Non-peptidic cell-penetrating motifs
Disclosed are compounds that can penetrate the mitochondrial membrane and that are able to deliver cargo (e.g., therapeutic agents) specifically to the mitochondria.
1. A compound having a structure according to Formula I or II
or pharmaceutically acceptable salt thereof,
wherein:
A is a non-peptidic multivalent moiety, wherein A is selected from the group consisting of:
(a) a carbocyclyl;
(b) a heterocyclyl;
(c) an aryl;
(d) a heteroaryl; and
(e) a sugar alcohol;
each L is independently a bond, or an alkylene, alkenylene, alkynylene, carbocyclyl, heterocyclyl, or —R c —X 1 —R d —, wherein R c and R d are independently selected from alkylene, alkenylene, alkynylene, carbocyclyl, or heterocarbocyclyl, each of which are optionally substituted, and X 1 is O, NH, or S;
each M is independently a bond, or an alkylene, alkenylene, alkynylene, carbocyclyl, heterocyclyl, or —R e —X 2 —R f —, wherein R e and R f are independently selected from alkylene, alkenylene, alkynylene, carbocyclyl, or heterocarbocyclyl, each of which are optionally substituted, and X 2 is O, NH, or S;
each X is independently a first bonding group that links R 1 to A, wherein X is a divalent group;
each Y is a second bonding group that directly or indirectly links A to a guanidine group, wherein the guanidine group refers to the structure:
each Z is a lone pair;
each R 1 is independently a hydrophobic amino acid residue, or analog thereof, having an aromatic side chain;
each R 2 is independently absent or a moiety comprising hydrophobic residue;
each R 3 is independently a cargo moiety;
each p is independently 1 to 3;
each q is independently 2 to 7; and
each s is independently an integer from 1 to 3.
2. The compound of claim 1 , wherein A is an aryl.
3. The compound of claim 1 , wherein A is:
wherein:
each wavy line denotes the point of attachment to L and each asterisk denotes the point of attachment to X.
4. The compound of claim 1 , wherein X is a bonding group selected from,
wherein each a is independently number from 0 to 10.
5. The compound of claim 1 , wherein Y is selected from N, S,
wherein each b is independently a number from 0 to 10.
6. The compound of claim 1 , wherein R 2 is independently selected from the group consisting of:
(a) a moiety comprising an aryl or heteroaryl moiety and
(b) an amino acid residue or analog thereof, having an aromatic side chain.
7. The compound of claim 1 , wherein R 1 and R 2 are each independently an amino acid selected from the group consisting of phenylalanine, tryptophan, naphthylalanine, phenylglycine, homophenylalanine, tyrosine, cyclohexylglycine, piperidine-2-carboxylic acid, cyclohexylalanine, 3-(3-benzothienyl)-alanine, 3-(2-quinolyl)-alanine, O-benzylserine, 3-(4-(benzyloxy)phenyl)-alanine, S-(4-methylbenzyl) cysteine, N-(naphthalen-2-yl) glutamine, and 3-(1,1′-biphenyl-4-yl)-alanine, each of which is optionally substituted with one or more substituents.
8. The compound of claim 1 , wherein p is 2 or 3.
9. The compound of claim 1 , wherein Y is N and p is 2.
10. The compound of claim 1 , wherein q is 2 or 3.
11. The compound of claim 1 , wherein s is 1.
12. The compound of claim 1 , wherein the cargo moiety comprises a therapeutic agent.
13. The compound of claim 12 , wherein the therapeutic agent is an anticancer agent.
14. The compound of claim 1 , wherein the compound is a compound of the formula:
15. The compound of claim 1 , wherein R 1 is a D-amino acid residue.
16. A pharmaceutical composition comprising a compound of claim 1 .