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:
wherein:
R 1 and R 2 are each independently selected from hydrogen, halo, hydroxy, amino, mercapto, alkoxy (c≤12) , substituted alkoxy (c≤12) , or
wherein n is 1-20 and R 3 is hydrogen, alkyl (c≤6) , or substituted alkyl (c<6) , or a platinum(IV) chelating group;
A 1 and A 2 are each independently selected from hydrogen, halo, hydroxy, alkyl (c≤12) , substituted alkyl (c≤12) , alkoxy (c≤12) , substituted alkoxy (c<12) , or
wherein n is 1-20 and R 3 is hydrogen, alkyl (c≤6) , or substituted alkyl (c≤6) , or a platinum(IV) chelating group;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from hydrogen, halo, alkyl (c≤12) , aryl (c≤12) , substituted alkyl (c≤12) , or substituted aryl (c≤12) ;
X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from hydrogen, hydroxy, halo, amino, carboxy, nitro, or cyano,
alkyl (c≤12) , alkenyl (c≤12) , alkynyl (c≤12) , aryl (c≤12) , aralkyl (c≤12) , acyl (c≤12) , amido (c≤12) , or a substituted version of any of these groups, or
a platinum(IV) chelating group; wherein the platinum(IV) chelating group is —A 3 —X 7 —A 4 —R 4 , wherein A 3 and A 4 are each independently alkanediyl (c≤12) , alkenediyl (c≤12) , arenediyl (c≤12) , alkoxydiyl (c≤12) , alkylaminodiyl (c≤12) , or a substituted version of any of these groups, X 7 is —O—, —S—, —NR 5 —, —C(O)NR 5 —, or —NR 5 C(O)—, wherein R 5 is hydrogen, alkyl (c≤6) , or substituted alkyl (c≤6) , and R 4 is amino, hydroxy, mercapto, carboxy, dicarboxy, or
wherein:
R 6 is amino or carboxy;
L 5 is aqua, ammonia, nitrate, sulfate, halide, hydroxide, phosphate, or glucose-6-phosphate,
alkylamine (c≤12) , cycloalkylamine (c≤12) , dialkylamine (c≤18) , dicycloalkylamine (c≤18) , arylamine (c≤12) , diarylamine (c≤18) , diaminoalkane (c≤12) , diaminocycloalkane (c≤12) , diaminoarene (c≤12) , heteroarene (c≤12) , alkylcarboxylate (c≤12) , alkyldicarboxylate (c≤18) , arylcarboxylate (c≤12) , aryldicarboxylate (c≤18) , or a substituted version of any of these groups;
L 3 , L 4 , and L 6 are each independently amino, halide, or L 3 and L 6 are taken together and are alkyldicarboxylate (c≤18) or substituted alkyldicarboxylate (c≤18) ;
L 7 is amino, or L 7 is taken together with L 4 and is diaminocycloalkane (c≤12) , or substituted diaminocycloalkane (c≤12) ;
provided that R 6 , L 3 , L 4 , L 5 , L 6 , and L 7 are appropriately charged to obtain a neutral complex
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is a platinum(IV) chelating group;
M is a divalent metal ion or a trivalent metal ion; and
L 1 and L 2 are each absent or anionic ligands independently selected from fluoride, chloride, bromide, carbonate, hydroxide, perchlorate, nitrate, sulfate, trifluoromethylsulfonate, acetylacetonate, acetate, or trifluoroacetate;
provided that when M is a divalent metal ion, then L 1 or L 2 is absent;
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
2. The compound of claim 1 , wherein the formula is further defined as:
wherein:
R 1 and R 2 are each independently selected from hydroxy, alkoxy (c≤12) , substituted alkoxy (c≤12) , or
wherein n is 1-20 and R 3 is hydrogen, alkyl (c≤6) , or substituted alkyl (c≤6) , or a platinum(IV) chelating group;
A 1 and A 2 are each independently selected from hydrogen;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from hydrogen;
X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from hydrogen, alkyl (c≤12) , alkenyl (c≤12) , aryl (c≤12) , or a substituted version of any of these groups, or
a platinum chelating group of the formula: —A 3 —X 7 —A 4 —R 4 , wherein A 3 and A 4 are each independently alkanediyl (c≤12) , alkoxydiyl (c≤12) , alkylaminodiyl (c≤12) , or a substituted version of any of these groups, X 7 is —NR 5 —, —C(O)NR 5 —, or —NR 5 C(O)—, wherein R 5 is hydrogen, alkyl (c≤12) , or substituted alkyl (c≤12) , and R 4 is hydroxy, carboxy, dicarboxy, or
wherein:
R 6 is amino or carboxy,
L 5 is selected from aqua, ammonia, halide, or hydroxide,
diaminoalkane (c≤12) , diaminocycloalkane (c≤12) , diaminoarene (c≤12) , alkyldicarboxylate (c≤18) , aryldicarboxylate (c≤18) , or a substituted version of any of these groups;
