Texaphyrin-Pt(IV) conjugates and compositions for use in overcoming platinum resistance
The present disclosure relates platinum(IV) and texaphyrin linked conjugates and compositions comprising a texaphyrin and a platinum(IV) agent. The present disclosure also provides pharmaceutical compositions of the conjugates and compositions. Also, provided herein are methods of using the instant compounds in the treatment of cancer such as a platinum resistant cancer.
1. A compound of the formula (VIII):
wherein:
R 1 and R 2 are each
wherein n is 3 and R 3 is hydrogen or methyl;
X 1 , X 3 , X 4 , and X 6 are each independently selected from alkyl (C≤12) or substituted alkyl (C≤12) ,
X 2 is
wherein:
L 3 , L 4 , and L 6 are each independently selected from ammonia, halide, or L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) ;
L 5 is aqua, ammonia, halide, hydroxide, alkylcarboxylate (C≤12) , or substituted alkylcarboxylate (C≤12) ;
L 7 is amino, or L 4 and L 7 are taken together and are diaminocycloalkane (C≤12) ;
X 5 are each independently selected from hydroxy or
wherein: L 3 -L 7 are as defined above;
M is a gadolinium(III) ion; and
L 1 and L 2 are each anionic ligands independently selected from fluoride, chloride, bromide, carbonate, hydroxide, perchlorate, nitrate, sulfate, trifluoromethylsulfonate, acetylacetonate, acetate, or trifluoroacetate;
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
2. The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
3. A pharmaceutical composition comprising:
(A) a pharmaceutically acceptable carrier; and
(B) a compound of claim 1 .
4. A method of treating a cancer selected from ovarian cancer, lung cancer, breast cancer, endometrial cancer, brain cancer, skin cancer, head and neck cancer, and colorectal cancer in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1 .
5. The method of claim 4 , wherein the cancer is resistant to a platinum chemotherapeutic.
6. The compound of claim 2 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
7. The compound of claim 1 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
8. The compound of claim 7 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
9. The compound of claim 7 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
10. The compound of claim 7 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
11. The pharmaceutical composition of claim 3 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
12. The method of claim 4 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
13. The pharmaceutical composition of claim 3 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
14. The method of claim 4 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
15. The pharmaceutical composition of claim 3 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
16. The method of claim 4 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
17. The pharmaceutical composition of claim 3 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
18. The method of claim 4 , wherein the compound is further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
19. The method of claim 4 , wherein the cancer is ovarian cancer.
20. The compound of claim 1 , further defined as:
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.