Small molecule conjugates specifically activated in tumor microenvironment for targeting and use thereof
Provided is an anticancer compound including a cleavable linker specifically activated in a tumor microenvironment, and use thereof. The anticancer compound is represented by the following formula, wherein, R 1 is a normal functional group or a protection group; R 2 is Ala, Thr, Val or Ile; R 3 is Ala, Val or Asn; R 4 is a drug group linked via a hydroxyl group or an amino group; and the general formula of the drug is R 4 H. The anticancer compound is only activated at a local portion of a tumor, thus avoiding the defect of immune system damage of a traditional chemotherapeutic drug, and promoting tumor immunization by removing a tumor immunosuppression cell. The anticancer compound or pharmaceutical composition thereof is jointly used with immunotherapy, thus improving the effect of treating the tumor, and effectively inhibiting tumor metastasis and osseous metastasis.
1. A compound of formula (III) or (IV) comprising a cleavable linker, wherein the cleavable linker is —R 2 -R 3 -Asn-4-aminobenzyl-OC(O)—:
wherein
R 1 is selected from the group consisting of 6-maleimide-C 1-10 alkylcarbonyl, hydroyxlaminocarbonyl-C 1-10 alkylcarbonyl, C 1-4 alkoxyl-(C 1-4 alkoxyl) n -C 1-6 alkylcarbonyl, and
wherein each R is independently a C 1-4 alkylene, and each n is independently any integer between 1 and 300;
R 2 is an amino acid moiety selected from the group consisting of Ala, Thr, Val and Ile;
R 3 is an amino acid moiety selected from the group consisting of Ala, Thr, Val and Asn;
R 2 links to R 3 through an amide bond, R 3 links to Asn through an amide bond, and Asn links to —NH— through its carbonyl;
R 5 is an active moiety of an anticancer drug containing a hydroxyl group (R 5 —OH), wherein the anticancer drug is selected from the group consisting of Camptothecin, 10-Hydroxyl Camptothecin, Topotecan, Floxuridine, 5′-Deoxy-5-Fluorouridine, Cytarabine, Etoposide, Fludarabine, Capecitabine, Vincristine, Epothilone B, Paclitaxel and Docetaxel, wherein Paclitaxel and Docetaxel link to the cleavable linker through the hydroxyl group at position 2 when the anticancer drug is Paclitaxel or Docetaxel;
R 6 is an active moiety of an anticancer drug containing an amino group (R 6 —NH 2 ), wherein the anticancer drug is selected from the group consisting of Daunorubicin, Epirubicin, Methotrexate, Fludarabine, Gemcitabine, Cytarabine, Melphalan, Nimustine, Mitoxantrone, Doxorubicin and Mitomycin;
the cleavable linker is characterized in that it is cleavable by contact with an asparagine endopeptidase,
and the compound is characterized by release of R 5 or R 6 through a cleavage of the cleavable linker by contact with the asparagine endopeptidase.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of C 1-4 alkoxyl-(C 1-4 alkoxyl) n -C 1-6 alkylcarbonyl, and
wherein each R is independently a C 1-4 alkylene, and each n is independently any integer between 1 and 300.
3. The compound of claim 2 , wherein said each n is independently any integer between 1 and 150.
4. The compound of claim 1 , wherein the compound has a structure as set forth in any of the following formulae (V), (VI), (VII), (VIII), and (IX):
wherein
each n is independently any integer between 1 and 300;
R 2 is Ala, Thr, Val or Ile; and
R 3 is Ala, Thr, Val or Asn.
5. The compound of claim 4 , wherein said each n is independently any integer between 1 and 150.
6. The compound of claim 1 , wherein the compound is selected from the group consisting of:
7. The compound of claim 1 , wherein the compound is selected from the group consisting of:
wherein, in compounds S7-S15 and S17-S18, R 1 is 2-(2-methoxyethoxy)acetyl, R 2 is Thr, R 3 is Ala;
wherein, in compounds S19-S28, R 1 is 2-(2-methoxyethoxy)acetyl, R 2 and R 3 are Ala;
S29-S43 represented by a formula
wherein, in compounds S29-S43, R 1 is 2-(2-methoxyethoxy)acetyl, and R 2 and R 3 are shown below:
No. of Compound
R 2
R 3
S29
Thr
Thr
S30
Thr
Val
S31
Thr
Asn
S32
Val
Ala
S33
Val
Thr
S34
Val
Val
S35
Val
Asn
S36
Ile
Ala
S37
Ile
Thr
S38
Ile
Val
S39
Ile
Asn
S40
Ala
Ala
S41
Ala
Thr
S42
Ala
Val
S43
Ala
Asn
S10′-S24′ represented by formula
in which n is 1 and R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
S10′
Ala
Thr
S11′
Ala
Val
S12′
Ala
Asn
S13′
Thr
Ala
S14′
Thr
Thr
S15′
Thr
Val
S16′
Thr
Asn
S17′
Val
Ala
S18′
Val
Thr
S19′
Val
Val
S20′
Val
Asn
S21′
Ile
Ala
S22′
Ile
Thr
S23′
Ile
Val
S24′
Ile
Asn
A10-A24 represented by formula
wherein n is 5 and R 2 and R 3 are shown in the following table:
No. of Compound
R 2
R 3
A10
Ala
Thr
A11
Ala
Val
A12
Ala
Asn
A13
Thr
Ala
A14
Thr
Thr
A15
Thr
Val
A16
Thr
Asn
A17
Val
Ala
A18
Val
Thr
A19
Val
Val
A20
Val
Asn
A21
Ile
Ala
A22
Ile
Thr
A23
Ile
Val
A24
Ile
Asn
B10-B24 represented by
in which n, R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
n
B10
Ala
Thr
5
B11
Ala
Val
5
B12
Ala
Asn
5
B13
Thr
Ala
5
B14
Thr
Thr
5
B15
Thr
Val
5
B16
Thr
Asn
5
B17
Val
Ala
5
B18
Val
Thr
5
B19
Val
Val
5
B20
Val
Asn
5
B21
Ile
Ala
5
B22
Ile
Thr
5
B23
Ile
Val
5
B24
Ile
Asn
5
D10-D24 represented by
in which n, R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
n
D10
Ala
Thr
1
D11
Ala
Val
1
D12
Ala
Asn
1
D13
Thr
Ala
1
D14
Thr
Thr
1
D15
Thr
Val
1
D16
Thr
Asn
1
D17
Val
Ala
1
D18
Val
Thr
1
D19
Val
Val
1
D20
Val
Asn
1
D21
Ile
Ala
1
D22
Ile
Thr
1
D23
Ile
Val
1
D24
Ile
Asn
1
E10-E24 represented by formula
in which n, R 2 and R 3 are shown as follows:
No. of
Compound
R 2
R 3
n
E10
Ala
Thr
1
E11
Ala
Val
1
E12
Ala
Asn
1
E13
Thr
Ala
1
E14
Thr
Thr
1
EIS
Thr
Val
1
E16
Thr
Asn
1
E17
Val
Ala
1
E18
Val
Thr
1
E19
Val
Val
1
E20
Val
Asn
1
E21
Ile
Ala
1
E22
Ile
Thr
1
E23
Ile
Val
1
E24
Ile
Asn
1.
8. The compound of claim 1 , wherein R 2 is Thr, R 3 is Ala; or R 2 is Val, R 3 is Ala; or R 2 is Ile, R 3 is Ala; or both R 2 and R 3 are Ala.
9. The compound of claim 1 , wherein R 1 is 2-(2-Methoxyethoxy)acetyl, 6-maleimide caproyl or N-hydroxylamino-1,8-octandioic acid-1-monoacyl.
10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
11. The pharmaceutical composition of claim 10 , wherein R 1 is selected from the group consisting of C 1-4 alkoxyl-(C 1-4 alkoxyl) n -C 1-6 alkylcarbonyl, and
wherein each R is independently a C 1-4 alkylene, and each n is independently any integer between 1 and 300.
