Inactivators of O6-alkylguanine-DNA alkyltransferase
Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X 1 , X 2 , R 1 , and R 2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).
1. A compound of formula (I):
wherein
X 1 is selected from the group consisting of
hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylaminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carbamoylalkyl, C 1 -C 6 pivaloylalkyl, C 1 -C 6 alkylcarbonyloxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylalkyl, ribose, 2′-deoxyribose, the conjugate acid form of a C 1 -C 6 carboxyalkyl, and the carboxylate anion of a C 1 -C 6 carboxyalkyl as the sodium salt;
X 2 is selected from the group consisting of
hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, a C 1 -C 6 alkyl substituted aryl, nitro, a polycyclic aromatic C 1 -C 6 alkyl containing 2-4 aromatic rings, a C 3 -C 8 cycloalkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a C 2 -C 8 alkoxyalkyl, aryloxy, acyloxy, an acyloxy-C 1 -C 6 alkyl, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, acylamino, ureido, thioureido, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, formyl, acyl, a di-C 1 -C 6 alkoxymethyl, an amino-C 1 -C 6 alkyl, and SO n R a , wherein n is 0, 1, 2, or 3 and R a is H, a C 1 -C 6 alkyl, or aryl;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, mercapto, C 1 -C 4 alkylthio, trifluoromethylthio, C 1 -C 4 thioacyl, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, C 1 -C 4 acyloxy, amino, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, C 1 -C 4 aminoacyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C 1 -C 4 alkyldiazo, C 5 -C 6 aryldiazo, trifluoromethyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, cyano, C 1 -C 4 alkyloxycarbonyl, C 1 -C 4 alkylcarbonyl, phenyl, phenylcarbonyl, formyl, C 1 -C 4 alkoxymethyl, phenoxymethyl, C 2 -C 4 vinyl, C 2 -C 4 ethynyl, and SO m R b , wherein m is 0, 1, 2, or 3 and R b is hydrogen, C 1 -C 4 alkyl, amino, or aryl;
R 2 is selected from the group consisting of hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, a C 1 -C 6 alkyl substituted aryl, nitro, a polycyclic aromatic C 1 -C 6 alkyl containing 2-4 aromatic rings, a C 3 -C 8 cycloalkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a C 2 -C 8 alkoxyalkyl, aryloxy, acyloxy, an acyloxy-C 1 -C 6 alkyl, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, acylamino, ureido, thioureido, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, formyl, acyl, a di-C 1 -C 6 alkoxymethyl, a C 1 -C 6 aminoalkyl, and SO p R c , wherein p is 0, 1, 2, or 3 and R c is H, a C 1 -C 6 alkyl, or aryl;
or a pharmaceutically acceptable salt thereof;
provided that at least one of X 1 and X 2 is a folate residue and the other of X 1 and X 2 is a moiety other than a folate residue.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein
X 1 is selected from the group consisting of
X 2 is selected from the group consisting of hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, a C 1 -C 6 alkyl substituted aryl, nitro, a polycyclic aromatic C 1 -C 6 alkyl containing 2-4 aromatic rings, a C 3 -C 8 cycloalkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a C 2 -C 8 alkoxyalkyl, aryloxy, acyloxy, an acyloxy-C 1 -C 6 alkyl, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, acylamino, ureido, thioureido, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, formyl, acyl, a di-C 1 -C 6 alkoxymethyl, an amino-C 1 -C 6 alkyl, and SO n R a , wherein n is 0, 1, 2, or 3 and R a is H, a C 1 -C 6 alkyl, or aryl;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, mercapto, C 1 -C 4 alkylthio, trifluoromethylthio, C 1 -C 4 thioacyl, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, C 1 -C 4 acyloxy, amino, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, C 1 -C 4 aminoacyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C 1 -C 4 alkyldiazo, C 5 -C 6 aryldiazo, trifluoromethyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, cyano, C 1 -C 4 alkyloxycarbonyl, C 1 -C 4 alkylcarbonyl, phenyl, phenylcarbonyl, formyl, C 1 -C 4 alkoxymethyl, phenoxymethyl, C 2 -C 4 vinyl, C 2 -C 4 ethynyl, and SO m R b , wherein m is 0, 1, 2, or 3 and R b is hydrogen, C 1 -C 4 alkyl, amino, or aryl;
R 2 is selected from the group consisting of hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, a C 1 -C 6 alkyl substituted aryl, nitro, a polycyclic aromatic C 1 -C 6 alkyl containing 2-4 aromatic rings, a C 3 -C 8 cycloalkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a C 2 -C 8 alkoxyalkyl, aryloxy, acyloxy, an acyloxy-C 1 -C 6 alkyl, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, acylamino, ureido, thioureido, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, formyl, acyl, a di-C 1 -C 6 alkoxymethyl, a C 1 -C 6 aminoalkyl, and SO p R c , wherein p is 0, 1, 2, or 3 and R c is H, a C 1 -C 6 alkyl, or aryl.
