A method for inducing cell death in neoplastic cells, includes the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof, as a primary chemotherapeutic agent or substantially contemporaneously with chemotherapy, to a patient having multidrug-resistant neoplastic cells, in an amount sufficient to induce cell death in the neoplastic cells: ##STR1## where R.sup.1 is hydroxyl, C1-4 alkoxyl, C1-4 alkylcarboxyloxymethoxyl, phenyl C1-2 alkylamino group, 2,5-pyrrolidinedione-1-alkoxyl (C1-4), or ##STR2## wherein X.sup.1 is a chemical bond or C1-2 alkylene, X.sup.2 is hydrogen or carboxyl forming a 5-membered ring with X.sup.1 when X.sup.2 is methylene, X.sup.3 is hydrogen or C1-2 alkyl, X.sup.4 is hydrogen or C1-2 alkyl, or X.sup.3 and X.sup.4 together form a 5-membered ring, in which at least one of X.sup.2, X.sup.3, and X.sup.4 is hydrogen, R.sup.2 is C3-4 alkyl, R.sup.3 is C1-4 alkyl, ##STR3## in which n is an integer of 0 to 3.
Oncoproteins such as Ras and RhoB are known to induce cell division in an unrestrained manner when such proteins are localized at the inner surface of a cancer cell membrane. The localization is effected by the prenylation reaction, whereby a hydrophobic group (e.g. a farnesyl group) is attached to the protein in the presence of an enzyme (e.g. farnesyl protein transferase). Deactivation of the prenylation enzyme through covalent modification can therefore ultimately result in the mitigation and/or cessation of cancer cell growth. Various prenylation inhibitors having the necessary structural groups to bond covalently, or essentially irreversibly, to the prenylation enzyme include carbonyl or thiocarbonyl compounds (or masked versions of these compounds) and alpha oxo-epoxides bonded to a hydrophobic, substrate-mimicking group. The carbonyl or thiocarbonyl compounds also contain a nucleofugal atom or group to enhance the tendency to form covalent bonds.
Oncoproteins such as Ras and RhoB are known to induce cell division in an unrestrained manner when such proteins are localized at the inner surface of a cancer cell membrane. The localization is effected by the prenylation reaction, whereby a hydrophobic group (e.g. a farnesyl group) is attached to the protein in the presence of an enzyme (e.g. farnesyl protein transferase). Deactivation of the prenylation enzyme through covalent modification can therefore ultimately result in the mitigation and/or cessation of cancer cell growth. Various prenylation inhibitors having the necessary structural groups to bond covalently, or essentially irreversibly, to the prenylation enzyme include carbonyl or thiocarbonyl compounds (or masked versions of these compounds) and alpha oxo-epoxides bonded to a hydrophobic, substrate-mimicking group. The carbonyl or thiocarbonyl compounds also contain a nucleofugal atom or group to enhance the tendency to form covalent bonds.
A method for inducing cell death in neoplastic cells, includes the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof, as a primary chemotherapeutic agent or substantially contemporaneously with chemotherapy, to a patient having multidrug-resistant neoplastic cells, in an amount sufficient to induce cell death in the neoplastic cells: ##STR1## where R.sup.1 is hydroxyl, C1-4 alkoxyl, C1-4 alkylcarboxyloxymethoxyl, phenyl C1-2 alkylamino group, 2,5-pyrrolidinedione-1-alkoxyl (C1-4), or ##STR2## wherein X.sup.1 is a chemical bond or C1-2 alkylene, X.sup.2 is hydrogen or carboxyl forming a 5-membered ring with X.sup.1 when X.sup.1 is methylene, X.sup.3 is hydrogen or C1-2 alkyl, X.sup.4 is hydrogen or C1-2 alkyl, or X.sup.3 and X.sup.4 together form a 5-membered ring, in which at least one of X.sup.2, X.sup.3, and X.sup.4 is hydrogen, R.sup.2 is C3-4 alkyl, R.sup.3 is C1-4 alkyl, ##STR3## in which n is an integer of 0 to 3.
Substituted heterocyclic compounds for treating multidrug resistance are disclosed. Compositions and methods of use for the substituted heterocyclic compounds are disclosed. Suitable substituted heterocyclic compounds include: ##STR1##
Substituted heterocyclinc compounds are disclosed. The compounds are useful for treating multidrug resistance. The compounds can be formulated in compositions with a carrier and, optionally, a therapeutic agent. One suitable substituted heterocyclic compound has the formula: ##STR00001##
