Compounds and methods for trans-membrane delivery of molecules

A method for delivery of a drug across biological membranes, the method comprising utilization of a Conjugate, having the structure as set forth in Formula I:

• including pharmaceutically acceptable salts, hydrates, solvates and metal chelates of the compound represented by the structure as set forth in Formula (I), and solvates and hydrates of the salts, wherein:
• D is a drug, selected from the group consisting of a small-molecule drug, a peptide, a protein;
• a single-stranded or a double-stranded DNA or RNA;
• siRNA and ASO;
• y, z and w are each an integer, independently selected from 0, 1, 2, 3, 4, 5, 6, wherein at least one of y, z or w is different from 0;
• E, E′ or E″ are the same or different, and are described by the general Formula (II):
• (A)a-B-L1-Q-L2 Formula(II)
• wherein A is selected from the structures as set forth in Formulae (III), (IV), (V) and (VI):
• M is selected from —O— or —CH2—;
• and g, h and k are each individually an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
• * is selected from —H and a point of linkage to B, Q, D or L;
• a is an integer of 1, 2, 3 or 4;
• B is selected from the group consisting of:
• linear, cyclic or branched C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14, alkyl or hetero-alkyl;
• linear, cyclic or branched C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 alkylene or heteroalkylene;
• C5, C6, C,7, C8, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl;
• one or more steroid moiety, cholesterol, bile acid, estradiol, estriol, nucleoside, nucleotide;
• and any combination thereof;
• wherein each group is optionally substituted by hydroxyl, amine, or thiol;
• Q is selected from null, ester, thio-ester, amide [e.g., —C(═O)—NH— or —NH—C(═O)—], carbamate [e.g., —O—C(═O)—NH— or —NH—C(═O)—O—], disulfide [—(S—S)—], ether [—O—], triazole;
• and a metal chelator, including its chelated metal ion,
• L1 and L2 are each independently selected from null and the group consisting of:
• linear, cyclic or branched C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14, alkyl or hetero-alkyl;
• linear, cyclic or branched C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 alkylene or heteroalkylene;
• C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl;
• —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4, 5;
• nucleoside, nucleotide;
• or a group selected from one or more amine group(s), azide and acetylene moiety;
• and any combinations thereof;
• wherein each of Q, L1 and L2 is optionally substituted by T;
• wherein T is an initiator group selected from C5, C6, C7-1,2-dithiocycloalkyl (1,2-dithiocyclopentane, 1,2-dithiocyclohexane, 1,2-dithiocycloheptane);
• γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ∈-Lactam (7 atoms amide ring);
• γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring).