O6-alkylguanine-DNA alkyltransferase inactivators and beta-glucuronidase cleavable prodrugs
Disclosed are prodrugs of inactivators of O 6 -alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the β-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring-substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted O 6 -benzylguanine or O 6 -benzyl-2′-deoxyguanosine. Also disclosed are additional inactivators of AGT, pharmaceutical compositions comprising an inactivator or prodrug and a pharmaceutically acceptable carrier, and a method of use of the inactivator or prodrug in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6 -position of guanine.
1. A compound of the formula (I):
wherein R is amino C 1 -C 6 alkyl;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, thiol, 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, halomethyl, C 1 -C 4 cyanoalkyl, cyanomethyl, 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 n R′ wherein n is 0, 1, 2, or 3 and R′ is hydrogen, C 1 -C 4 alkyl, amino, or phenyl;
and R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 aminoalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkylaminoalkyl, C 1 -C 4 dialkylaminoalkyl, C 1 -C 4 cyanoalkyl, C 1 -C 4 carbamoylalkyl, C 1 -C 4 pivaloylalkyl, C 1 -C 6 alkylcarbonyloxy C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonylalkyl, ribose, 2′-deoxyribose, the conjugate acid form of a C 1 -C 4 carboxyalkyl, and the carboxylate anion of a C 1 -C 4 carboxyalkyl as the sodium salt;
or a pharmaceutically acceptable salt thereof;
with the proviso that when R 1 and R 3 are hydrogen, R cannot be ortho-aminoalkyl or para-aminoalkyl.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R is meta-amino C 1 -C 6 alkyl.
3. The compound or pharmaceutically acceptable salt of claim 2 , wherein R is meta-amino methyl and R 1 and R 3 are hydrogen.
4. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 2 and a pharmaceutically acceptable carrier.
5. 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 a mammal an effective amount of the compound of formula (I) and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O 6 -position of guanine:
wherein R is amino C 1 -C 6 alkyl;
R 1 is selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, thiol, 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, halomethyl, C 1 -C 4 cyanoalkyl, cyanomethyl, 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 n R′ wherein n is 0, 1, 2, or 3 and R′ is hydrogen, C 1 -C 4 alkyl, amino, or phenyl;
and R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 aminoalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkylaminoalkyl, C 1 -C 4 dialkylaminoalkyl, C 1 -C 4 cyanoalkyl, C 1 -C 4 carbamoylalkyl, C 1 -C 4 pivaloylalkyl, C 1 -C 6 alkylcarbonyloxy C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonylalkyl, ribose, 2′-deoxyribose, the conjugate acid form of a C 1 -C 4 carboxyalkyl, and the carboxylate anion of a C 1 -C 4 carboxyalkyl as the sodium salt;
or a pharmaceutically acceptable salt thereof;
with the proviso that when R 1 and R 3 are hydrogen, R cannot be ortho-aminoalkyl or para-aminoalkyl.
6. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 3 and a pharmaceutically acceptable carrier.