SYNTHESIS, ANTINEOPLASTIC ACTIVITY AND MODE OF ACTION OF NOVEL STYRYL KETONES

The preparation, antineoplastic activities and investigation into the mode of action of some a,13-unsaturated ketones are presented. A number of tumors are known to be more acidic than normal cells and this pH differential can be increased by the administration of glucose. 1-(m-Ethoxymethyloxypheny1)-1-nonen-3-one has been found to increase the mean survival time of mice by 25% in the P388 lymphocytic leukemia screen. The possible active moiety of this compound, 1-(m-hydroxy-pheny1)-1-nonen-3-one,XXIXd, was thought to be released in the acidic milieu of the tumor cell. A series of substituted benzyl ethers of 1-(m-hydroxypheny1)-1-nonen-3-one were developed as prodrugs to release the active moiety, XXIXd, in or near the tumor cells. Three compounds from this series were found not to hydrolyse at three pH levels 7.4, 6.9 or 6.4 which may account for the lack of antineoplastic activity displayed by this series of compounds. The known acid lability of enol and thioenol ethers prompted the attempted synthesis of a series of enol and thioenol ethers of 1-phenyl-1-nonen-3-one and 4-pheny1-3-buten-2-one. The marked instability of 3-ethoxy-l-phenyl-1,3-butadiene indicated that these derivatives were unlikely to be useful prodrugs of conjugated styryl ketones. Reac-tion of 1-phenyl-1-buten-3-one with dimethoxypropane in the presence of zinc chloride, led to the isolation of a compound which was tentatively assigned the structure of 1,7-dipheny1-5-methyl-1,4,6-heptatrien-3-one, principally on the basis of 13 C nuclear magnetic resonance spectroscopy. Prodrugs were developed which could release various hydroxy or polyhydroxy compounds in vivo by enzymatic degradation. Some but not all of these compounds could be converted into the corresponding ortho and para quinones which would be expected to react with cellular nucleophiles. However this series of compounds, although bereft of murine toxicity at the dose level examined, were inactive against P388 lymphocytic leukemia. It is conceivable that alteration in the branching of the alkyl chains might alter the lipophilicity or steric properties and confer antineoplastic activity on a series of l-phenyl-l-alken-3-ones, since 4-methyl-l-phenyl-1-octen-3-one and its 3,4-dichloro analogue displayed antineoplastic activities. This series of compounds was found to be inactive in the P388 lymphocytic leukemia screen. The mode of action of 1-(m-ethoxymethyloxypheny1)-1-nonen-3-one (XXIXa), three related styryl ketones and the Mannich base, 47dimethylaminomethy1-1-(m-hydroxypheny1)-1-nonen-3-one hydrochloride (XXX) was investigated. The antineoplastic activity of the series of styryl ketones was not correlated to inhibition of mitochondrial respira-tion. Compound XXX was shown to be an uncoupler of oxidative phosphorylation at low doses and to block the transportation of electrons between, cytochromes b and c at higher doses. The metabolic route of compound XXIXa was also investigated. The metabolites of this compound were not identified as it was rapidly removed from the blood stream after absorption and possibly distributed to lipophilic tissue where it was retained. A correlation between antineoplastic activity and inhibition of mitochondrial respiration at pH 7.4 was found in a series of Mannich bases. In general this inhibition was greater in the 5123 TCH Morris hepatoma than normal liver tissue and inhibition increased on lowering the pH of the media from 7.4 to 6.9 and 6.4. The mode of action of four hydrazones derived from 4-phenyl-3-buten-2-one was investigated. These compounds had been previously screened for anticancer activity and were tested for inhibition of mitochondrial respiration as well as chelating properties but a correla-tion of antineoplastic activity with these two parameters was not obtained