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) , and
wherein n is 1-20 and R 3 is hydrogen, alkyl (C≤6) , 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) , and
wherein n is 1-20 and R 3 is hydrogen, alkyl (C≤6) , 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) , and substituted alkyl (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, cyano,
alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , and 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
wherein:
R 6 is amino, or carboxy;
L 3 , L 4 , and L 6 are each ligands independently selected from aqua, ammonia, halide, or hydroxide, or
L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) , aryldicarboxylate (C≤18) , or a substituted version of any either group;
L 5 is aqua, amino, nitrate, sulfate, halide, nitrate, sulfate, or hydroxide,
alkylamine (C≤12) , cycloalkylamine (C≤12) , dialkylamine (C≤18) , dicycloalkylamine (C≤18) , arylamine (C≤12) , diarylamine (C≤18) , heteroarene (C≤12) , alkylcarboxylate (C≤12) , arylcarboxylate (C≤12) , and a substituted version of any of these groups;
L 7 is amino or L 4 and L 7 are taken together and arc 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 fluoride, chloride, bromide, perchlorate, nitrate, sulfate, trifluoromethylsulfonate, acetate, and trifluoroacetate;
or a pharmaceutically acceptable salt 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) , and
wherein n is 1-20 and R 3 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) ;
or a pharmaceutically acceptable salt thereof.
3 . 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 hydrogen, hydroxy, halo,
alkyl (C≤12) , substituted alkyl (C≤12) , and
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 —NRSC(O)—, wherein R 5 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) , and R 4 is
wherein:
R 6 is
L 3 , L 4 , and L 6 are each ligands independently selected from ammonia, halide, or
L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) , aryldicarboxylate (C≤18) , or a substituted version of any either group;
L 5 is aqua, amino, nitrate, sulfate, halide, nitrate, sulfate, or hydroxide,
alkylamine (C≤12) , cycloalkylamine (C≤12) , dialkylamine (C≤18) , dicycloalkylamine (C≤18) , arylamine (C≤12) , diarylamine (C≤18) , heteroarene (C≤12) , alkylcarboxylate (C≤12) , arylcarboxylate (C≤12) , and a substituted version of any of these groups;
L 7 is amino or L 4 and Ly are taken together and are 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, and trifluoroacetate;
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein R 2 is a platinum (IV) chelating group of the formula:
wherein: R 4 is as defined above.
5 . The compound of claim 1 , wherein R 4 is
6 . The compound of claim 5 , wherein R 6 is carboxy.
7 . The compound of claim 5 , wherein L 3 is halide.
8 . The compound of claim 5 , wherein L 6 is halide.
9 . The compound of claim 5 , wherein L 3 and L 6 are taken together and are alkyldicarboxylate (C≤18) .
10 . The compound of claim 5 , wherein L 7 is amino.
11 . The compound of claim 5 , wherein L 4 and L 7 are taken together and are diaminocycloalkane (C≤12) .
12 . The compound of claim 1 , wherein X 3 and X 4 are alkyl (C<12) or substituted alkyl (C<12) .
13 . The compound of claim 1 , wherein X 5 is a platinum (IV) chelating group or alkyl (C≤12) or substituted alkyl (C≤12) .
14 . The compound of claim 1 , wherein X 1 and X 6 is alkyl (C≤12) or substituted alkyl (C≤12) .
15 . The compound of claim 1 , wherein M is gadolinium.
16 . The compound of claim 1 , wherein L 1 or L 2 is acetate or nitrate.
17 . The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt thereof.
18 . A pharmaceutical composition comprising:
(A) a pharmaceutically acceptable carrier; and
(B) a compound of claim 1 .
19 . A method of treating a platinum resistant cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of claim 1 .
20 . The method of claim 19 , wherein the cancer is colon cancer or colorectal cancer.
21 . The method of claim 19 , wherein the cancer is ovarian cancer.