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5,6-Dihydro-8(7H)-quinolinone was synthesized and converted into thiosemicarbazones which could be considered to be semirigid analogues of the 2-formylpyridine thiosemicarbazone class of antitumor agents. The Z and E isomers were separated and identified by 1H NMR and UV. Although the compounds showed essentially no inhibitory activity against the enzyme alkaline phosphatase, several of these agents had demonstrable anticancer activity in mice bearing the P388 leukemia. The E-configuration analogues in general were slightly more active than their corresponding Z isomers.

A new class of 2,3-diaziridinyl-1,4-naphthoquinone sulfonates (27 compounds) has been synthesized and evaluated as potential antineoplastic agents. The most active compounds, benzenesulfonate 4, p-toluenesulfonate 5, p-methoxybenzenesulfonate 7,8-quinolinesulfonate 17, and 2-thiophenesulfonate 20, in the aromatic sulfonate series, at their optimum daily dosage level of 25 mg/kg X 6, produced 100%, 90%, 75%, 80%, and 100% 50-day survivors, respectively, of L1210 tumor-bearing mice. At a lower optimum daily dosage level of 20 mg/kg X 6, treatments with p-fluorobenzenesulfonate 11 and p-nitrobenzenesulfonate 15 resulted in 100% and 80% 50-day survivors. In the aliphatic sulfonate series, methanesulfonate 21 produced 80% 50-day survivors at a 10 mg/kg daily dosage level X 6. Benzenesulfonate 4, p-fluorobenzenesulfonate 11, 8-quinolinesulfonate 17, and 2-thiophenesulfonate 20 derivatives were also tested in mice bearing the B16 melanoma; these agents gave T/C X 100 values of 180, 182, 219, and 161, respectively, in this neoplastic cell system. Structure-activity relationships of compounds of this class are discussed.

A variety of derivatives of 2-pyridinecarboxaldehyde 1-oxide benzenesulfonylhydrazone, containing substituents on the benzene or pyridine rings as well as on the nitrogen atom which is bonded directly to the sulfonyl group, have been synthesized. The antineoplastic activity of these compounds has been assessed in mice bearing either leukemia L1210 or P388. The most potent agents in this series were 2,4-dimethoxy,3,4-dimethoxy-, and 2,4,6-trimethylbenzenesulfonylhydrazone of 2-pyridinecarboxyaldehyde 1-oxide, all causing disappearance of tumors in 20-80% of leukemia-bearing mice.

A number of antineoplastic agents possess both the quinone nucleus and an appropriate substituent that permits them to function as bioreductive alkylating agents. To develop new compounds of this type with unique properties, we have synthesized a series of 2- and 6-methyl-1,4-naphthoquinone derivatives and have evaluated them for antineoplastic activity against Sarcoma 180 ascites cells. Several of these quinones showed antitumor activity, causing significant prolongation of the survival time of tumor-bearing mice. Among the most active agents were the mesylates, tosylates, and N-(chloroethyl)carbamates of 2- and 6-methyl-1,4-naphthoquinone. That bioreductive activation to a quinone methide might be involved in the mechanism of action of these agents was shown by the finding that compounds with the best leaving groups were the most efficacious as antineoplastic agents.

Several 1,2-bis(arylsulfonyl)-1-methylhydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia. The most active compound to emerge from this study, 2-[(4-chlorophenyl)sulfonyl]-1-methyl-1-(4-tolylsulfonyl)hydrazine , increased the survival time of tumor-bearing mice by 88%. The alkylating activity of the synthesized analogues and several compounds reported earlier was determined by measuring the absorbance at 540 nm of the alkylated product of 4-(4-nitrobenzyl)pyridine. The results obtained support the concept that the ability to alkylate is a necessary but not a sufficient condition for the expression of antitumor activity by agents of this class.

1-(Arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines, with the potential to function as biological methylating agents, were synthesized and evaluated as antineoplastic agents against the L1210 leukemia and the B16 melanoma in mice. All of the compounds of this class had significant activity against the B16 melanoma, with the most active compound, 2-[(methoxycarbonyl)sulfenyl]-1-methyl-1-[(4- methylphenyl)sulfonyl]hydrazine, producing percent T/C values for B16 melanoma tumor bearing mice of between 182 and 232 at dosage levels of from 12.5 to 50 mg/kg daily for 6 consecutive days. In contrast to the related class of agents, the N,N'-bis(sulfonyl)hydrazines reported earlier by this laboratory,1 the 1-(arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines were found to be inactive against the L1210 leukemia in vivo.

Bioreducible 2,3-disubstituted 1,4-naphthoquinones have been synthesized and evaluated for anticancer activity by measuring their capacity to prolong the life span of Sarcoma 180 tumor bearing mice. The leaving group in the 2- and 3-positions of these agents significantly influenced the degree of antineoplastic activity, with the most active agents being the methyl sulfonate (5), the methyl carbamate (9), and the 2-chloroethyl carbamate (10) derivatives; when these quinones were administered daily for 6 consecutive days, they produced maximum T/C X 100 values of 232, 266, and 230, respectively.

