Compound bearing beta-galactoside-introduced self-immolative linker

1. A compound comprising a β-galactoside-introduced self-immolative linker represented by Chemical Formula 1 below:

in Chemical Formula 1,

R is hydrogen or a hydroxy protection group;

X is —C(═O)—, —NH—, —O—, or —S—;

T is an active agent;

Q is B′—U1-(CH 2 CH 2 X 3 ) p4 —(CH 2 ) p3 —Wa 4 -Q 2 -W a3 —W 1 ┤;

n is an integer of 0 or 1;

Y is hydrogen, haloC 1 -C 8 alkyl, halogen, cyano or nitro;

z is an integer of 1 to 3, and Y may be the same or different from each other, if z is an integer of not less than 2;

z1 is an integer of 0 or 1;

W 1 is ├W a2 —(CH 2 ) a1 —W b1 -Q 1 ┤;

W 2 is ├W a4 -Q 2 -W a3 ┤;

W a1 and W a2 are each independently —NH—, —C(═O)—, or —CH 2 —;

W a3 and W a4 are each independently —NH—, —C(═O)—, —CH 2 —, —C(═O)NH—, —NHC(═O)—, or triazolylene;

W b1 is an amide bond or triazolylene;

L is an amino acid, peptide, or amide bond as a linker connecting W a2 and Z;

Z is a single bond, —W a5 —(CH 2 ) a2 —W b2 —(CH 2 ) a3 —W a6 —, or —W a7 —(CH 2 ) a4 —CR′R″—X″—;

R′ is C 1 -C 8 alkyl or B—W a8 -Q 3 -W c1 —(CH 2 ) a5 —;

R″ is B—W a8 -Q 3 -W c1 —(CH 2 ) a5 —;

Q 1 and Q 3 are each independently —(CH 2 ) a6 —(X 1 CH 2 CH 2 ) b1 —(CH 2 ) a7 —;

X 1 and X 3 are each independently —O—, —S—, —NH—, or —CH 2 —;

X″ is —NHC(═O)—(CH 2 ) a8 —W a9 — or —C(═O) NH—(CH 2 ) a8 —W a9 —;

W a5 , W a6 , W a7 , W a8 , and W a9 are each independently —NH—, —C(═O)—, or —CH 2 —;

W b2 is an amide bond or triazolylene;

W c1 is —NHC(═O)— or —C(═O)NH—;

Q 2 is a saturated or unsaturated alkylene, which is linear or branched with a carbon number of 1 to 50, satisfying any one of (i) to (iii) below;

(i) at least one —CH 2 — in the alkylene is substituted with one or more heteroatoms selected from —NH—, —C(═O), —O—, and —S—,

(ii) at least one arylene or heteroarylene is included in the alkylene,

(iii) the alkylene is further substituted with one or more selected from the group consisting of C 1 -C 20 alkyl, C 6 -C 20 arylC 1 -C 8 alkyl, —(CH 2 ) s1 COOR 3 , —(CH 2 ) s1 COR 3 , —(CH 2 ) s2 CONR 4 R 5 , and —(CH 2 ) s2 NR 4 R 5 ;

arylene or heteroarylene of (ii) above may be further substituted with nitro;

R 3 , R 4 , and R 5 are each independently hydrogen or C 1 -C 15 alkyl;

X 2 is —O—, —S—, —NH—, or —CH 2 —;

U1 is bound to B′ in the position of asterisk (*) with a linking group selected from the following structures:

R is C1-C10 alkyl, C6-20 aryl or C2-C20 heteroaryl;

B and B′ are each independently a ligand or a protein having properties selectively targeting a particular organ with a drug, a tissue or a cell, that is, properties binding to a receptor;

a1, a2, a3, a4, a5, a6, a8, b1, p1, p2, p3 and p4 are each independently an integer of 1 to 10;

a7, y, s1, s2 and s4 are each independently an integer of 0 to 10; and

R 1 and R 2 are each independently hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.

