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1. A conjugate having the formula I: wherein
the Oligonucleotide is an oligonucleotide;the Biologically Active Agent is any biologically active agent;the Linker is a linking group between the Ligand(s) and the Oligonucleotide or other biologically active agent; andthe Ligand(s) are sugar-derived, where (i) the Ligand(s) may be attached to the same or different atoms in the Linker, and (ii) the conjugate contains from 1 to 12 Ligands, wherein at least one Linker is selected from Table 1 (where the DMTr group is removed and the adjacent oxygen atom is the site of attachment of the Linker to the oligonucleotide or other biologically active agent) or Table 1A and/or at least one Ligand is selected from
(a) the Ligands in Table 2 or 2A,(b) —R2—(R3)k, where
R2 is absent or a spacer having two or more sites of attachment for the R3 groups,R3 is a targeting monomer selected from Table 3, and n is 1 to 5 (preferably 1 to 3), each R3 may be attached to the same or different atoms in R2,k is 1 to 6,(c) the Ligand has one of the structures below where
the arrow indicates the point of attachment to the oligonucleotide conjugate (i.e., the ligand is attached through its carbonyl group);R6 is H or Ac;R7 is —OH or —NHR9;R8 is Ac or R9; where at least one of R7 and R8 is a nitrogen containing moiety;R9 is Q1 is H, C1-C4 alkyl, Q2 is H or C1-C4 alkyl;X is H or Me;Y is H, Ac, or COCF3; andn is 1 to 8 (e.g., 1 to 4), and(d) the Ligands in Table 4 or 4A;TABLE 1Linker Groupsa,b
The top right squiggly line is the point of attachment to the oligonucleotide or otherbiologically active agent. The bottom left squiggly link is the point of attachment for the Ligand.
where y is 1-20 and z is 1-20abEach structure represents chirally pure or racemic isomers when one or more asymmetric centers are present.TABLE 1A
Each structure represents chirally pure or racemic isomers when one or more asymmetric centers present.The linkage between oligonucleotide/nucleotide and the conjugate moiety is phosphate or phosphorothioate.m and p are independently 1-8 (e.g.,1-4).The Linkers in Table 1A are shown with one or more oligonucleotides attached to them.It will be understood to those skilled in the art that the Linker is the chemical moiety without the oligonucleotide(s).X is hydrogen.TABLE 2Ligandsa,b,c,da Q = O, S, CH2;Z = —CONH—, —NHCO—, —OC(O)NH—, —NHC(O)O—;R = a Linker such as that shown in Table 1;R′ = Ac, COCF3 or any amine protecting group compatible with oligonucleotide (RNA/DNA) synthesis and deprotection conditions.b each of the variables 1, m, n, p, q, and r independently ranges from about 0 to about 10.c d Each structure represents chirally pure or racemic isomers when one or more asymmetric centers are present.TABLE 2ALigandsa,b,c,da Q is O, S, or CH2;and Z is —CONH—, —NHCO—, —OC(O)NH—, or —NHC(O)O—.b each of the variables 1, m, n, p, q, and r independently ranges from about 0 to about 10.cd Each structure represents chirally pure or racemic isomers when one or more asymmetric centers are present.The variable R, unless otherwise specified, is OH or NHAc.TABLE 3aTargeting Monomers (R3)a These groups are functional monomers to conjugate to amino linked oligonucleotides.Each structure represents chirally pure or racemic isomers when one or more asymmetric centers are present.→ indicate site of conjugation.TABLE 3ATargeting Monomers (R3)Table 1. ASGPR Ligand Mimics'gThe variable R, unless otherwise specified, is OH or NHAc.The variable n, unless otherwise specified, is 1-8 (for example, 1-4).The variable R′, unless otherwise specified, is H or Ac.The variable X, unless otherwise specified, is O, S, C, or NHCO.The variable Z, unless otherwise specified, is NH, NHAc, S, or O.TABLE 4X =H, MeY =H, Ac, COCF3Q1 =H, CH3, Et, nPr, isoPr, nBu, isoBuQ2 = H, Me, Et, nPr, isoPr, isoBu, nBun is 1 to 8, e.g., 1 to 4a Each structure represents chirally pure or racemic isomers when one or more asymmetric centers are present.TABLE 4AbX =H, MeY =H, Ac, COCF3Q1 =H, CH3, Et, nPr, isoPr, nBu, isoBuQ2 =H, Me, Et, nPr, isoPr, isoBu, nBun is 1 to 8, e.g., 1 to 4b Each structure represents chirally pure or racemic isomers when one or more asymmetric centers presentR = OH or NHAc in all occurrenceThe squiggly linke indicates the point of attachment to the Linker. |