L 3 , L 4 , and L 6 are each independently amino, halide, or L 3 and L 6 are taken together and are alkyldicarboxylate (c≤18) or substituted alkyldicarboxylate (c≤18) ; and
L 7 is amino, or L 7 is taken together with L 4 and is diaminocycloalkane (c≤12) , or substituted diaminocycloalkane (c≤12) ;
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is a platinum(IV) chelating group;
M is a trivalent lanthanide metal ion or a divalent metal ion; and
L 1 and L 2 are each anionic ligands independently selected from fluoride, chloride, bromide, perchlorate, nitrate, sulfate, trifluoromethylsulfonate, acetate, or trifluoroacetate;
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
3. The compound of claim 1 , wherein the formula is further defined as:
wherein:
R 1 and R 2 are each independently selected from alkoxy (c≤12) , substituted alkoxy (c≤12) , or
wherein n is 1-20 and R 3 is hydrogen, alkyl (c≤6) , or substituted alkyl (c≤6) ;
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
4. The compound of claim 1 , wherein the formula is further defined as:
wherein:
o and p are each independently 1, 2, 3, 4, 5, or 6 or any range derivable therein;
X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently selected from alkyl (c≤12) or substituted alkyl (c≤12) , or
a platinum chelating group of the formula: —A 3 —X 7 —A 4 —R 4 , wherein A 3 and A 4 are each independently alkanediyl (c≤12) , alkoxydiyl (c≤12) , or a substituted version of any of these groups, X 7 is —C(O)NR 5 —, or —NR 5 C(O)—, wherein R 5 is hydrogen, alkyl (c≤12) , or substituted alkyl (c≤12) , and R 4 is carboxy or
wherein:
R 6 is carboxy;
L 5 is aqua, ammonia, halide, or hydroxide,
diaminoalkane (c≤12) , diaminocycloalkane (c≤12) , alkyldicarboxylate (c≤18) , or a substituted version of any of these groups;
L 3 , L 4 , and L 6 are each independently amino, halide, or L 3 and L 6 are taken together and are alkyldicarboxylate (c≤18) or substituted alkyldicarboxylate (c≤18) ; and
L 7 is amino, or L 7 is taken together with L 4 and is diaminocycloalkane (c≤12) , or substituted diaminocycloalkane (c≤12) ;
provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is a platinum(IV) chelating group;
M is a trivalent lanthanide metal ion; and
L 1 and L 2 are each anionic ligands independently selected from nitrate, acetate, or trifluoroacetate;
or a pharmaceutically acceptable salt, organometallic isomer, or tautomer thereof.
5. The compound of claim 4 , wherein o or p are 2, 3, or 4.
6. The compound of claim 1 , wherein X 1 , X 3 , X 4 , X 5 , or X 6 are alkyl (c≤12) or substituted alkyl (c≤12) .
7. The compound of claim 1 , wherein X 2 is a platinum(IV) chelating group of the formula: —A 3 —X 7 —A 4 —R 4 , wherein A 3 and A 4 are each independently alkanediyl (c≤12) , alkoxydiyl (c≤12) , or a substituted version of any of these groups, X 7 is —C(O)NR 5 — or —NR 5 C(O)—, wherein R 5 is hydrogen, alkyl (c≤12) , or substituted alkyl (c≤12) , and R 4 is
wherein:
R 6 is carboxy;
L 5 is aqua, ammonia, halide, or hydroxide,
alkylcarboxylate (c≤12) or a substituted version thereof; and
L 3 , L 4 , and L 6 are each independently amino, halide, or L 3 and L 6 are taken together and are alkyldicarboxylate (c≤18) or substituted alkyldicarboxylate (c≤18) ;
L 7 is amino, or L 7 is taken together with L 4 and is diaminocycloalkane (c≤12) , or substituted diaminocycloalkane (c≤12) .
8. The compound of claim 7 , wherein A 4 is alkanediyl (c≤12) or substituted alkanediyl (c≤12) .
9. The compound of claim 7 , wherein R 6 is carboxy.
10. The compound of claim 7 , wherein L 3 or L 6 are halide.
11. The compound of claim 7 , wherein L 3 and L 6 are taken together and are the same alkyldicarboxylate (c≤18) .
12. The compound of claim 7 , wherein L 7 is amino.
13. The compound of claim 7 , wherein L 4 and L 7 are taken together and are diaminocycloalkane (c≤12) .
14. The compound of claim 1 , wherein M is gadolinium.
15. The compound of claim 1 , wherein L 1 and L 2 are acetate or nitrate.
16. A pharmaceutical composition comprising:
(A) a pharmaceutically acceptable carrier; and
(B) a compound of claim 1 .
17. A method of treating cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1 .
18. The method of claim 17 , wherein the cancer is ovarian cancer, testicular cancer, bladder cancer, or colorectal cancer.