3. The compound or pharmaceutically acceptable salt of claim 1 , wherein
X 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylaminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carbamoylalkyl, C 1 -C 6 pivaloylalkyl, C 1 -C 6 alkylcarbonyloxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylalkyl, ribose, 2′-deoxyribose, the conjugate acid form of a C 1 -C 6 carboxyalkyl, and the carboxylate anion of a C 1 -C 6 carboxyalkyl as the sodium salt;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, mercapto, C 1 -C 4 alkylthio, trifluoromethylthio, C 1 -C 4 thioacyl, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, C 1 -C 4 acyloxy, amino, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, C 1 -C 4 aminoacyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C 1 -C 4 alkyldiazo, C 5 -C 6 aryldiazo, trifluoromethyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, cyano, C 1 -C 4 alkyloxycarbonyl, C 1 -C 4 alkylcarbonyl, phenyl, phenylcarbonyl, formyl, C 1 -C 4 alkoxymethyl, phenoxymethyl, C 2 -C 4 vinyl, C 2 -C 4 ethynyl, and SO m R b , wherein m is 0, 1, 2, or 3, and R b is hydrogen, C 1 -C 4 alkyl, amino, or aryl;
R 2 is selected from the group consisting of hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, a C 1 -C 6 alkyl substituted aryl, nitro, a polycyclic aromatic C 1 -C 6 alkyl containing 2-4 aromatic rings, a C 3 -C 8 cycloalkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a C 2 -C 8 alkoxyalkyl, aryloxy, acyloxy, an acyloxy-C 1 -C 6 alkyl, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, acylamino, ureido, thioureido, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, formyl, acyl, a di-C 1 -C 6 alkoxymethyl, a C 1 -C 6 aminoalkyl, and SO p R c , wherein p is 0, 1, 2, or 3, and R c is H, a C 1 -C 6 alkyl, or aryl.
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, mercapto, C 1 -C 4 alkylthio, hydroxy, C 1 -C 4 alkoxy, amino, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, nitro, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, cyano, phenyl, phenylcarbonyl, or C 1 -C 4 alkoxymethyl.
5. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, nitro, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a aryloxy, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, or a C 1 -C 6 aminoalkyl.
6. The compound or pharmaceutically acceptable salt of claim 1 , wherein X 2 is hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, nitro, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a aryloxy, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, or a C 1 -C 6 aminoalkyl.
7. The compound or pharmaceutically acceptable salt of claim 1 , wherein X 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylaminoalkyl, and C 1 -C 6 cyanoalkyl.
8. The compound or pharmaceutically acceptable salt of claim 7 , wherein X 1 is hydrogen.
9. The compound or pharmaceutically acceptable salt of claim 1 , which is
or pharmaceutically acceptable salt thereof.
10. The compound or pharmaceutically acceptable salt of claim 1 , which is
or pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , which is
or pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising (a) a compound or pharmaceutically acceptable salt of claim 1 and (b) a pharmaceutically acceptable carrier.
13. A method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6 -position of guanine, which method comprises administering to the mammal an effective amount of the compound or pharmaceutically acceptable salt of claim 1 , and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O 6 -position of guanine.
14. The method of claim 13 , wherein the mammal is a human.
15. A method of inactivating O 6 -alkylguanine-DNA-alkyltransferase (AGT) in a tumor cell comprising contacting said tumor cell with an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
16. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 1 is hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, mercapto, C 1 -C 4 alkylthio, hydroxy, C 1 -C 4 alkoxy, amino, C 1 -C 4 aminoalkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, nitro, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, cyano, phenyl, phenylcarbonyl, or C 1 -C 4 alkoxymethyl.
17. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 2 is hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, nitro, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a aryloxy, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, or a C 1 -C 6 aminoalkyl.
18. The compound or pharmaceutically acceptable salt of claim 2 , wherein X 2 is hydrogen, halo, hydroxy, a C 1 -C 6 alkyl, aryl, nitro, a C 1 -C 6 hydroxyalkyl, a C 1 -C 8 alkoxy, a aryloxy, amino, a C 1 -C 6 alkylamino, a C 1 -C 6 dialkylamino, carboxy, a carboxy-C 1 -C 6 alkyl, cyano, a C 1 -C 6 cyanoalkyl, or a C 1 -C 6 aminoalkyl.
19. The compound or pharmaceutically acceptable salt of claim 3 , wherein X 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylaminoalkyl, and C 1 -C 6 cyanoalkyl.
20. A pharmaceutical composition comprising (a) a compound or pharmaceutically acceptable salt of claim 2 and (b) a pharmaceutically acceptable carrier.
21. A method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6 -position of guanine, which method comprises administering to the mammal an effective amount of the compound or pharmaceutically acceptable salt of claim 2 , and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O 6 -position of guanine.