Multivalent terpene-based bolaamphiphiles for gene delivery
Multifunctional amine-containing bolaamphiphilic compositions comprising hydrocarbon terpenes, methods of preparing such compositions, and the use of these compositions in gene delivery applications are disclosed.
1 . A compound of Formula (I):
wherein:
each A is independently selected from:
each Z is independently —S—R 1 ;
each R 1 is independently selected from:
each R 2 or R 3 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, aralkyl, or hydroxyalkyl;
each R 4 , R 6 or R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or hydroxyalkyl;
each R 5 is hydrogen or C 1 -C 3 alkyl;
each X is halogen;
each m is an integer independently selected from 1-10;
each q is an integer independently selected from 1-200;
each B is independently selected from:
wherein each R is independently selected from hydrogen or C 1 -C 6 alkyl; and
C is:
a. a C2-C100 hydrocarbon chain which can optionally contain one or more S atoms;
b. Cyc A -L-Cyc B , wherein Cyc A and Cyc B are each independently a 5-8 membered cycloalkyl chain and L is C 1 -C 3 alkylene;
c. a polyalkylene oxide or polyalkylene oxide block copolymers of 200-5,000 molecular weight;
d. an aliphatic or aromatic polyester of 200-5,000 molecular weight; or
e. an aliphatic or aromatic polyurethane of 200-5,000 molecular weight; or
together form:
wherein each R 8 is independently selected from C2-C6 alkyl, aryl,
and wherein each t is an integer independently selected from 1-10.
2 . The compound of claim 1 , wherein each A is:
3 . The compound of claim 1 , wherein each A is:
4 . The compound according to claim 2 , wherein Z is —S—R 1 , and wherein at least one R 1 is:
5 . The compound of claim 4 , wherein m is one, R 2 and R 3 are each C 1 -C 6 alkyl.
6 . The compound of claim 5 , wherein each C 1 -C 6 alkyl is methyl.
7 . The compound according to claim 2 , wherein each B is:
wherein the carbonyl group of each B is linked to A in Formula (I).
8 . The compound of claim 7 , wherein R is hydrogen.
9 . The compound according to claim 2 , wherein each B is:
wherein the carbonyl group of each B is linked to A in Formula (I).
10 . The compound according to claim 2 wherein each B is
wherein the carbonyl group of each B is linked to A in Formula (I).
11 . The compound according to claim 10 , wherein R is hydrogen.
12 . The compound according to claim 2 , wherein C is a C2-C100 hydrocarbon chain.
13 . The compound of claim 12 , wherein the C2-C100 hydrocarbon chain is C6 hydrocarbon chain.
14 . The compound of claim 13 , wherein the C6 hydrocarbon chain is hexanylene.
15 . The compound of claim 12 , wherein the C2-C100 hydrocarbon chain is C12 hydrocarbon chain.
16 . The compound of claim 15 , wherein the C12 hydrocarbon chain is dodecanylene.
17 . The compound of claim 12 , wherein C2-C100 hydrocarbon chain is C20 hydrocarbon chain.
18 . The compound of claim 17 , wherein the C20 hydrocarbon chain is icosanylene.
19 . The compound according to claim 2 , wherein C is Cyc A -L-Cyc B , wherein Cyc A and Cyc h are each independently a 5-8 membered cycloalkyl chain and L is C 1 -C 3 alkylene.
20 . The compound of claim 19 , wherein Cyc A and Cyc B are each cyclohexyl and L is methylene.
21 . The compound according to claim 2 , wherein C is:
wherein each Ra is independently selected from C2-C6 alkyl, aryl,
and wherein each t is an integer independently selected from 1-10.
22 . The compound of claim 1 , wherein the compound is:
23 . A pharmaceutical composition, comprising at least one nucleic acid, a compound of claim 1 , and at least pharmaceutically acceptable excipient or diluent.
24 . A lipoplex nanoparticle, comprising at least one nucleic acid and a compound of claim 1 .
25 . A method for delivering a nucleic acid to a cell, tissue, organ, animal or subject, comprising contacting the cell, the tissue, the organ, the animal or the subject with an effective amount of the pharmaceutical composition of claim 23 .