Compounds and methods for trans-membrane delivery of molecules

A Conjugate according to general Formula (I), having the structure:

• or 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 the drug to be delivered across biological membranes, selected from a group consisting of a small-molecule drug, a peptide, a protein, and a native or modified, single-stranded or double-stranded DNA or RNA, siRNA or ASO;
• y, z and w are each an integer, independently selected from 0, 1, 2, 3, 4, 5 or 6, wherein whenever the integer is 0, it means that the respective E moiety is null;
• at least one of y, z or w is different from 0;
• E, E′, or E″ can be the same or different, each having the structure as set forth in general Formula (VII):
• U is selected from the group consisting of null, —O—, ester, amide, and amine (secondary or tertiary amine);
• Q1 and Q2 are each a cleavable group, independently 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—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], amine, imidazole, triazole, dilactone;
• a metal chelator selected from BAPT A and EGT A, including its chelated metal ion;
• and any combinations thereof;
• L1, L2 and L3 are each independently selected from null and the group consisting of:
• linear, cyclic or branched C1, C2, C3, C4, Cs, C6, C7, Cs, C9, C10, C11, C12, C13 or C14, alkyl or hetero-alkyl, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol;
• or linked to an ether group;
• linear, cyclic or branched C2, C3, C4, Cs, C6, C7, Cs, C9, C10, C11, C12, C13 or C14 alkylene or heteroalkylene, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, thiol;
• or linked to an ether group;
• Cs, C6, C7, Cs, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, thiol;
• or linked to an ether group;
• —(O—CH2-CH2)u-, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol;
• nucleoside, nucleotide;
• imidazole, azide, acetylene;
• and any combinations thereof, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, thiol;
• or linked to an ether group;
• and
• wherein u is an integer of 1, 2, 3, 4 or 5;
• and any combinations thereof;
• wherein at least one of Q1, Q2, L1, L2 and L3 is not null, and wherein each of Q1, Q2, L1, L2 and L3 optionally comprises a T moiety;
• wherein T is an initiator group, selected from C4, C5, C6-1,2-dithiocycloalkyl (1,2-dithiocyclo-butane;
• 1,2-dithiocyclo-pentane;
• 1,2-dithiocyclohexane;
• 1,2-dithiocycloheptane);
• y-Lactam (5 atoms amide ring), 8-Lactam (6 atoms amide ring) or E-Lactam (7 atoms amide ring);
• y-butyrolactone (5 atoms ester ring), 8-valerolactone (6 atoms ester ring) or E-caprolactone (7 atoms ester ring);
• wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol;
• R and R′ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl group, a methoxy group, and a fluorocarbon group;
• W and G are each independently selected from null, oxygen, ester, amide or amine (secondary or tertiary amine) groups;
• k and d, each stands independently for an integer, selected from null, 0, 1, 2, 3, 4, 5 or 6;
• and the E, E′ or E″ moiety is conjugated to D, wherein D is a drug, as defined in Formula (I);
• including pharmaceutically acceptable salts, hydrates, solvates and metal chelates of the Compound represented by the structure as set forth in Formula (VII), and solvates and hydrates of the salts.