2. The compound of claim 1 , wherein L comprises one or more units represented by the following Chemical Formula A or B.

in Chemical Formulas A and B,

R 11 is hydrogen, C 1 -C 8 alkyl, —(CH 2 ) s3 COOR 13 , —(CH 2 ) s3 COR 13 , —(CH 2 ) s3 CONR 14 R 15 or —(CH 2 ) s4 NR 14 R 15 ;

R 13 , R 14 , and R 15 are each independently hydrogen or C 1 -C 15 alkyl;

s3 and s4 are each independently an integer of 1 to 10;

X 3 is —O—, —S—, —NH—, or —CH 2 —; and

p3 and p4 are each independently an integer of 1 to 10.

3. The compound of claim 1 , wherein X is —C(═O)—, W a1 is —NH—.

4. The compound of claim 1 , wherein Z is a single bond or is selected from the following structures:

in the structures,

W b2 is —C(═O)NH—, —NHC(═O)—,

R′ is C 1 -C 8 alkyl or B—NH—(CH 2 ) a6 —(X 1 CH 2 CH 2 ) b1 —NH—C(═O)—(CH 2 ) a5 —;

R″ is B—NH—(CH 2 ) a6 —(X 1 CH 2 CH 2 ) b1 —NH—C(═O)—(CH 2 ) a5 —;

X″ is —NHC(═O)—(CH 2 ) a8 —NH— or —C(═O)NH—(CH 2 ) a8 —NH—;

a2, a3, a4, a5, a6, a8 and b1 are each independently an integer of 1 to 10;

X 1 is —O—, —S—, —NH—, or —CH 2 —; and

B is the same as defined in claim 1 .

5. The compound of claim 1 , wherein Q 2 is selected from the following Chemical Formula C to Chemical Formula I:

in Chemical Formulas C to I,

X 11 and X 12 are each independently —O—, —S—, —NH—, or —CH 2 —

R 12 to R 14 are each independently hydrogen, C 1 -C 20 alkyl, C 6 -C 20 arylC 1 -C 8 alkyl, —(CH 2 ) s1 COOR 3 , —(CH 2 ) s1 COR 3 , —(CH 2 ) s2 CONR 4 R 5 or —(CH 2 ) s2 NR 4 R 5 ;

R 3 , R 4 , and R 5 are each independently hydrogen or C 1 -C 15 alkyl;

X 2 is —O—, —S—, —NH—, or —CH 2 —;

R a is hydrogen or nitro;

c1, c2, c3, c4, and d1 are each independently an integer of 1 to 10;

q1 and q2 are each independently an integer of 0 to 5;

s1 and s2 are each independently an integer of 0 to 5; and

p1 and p2 are each independently an integer of 1 to 10.

6. The compound of claim 1 , wherein the active agents are a drug, a toxin, an affinity ligand, a probe for a detection or a combination thereof.

7. The compound of claim 6 , wherein the drugs are cytokine, an immuno-regulatory compound, an anti-cancer agent, an anti-virus agent, an anti-bacteria agent, an anti-fungi agent, a helminthic or a combination thereof.

8. The compound of claim 1 , wherein the ligand is selected from the group consisting of peptides, tumor cell-specific peptides, tumor cell-specific aptamers, tumor cell-specific carbohydrates, tumor cell-specific monoclonal or polyclonal antibodies and antibody fragments.

9. The compound of claim 1 , wherein the proteins are an oligopeptide, a polypeptide, an antibody, a fragment of antigenic polypeptide or a Repebody.

10. The compound of claim 9 , wherein the antibody is selected from the group consisting of an intact polyclonal antibody, an intact monoclonal antibody, an antibody fragment, a single chain Fv (scFv) mutant, a multispecific antibody, a bispecific antibody, a chimeric antibody, humanized antibody, a human antibody, a fusion protein comprising an antigenic determinant portion of an antibody, and other modified immunoglobulin molecule comprising an antigen recognition site.

