from 5-20;
• R is hydrogen or an immunogenic carrier;
• the linker is either —O—, (carboxamido)alkyl carboxamide, MBS, primary carboxamide, mono- or dialkyl carboxamide, mono- or diarylcarboxamide, linear or branched chain (carboxy)alkyl carboxamide, linear or branched chain (alkoxycarbonyl)alkyl-carboxamide, linear or branched chain (carboxy)arylalkylcarboxamide, linear or branched chain (alkoxycarbonyl)alkylcarboxamide, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester;
• each occurrence of RA and RC is independently hydrogen, a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated aliphatic or heteroaliphatic moiety or a substituted or unsubstituted aryl or heteroaryl moiety;
• and wherein each occurrence of RD and RF is independently a glycosidic moiety having the structure:
• 187
• wherein
• each occurrence of L1 is independently a substituted or unsubstituted aliphatic or heteroaliphatic moiety;
• each occurrence of A is independently a carbohydrate domain having the structure:
• 188
• wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent furanose or pyranose moieties and the sum of b and c is 1 or 2, the sum of d and f is 1 or 2, and the sum of g and i is 1 or 2, and with the proviso that x, y and z are not simultaneously 0;
• wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:
• 189
• wherein Y and Z are independently NH or O;
• wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2;
• with the proviso that the v and w bracketed structures represent furanose or pyranose moieties and the sum of l and k is 1 or 2, and the sum of s and u is 1 or 2, and with the proviso that v and w are not simultaneously 0;
• wherein R′0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group;
• wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group;
• and wherein the glycosidic moiety is either α- or β-linked to an amino acid.

A synthetic construct having the structure:

• 190
• wherein n is 0-8;
• wherein the carrier a lipid or protein linked directly or through a crosslinker;
• each occurrence of Rx is independently hydrogen or a protecting group;
• and wherein t′ is at least 1.

A method for the synthesis of a glycoamino acid comprising steps of:

• (a) providing a suitable alkenyl glycoside;
• (b) providing a suitably protected alkenylamino acid;
• (c) reacting said alkenyl glycoside with the alkenylamino acid suitable conditions in the presence of a suitable catalyst to generate a glycoenamide ester;
• and
• (d) subjecting the glycoenamide ester to suitable conditions to generate a glycoamino acid.

A pharmaceutical composition comprising:

• a pharmaceutically acceptable carrier;
• an immunogenic carrier;
• and
• a multi-antigenic glycopeptide comprising a peptidic backbone made up of two or more amino acids, wherein one or more of said amino acids is/are independently substituted with a glycosidic moiety having the structure:
• 202
• wherein
• each occurrence of L1 is independently a substituted or unsubstituted aliphatic or heteroaliphatic moiety;
• each occurrence of A is independently a carbohydrate determinant having the structure:
• 203
• wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent furanose or pyranose moieties and the sum of b and c is 1 or 2, the sum of d and f is 1 or 2, and the sum of g and i is 1 or 2, and with the proviso that x, y and z are not simultaneously 0;
• wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R1, R2, R3, R4, R5, R6 , R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:
• 204
• wherein
• Y and Z are independently NH or O;
• wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2;
• with the proviso that the v and w bracketed structures represent furanose or pyranose moieties and the sum of l and k is 1 or 2, and the sum of s and u is 1 or 2, and with the proviso that v and w are not simultaneously 0;
• wherein R′0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group;
• wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group;
• whereby the glycopeptide has not been conjugated to the immunogenic carrier.

A method of inducing antibodies in a subject, wherein the antibodies are capable of specifically binding with tumor cells, which comprises administering to the subject:

• an amount of a multi-antigenic glycopeptide comprising a peptidic backbone made up of two or more amino acids, wherein one or more of said amino acids is/are independently substituted with a glycosidic moiety having the structure:
• 206
• wherein
• each occurrence of L1 is independently a substituted or unsubstituted aliphatic or heteroaliphatic moiety;
• each occurrence of A is independently a carbohydrate determinant having the structure:
• 207
• wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent furanose or pyranose moieties and the sum of b and c is 1 or 2, the sum of d and f is 1 or 2, and the sum of g and i is 1 or 2, and with the proviso that x, y and z are not simultaneously 0;
• wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R1, R2, R3, R4, R5, R6 , R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:
• 208
• wherein
• Y and Z are independently NH or O;
• wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2;
• with the proviso that the v and w bracketed structures represent furanose or pyranose moieties and the sum of l and k is 1 or 2, and the sum of s and u is 1 or 2, and with the proviso that v and w are not simultaneously 0;
• wherein R′0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group;
• wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group;
• whereby the glycopeptide has not been conjugated to an immunogenic carrier;
• and
• wherein the amount of glycopeptide is effective to induce the antibodies.

A method of inducing antibodies in a subject, wherein the antibodies are capable of specifically binding with tumor cells, which comprises administering to the subject an amount of a multi-antigenic glycopeptide effective to induce the antibodies, wherein the glycopeptide has the structure:

• 209
• wherein
• q is 0 or 1;
• m is an integer from 1-20;
• the linker is either —O— (carboxamido)alkyl carboxamide, MBS, primary carboxamide, mono- or dialkyl carboxamide, mono- or diarylcarboxamide, linear or branched chain (carboxy)alkyl carboxamide, linear or branched chain (alkoxycarbonyl)alkyl-carboxamide, linear or branched chain (carboxy)arylalkylcarboxamide, linear or branched chain (alkoxycarbonyl)alkylcarboxamide, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester;
• each occurrence of RA and RC is independently hydrogen, a substituted or unsubstituted, linear or branched, cyclic or acyclic, saturated or unsaturated aliphatic or heteroaliphatic moiety or a substituted or unsubstituted aryl or heteroaryl moiety;
• and wherein each occurrence of RD and RF is independently a glycosidic moiety having the structure:
• 210
• wherein
• each occurrence of L1 is independently a substituted or unsubstituted aliphatic or heteroaliphatic moiety;
• each occurrence of A is independently a carbohydrate domain having the structure:
• 211
• wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent furanose or pyranose moieties and the sum of b and c is 1 or 2, the sum of d and f is 1 or 2, and the sum of g and i is 1 or 2, and with the proviso that x, y and z are not simultaneously 0;
• wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R1, R2, R3, R4, R5, R6 , R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:
• 212
• wherein Y and Z are independently NH or O;
• wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2;
• with the proviso that the v and w bracketed structures represent furanose or pyranose moieties and the sum of l and k is 1 or 2, and the sum of s and u is 1 or 2, and with the proviso that v and w are not simultaneously 0;
• wherein R′0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group;
• wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group;
• wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group;
• and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group;
• and
• wherein the method further comprises administering an immunogenic carrier.