Peptide nucleic acid derivatives with good cell penetration and strong affinity for nucleic acid

1. A peptide nucleic acid derivative of Formula I or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer equal to or larger than 5;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n independently represent hydrido, deuterido, substituted or non-substituted alkyl, or substituted or non-substituted aryl radical;

X and Y independently represent hydrido, deuterido, substituted or non-substituted alkyl, substituted or non-substituted acyl, substituted or non-substituted sulfonyl, or substituted or non-substituted aryl radical;

Z represents hydroxy, substituted or non-substituted alkyloxy, substituted or non-substituted aryloxy, or substituted or non-substituted amino radical;

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from natural nucleobases including adenine, thymine, guanine, cytosine and uracil, and unnatural nucleobases; and,

at least one of B 1 , B 2 , . . . , B n-1 , and B n is independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV:

wherein,

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from substituted or non-substituted alkyl, and hydrido radical; and,

L 1 , L 2 and L 3 are a covalent linker represented by Formula V connecting a basic amino group to the moiety responsible for nucleobase pairing properties:

wherein,

Q 1 and Q m are substituted or non-substituted methylene (—CH 2 —) radical, and Q m is directly linked to the basic amino group;

Q 2 , Q 3 , . . . , and Q m-1 are independently selected from substituted or non-substituted methylene, oxygen (—O—), sulfur (—S—), and substituted or non-substituted amino radical [—N(H)—, or —N(substituent)-]; and,

m is an integer from 2 to 15.

2. The peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer from 8 to 30;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X and Y are independently selected from hydrido, substituted or non-substituted alkyl, substituted or non-substituted acyl, or substituted or non-substituted sulfonyl radical;

Z represents hydroxy, substituted or nonsubstituted alkyloxy, substituted or non-substituted aryloxy, or substituted or non-substituted amino radical; and,

at least two of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV.

3. The peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer from 8 to 25;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X and Y are independently selected from hydrido, substituted or non-substituted alkyl, and substituted or non-substituted acyl radical;

Z represents hydroxy, or substituted or non-substituted amino radical;

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from natural nucleobases including adenine, thymine, guanine, cytosine and uracil, and unnatural nucleobases;

at least two of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from substituted or non-substituted alkyl, and hydrido radical;

Q 1 and Q m are substituted or non-substituted methylene radical, and Q m is directly linked to the basic amino group;

Q 2 , Q 3 , . . . , and Q m-1 are independently selected from substituted or non-substituted methylene, oxygen, and amino radical; and,

m is an integer from 2 to 12.

4. The peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer from 10 to 25;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X and Y are independently selected from hydrido, and substituted or non-substituted acyl radical;

Z represents hydroxy or substituted or non-substituted amino radical; and,

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from natural nucleobases including adenine, thymine, guanine, cytosine and uracil, and unnatural nucleobases;

at least three of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from substituted or non-substituted alkyl, and hydrido radical;

Q 1 and Q m are methylene radical, and Q m is directly linked to the basic amino group;

Q 2 , Q 3 , . . . , and Q m-1 are independently selected from methylene, oxygen, and amino radical; and,

m is an integer from 2 to 10.

5. The peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer from 10 to 20;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X and Y are independently selected from hydrido, and substituted or non-substituted acyl radical;

Z represents hydroxy, or substituted or non-substituted amino radical;

B 1 , B 2 , . . . , B n-1 , and B n is independently selected from natural nucleobases including adenine, thymine, guanine, cytosine and uracil, and unnatural nucleobases;

at least three of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV;

R 1 , R 3 , and R 5 are hydrido radical, and R 2 , R 4 , and R 6 independently represent hydrido, or substituted or non-substituted amidinyl radical;

Q 1 and Q m are methylene radical, and Q m is directly linked to the basic amino group;

Q 2 , Q 3 , . . . , and Q m-1 are independently selected from methylene, oxygen, and amino radical; and,

m is an integer from 2 to 10.

6. The peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer from 10 to 20;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X and Y are independently selected from hydrido, and substituted or non-substituted acyl radical;

Z represents hydroxy, or substituted or non-substituted amino radical;

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from adenine, thymine, guanine, cytosine, and unnatural nucleobases;

at least three of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV;

R 1 , R 3 , and R 5 are hydrido radical, and R 2 , R 4 , and R 6 independently represents hydrido or amidinyl radical;

Q 1 and Q m are methylene radical, and Q m is directly linked to the basic amino group;

Q 2 , Q 3 , . . . , and Q m-1 are independently selected from methylene, and oxygen radical; and,

m is an integer from 2 to 8.

7. The peptide nucleic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof:

wherein,

n is an integer from 10 to 20;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X is hydrido radical;

Y represents hydrido, or substituted or non-substituted acyl radical;

Z represents hydroxy, or substituted or non-substituted amino radical;

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from adenine, thymine, guanine, cytosine, and unnatural nucleobases;

at least three of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV;

R 1 , R 3 , and R 5 are hydrido radical, and R 2 , R 4 , and R 6 independently represent hydrido or amidinyl radical;

L 1 represents —(CH 2 ) 2 —O—(CH 2 ) 2 —, —CH 2 —O—(CH 2 ) 2 —, or —CH 2 —O—(CH 2 ) 3 — with the right end is directly linked to the basic amino group; and,

L 2 and L 3 are independently selected from —(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 3 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 3 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —(CH 2 ) 7 —, and —(CH 2 ) 8 — with the right end is directly linked to the basic amino group.

8. A pharmaceutical composition containing a therapeutically effective amount of the peptide nucleic acid derivative of any one of claims 1 ˜ 7 or a pharmaceutically acceptable salt thereof for a therapeutic purpose.