11. The compound of claim 10 , wherein the antibody is selected from the group consisting of Muromonab-CD3 Abciximab, Rituximab, Daclizumab, Palivizumab, Infliximab, Trastuzumab (herceptin), Etanercept, Basiliximab, Gemtuzumabozogamicin, Alemtuzumab, Ibritumomab tiuxetan, Adalimumab, Alefacept, Omalizumab, Efalizumab, Tositumomob-I 131 , Cetuximab, Bevacizumab, Natalizumab, Ranibizumab, Panitumumab, Eculizumab, Rilonacept, Certolizumab pegol, Romiplostim, AMG-531, CNTO-148, CNTO-1275, ABT-874, LEA-29Y, Belimumab, TACI-Ig, Second generation anti-CD20, ACZ-885, Tocilizumab, Atlizumab, Mepolizumab, Pertuzumab, Humax CD20, Tremelimumab (CP-675 206), Ticilimumab, MDX-010, IDEC-114, Inotuzumabozogamycin, HuMax EGFR, Aflibercept, VEGF Trap-Eye, HuMax-CD4, Ala-Ala, ChAglyCD3, TRX4, Catumaxomab, IGN101, MT-201, Pregovomab, CH-14.18, WX-G250, AMG-162, AAB-001, Motavizumab, MEDI-524, efumgumab, Aurograb®, Raxibacumab, Third generation anti-CD20, LY2469298, and Veltuzumab.

12. The compound of claim 1 , wherein the compound is selected from the following structures:

in the structures,

Y is hydrogen, haloC 1 -C 8 alkyl, halogen, cyano or nitro;

z is an integer of 1 to 3, and Y may be the same or different from each other, if z is an integer of not less than 2;

z1 is an integer of 0 or 1;

W 1 is selected from the following structures:

W 2 is selected from the following structures:

X 1 , X 11 and X 12 are each independently —O—, —S—, —NH—, or —CH 2 —;

W b1 and W b2 are each independently —C(═O) NH—, —NHC(═O)—,

R 11 is hydrogen, C 1 -C 8 alkyl, —(CH 2 ) s3 COOR 13 , —(CH 2 ) s3 COR 13 , —(CH 2 ) s3 CONR 14 R 15 or —(CH 2 ) s4 NR 14 R 15 , R 13 , R 14 , and R 15 are each independently hydrogen or C 1 -C 15 alkyl;

X 3 is —O—, —S—, —NH—, or —CH 2 —;

R 12 to R 14 are each independently hydrogen, C 1 -C 20 alkyl, C 6 -C 20 arylC 1 -C 8 alkyl, —(CH 2 ) s1 COOR 3 , —(CH 2 ) s1 COR 3 , —(CH 2 ) s2 CONR 4 R 5 or —(CH 2 ) s2 NR 4 R 5 ;

R 3 , R 4 , and R 5 are each independently hydrogen or C 1 -C 15 alkyl;

X 2 is —O—, —S—, —NH—, or —CH 2 —;

R a is hydrogen or nitro;

R′ is C 1 -C 8 alkyl or B—NH—(CH 2 ) a6 —(X 1 CH 2 CH 2 ) b —NH—C(═O)—(CH 2 ) a5 —;

X″ is —NHC(═O)—(CH 2 ) a8 —NH— or —C(═O)NH—(CH 2 ) a8 —NH—;

a1, a2, a3, a4, a5, a6, a8, b1, c1, c2, c3, c4, d1, p1, p2, p3, and p4 are each independently an integer of 1 to 10;

q1 and q2 are each independently an integer of 0 to 5;

s1, s2, s3, and s4 are each independently an integer of 0 to 5;

B′—U1┤ is

B′ is an antibody;

B is a ligand selected from the following structures:

T is a drug selected from the following structures:

w is an integer of 1 to 10.