12. The pharmaceutical composition of claim 11 , wherein said each n is independently any integer between 1 and 150.
13. The pharmaceutical composition of claim 10 , wherein the compound has a structure as set forth in any of the following formulae (V), (VI), (VII), (VIII), and (IX):
wherein
each n is independently any integer between 1 and 300;
R 2 is Ala, Thr, Val or Ile; and
R 3 is Ala, Thr, Val or Asn.
14. The pharmaceutical composition of claim 13 , wherein said each n is independently any integer between 1 and 150.
15. The pharmaceutical composition of claim 10 , wherein the compound is selected from the group consisting of:
wherein, in compounds S7-S15 and S17-S18, R 1 is 2-(2-methoxyethoxy)acetyl, R 2 is Thr, R 3 is Ala;
wherein, in compounds S19-S28, R 1 is 2-(2-methoxyethoxy)acetyl, R 2 and R 3 are Ala;
S29-S43 represented by a formula
wherein, in compounds S29-S43, R 1 is 2-(2-methoxyethoxy)acetyl, and R 2 and R 3 are shown below:
No. of Compound
R 2
R 3
S29
Thr
Thr
S30
Thr
Val
S31
Thr
Asn
S32
Val
Ala
S33
Val
Thr
S34
Val
Val
S35
Val
Asn
S36
Ile
Ala
S37
Ile
Thr
S38
Ile
Val
S39
Ile
Asn
S40
Ala
Ala
S41
Ala
Thr
S42
Ala
Val
S43
Ala
Asn
S10′-S24′ represented by formula
in which n is 1 and R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
S10′
Ala
Thr
S11′
Ala
Val
S12′
Ala
Asn
S13′
Thr
Ala
S14′
Thr
Thr
S15′
Thr
Val
S16′
Thr
Asn
S17′
Val
Ala
S18′
Val
Thr
S19′
Val
Val
S20′
Val
Asn
S21′
Ile
Ala
S22′
Ile
Thr
S23′
Ile
Val
S24′
Ile
Asn
A10-A24 represented by formula
wherein n is 5 and R 2 and R 3 are shown in the following table:
No. of Compound
R 2
R 3
A10
Ala
Thr
A11
Ala
Val
A12
Ala
Asn
A13
Thr
Ala
A14
Thr
Thr
A15
Thr
Val
A16
Thr
Asn
A17
Val
Ala
A18
Val
Thr
A19
Val
Val
A20
Val
Asn
A21
Ile
Ala
A22
Ile
Thr
A23
Ile
Val
A24
Ile
Asn
B10-B24 represented by
in which n, R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
n
B10
Ala
Thr
5
B11
Ala
Val
5
B12
Ala
Asn
5
B13
Thr
Ala
5
B14
Thr
Thr
5
B15
Thr
Val
5
B16
Thr
Asn
5
B17
Val
Ala
5
B18
Val
Thr
5
B19
Val
Val
5
B20
Val
Asn
5
B21
Ile
Ala
5
B22
Ile
Thr
5
B23
Ile
Val
5
B24
Ile
Asn
5
D10-D24 represented by
in which n, R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
n
D10
Ala
Thr
1
D11
Ala
Val
1
D12
Ala
Asn
1
D13
Thr
Ala
1
D14
Thr
Thr
1
D15
Thr
Val
1
D16
Thr
Asn
1
D17
Val
Ala
1
D18
Val
Thr
1
D19
Val
Val
1
D20
Val
Asn
1
D21
Ile
Ala
1
D22
Ile
Thr
1
D23
Ile
Val
1
D24
Ile
Asn
1
E10-E24 represented by formula
in which n, R 2 and R 3 are shown as follows:
No. of Compound
R 2
R 3
n
E10
Ala
Thr
1
E11
Ala
Val
1
E12
Ala
Asn
1
E13
Thr
Ala
1
E14
Thr
Thr
1
E15
Thr
Val
1
E16
Thr
Asn
1
E17
Val
Ala
1
E18
Val
Thr
1
E19
Val
Val
1
E20
Val
Asn
1
E21
Ile
Ala
1
E22
Ile
Thr
1
E23
Ile
Val
1
E24
Ile
Asn
1.