The effects of various structural modifications on the antineoplastic activity of (arylsulfonyl)hydrazones of 4-pyridinecarboxaldehyde were examined in mice bearing either Sarcoma 180 or P388 leukemia. The introduction of different functional groups into the phenyl ring of the benzenesulfonyl moiety did not alter tumor inhibitory activity appreciably, and the pyridine ring could be replaced by 4-nitrobenzene without loss of antineoplastic activity. However, the aldehyde proton and the hydrazone proton alpha to the sulfonyl group were essential, and their substitution resulted in inactive anticancer agents.

Several N,N'-bis(arylsulfonyl)hydrazines, with the potential to function as biological methylating agents, were synthesized and evaluated for antineoplastic activity against the L1210 leukemia and other transplanted rodent tumors. In general, the N-methyl-N,N'-bis(arylsulfonyl)hydrazines that possess the capacity to generate an alkylating species under physiological conditions showed significant antineoplastic activity, while N,N'-bis(phenylsulfonyl)-hydrazine and N-methyl-N,N'-dibenzoylhydrazine were inactive.

A series of (o- and p-nitrobenzyloxycarbonyl)-5-fluorouracil derivatives were synthesized by reacting o- or p-nitrobenzyl chloroformate with 5-fluorouracil in the presence of triethylamine in DMF or Me2SO. The reductive activation of these agents was hypothesized to generate a reactive methide and 5-fluorouracil, two components that are capable of synergistic interaction through complementary inhibition. Measurement of the surviving fractions of EMT6 tumor cells treated with these agents in culture under conditions of hypoxia and aerobiosis resulted in equal cell kill regardless of the state of oxygenation. One of the synthesized agents, 3-(p-nitrobenzyloxycarbonyl)-5-fluorouracil (4), appeared to be superior to 5-fluorouracil in prolonging the survival time of mice bearing intraperitoneal implants of the P388 leukemia and Sarcoma 180.

Several N-2 substituted 1-methyl-1-(4-tolylsulfonyl)hydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. The most active compound to emerge from this study, 2-(methylsulfonyl)-1-methyl-1-(4-tolylsulfonyl)hydrazine, produced maximum percent T/C values with L1210 leukemia and B16 melanoma tumor bearing mice of 207 and 209, respectively. While the attachment of an aryl-, aralkyl-, or alkylsulfonyl moiety to N-2 resulted in retention of activity against both tumor systems, the corresponding benzoyl, 4-nitrobenzoyl, and (2-nitrophenyl)sulfenyl analogues only displayed activity against the L1210 leukemia.

5,6-Dihydro-8(7H)-quinolinone was synthesized and converted into thiosemicarbazones which could be considered to be semirigid analogues of the 2-formylpyridine thiosemicarbazone class of antitumor agents. The Z and E isomers were separated and identified by 1H NMR and UV. Although the compounds showed essentially no inhibitory activity against the enzyme alkaline phosphatase, several of these agents had demonstrable anticancer activity in mice bearing the P388 leukemia. The E-configuration analogues in general were slightly more active than their corresponding Z isomers.

The effects of various structural modifications on the antineoplastic activity of (arylsulfonyl)hydrazones of 4-pyridinecarboxaldehyde were examined in mice bearing either Sarcoma 180 or P388 leukemia. The introduction of different functional groups into the phenyl ring of the benzenesulfonyl moiety did not alter tumor inhibitory activity appreciably, and the pyridine ring could be replaced by 4-nitrobenzene without loss of antineoplastic activity. However, the aldehyde proton and the hydrazone proton alpha to the sulfonyl group were essential, and their substitution resulted in inactive anticancer agents.

A series of (o- and p-nitrobenzyloxycarbonyl)-5-fluorouracil derivatives were synthesized by reacting o- or p-nitrobenzyl chloroformate with 5-fluorouracil in the presence of triethylamine in DMF or Me2SO. The reductive activation of these agents was hypothesized to generate a reactive methide and 5-fluorouracil, two components that are capable of synergistic interaction through complementary inhibition. Measurement of the surviving fractions of EMT6 tumor cells treated with these agents in culture under conditions of hypoxia and aerobiosis resulted in equal cell kill regardless of the state of oxygenation. One of the synthesized agents, 3-(p-nitrobenzyloxycarbonyl)-5-fluorouracil (4), appeared to be superior to 5-fluorouracil in prolonging the survival time of mice bearing intraperitoneal implants of the P388 leukemia and Sarcoma 180.

Several N,N'-bis(arylsulfonyl)hydrazines, with the potential to function as biological methylating agents, were synthesized and evaluated for antineoplastic activity against the L1210 leukemia and other transplanted rodent tumors. In general, the N-methyl-N,N'-bis(arylsulfonyl)hydrazines that possess the capacity to generate an alkylating species under physiological conditions showed significant antineoplastic activity, while N,N'-bis(phenylsulfonyl)-hydrazine and N-methyl-N,N'-dibenzoylhydrazine were inactive.

Die Chlormethylierung von 2,3-Dimethyl-hydrochinondimethylather (I) liefert die beiden Chlormethylverbindungen (IIa) und (IIIa), aus denen die Acetoxymethyl-Verbindungen (IIb) und (IIIb) und das Diol (IIIc) zuganglich sind.