13. A compound represented by Chemical Formula 2 below:

in Chemical Formula 2,

R is hydrogen or a hydroxy protecting group;

X is —C(═O)—, —NH—, —O—, —CH 2 — or —S—;

W a1 is —NH—, —CH 2 — or —C(═O)—;

T is an active agent;

Y is hydrogen, haloC 1 -C 8 alkyl, halogen, cyano or nitro;

U is a single bond or

W a2 is —NH—, —C(═O)—, or —CH 2 —;

W a3 and W a4 are each independently —NH—, —C(═O)—, —CH 2 —, —C(═O)NH—, —NHC(═O)—, or triazolylene;

Q 2 is

R 21 is C 1 -C 20 alkyl, C 6 -C 20 arylC 1 -C 8 alkyl, —(CH 2 ) s1 COOR 3 , —(CH 2 ) s1 COR 3 , —(CH 2 ) s2 CONR 4 R 5 or —(CH 2 ) s2 NR 4 R 5 ;

R 3 , R 4 , and R 5 are each independently hydrogen or C 1 -C 15 alkyl;

s1 and s2 are each independently an integer of 0 to 10;

W b1 is —C(═O)NH—, —NHC(═O)—,

a1 is each independently an integer of 1 to 10;

s4 is an integer of 0 to 10;

p3 and p4 are each independently an integer of 1 to 10;

FG is —NH 2 , —C≡CH, C 4 -C 10 cycloalkynyl, —N 3 , —COOH, —SO 3 H, —OH, —NHOH, —NHNH 2 , —SH, haloacetamide (—NHC(O)CH 2 -hal, wherein hal is halogen), maleimide

halogen, tosylate (TsO − ), aldehyde (—COH), ketone (—COR, wherein R is C1-C10alkyl, C6-C20aryl, C2-C20 heteroaryl), diene,

or —OP(═O) (OH) 2 ;

X 1 and X 3 are each independently —O—, —S—, —NH—, or —CH 2 —;

a6 and b1 are each independently an integer of 1 to 10;

a7 is an integer of 0 to 10;

z is an integer of 1 to 3, and Y may be the same or different from each other, if z is an integer of not less than 2;

z1 is an integer of 0 or 1; and

R 1 and R 2 are each independently hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.

14. The compound of claim 13 , wherein the compound is represented by Chemical Formula 3 below.

in Chemical Formula 3,

Y is hydrogen, haloC 1 -C 8 alkyl, halogen, cyano or nitro;

z is an integer of 1 to 3, and Y may be the same or different from each other, if z is an integer of not less than 2;

z1 is an integer of 0 or 1;

U is a single bond or

R 21 is C 1 -C 20 alkyl, C 6 -C 20 arylC 1 -C 8 alkyl, —(CH 2 ) s1 COOR 3 , —(CH 2 ) s1 COR 3 , —(CH 2 ) s2 CONR 4 R 5 or —(CH 2 ) s2 NR 4 R 5 ;

R 3 , R 4 , and R 5 are each independently hydrogen or C 1 -C 15 alkyl;

s1 and s2 are each independently an integer of 0 to 10;

W b1 is —C(═O)NH—, —NHC(═O)—,

a1 is each independently an integer of 1 to 10;

s4 is an integer of 0 to 10;

p3 and p4 are each independently an integer of 1 to 10;

FG is —NH 2 , —C≡CH, C 4 -C 10 cycloalkynyl, —N 3 , —COOH, —SO 3 H, —OH, —NHOH, —NHNH 2 , —SH, haloacetamide (—NHC(O)CH 2 -hal, wherein hal is halogen), maleimide

halogen, tosylate (TsO − ), aldehyde (˜COH), ketone (˜COR, wherein R is C1-C10alkyl, C6-C20aryl, C2-C20 heteroaryl), diene,

or —OP(═O) (OH) 2 ;

X 1 and X 3 are each independently —O—, —S—, —NH—, or —CH 2 —;

a6 and b1 are each independently an integer of 1 to 10;

T is a drug selected from the following structures: and

w is an integer of 1 to 10.