SEMI-RIGID CONJUGATED POLYENES AS MODEL ANTICARCINOGENS

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Beta-Carotene is the naturally occurring polyene emerging as a potent anticarcinogenic agent in the normal human diet. It is presently the object of a large-scale epidemiological study. The long-range goal of this application is the rational creation of more effective anticarcinogens of the fat-soluble polyene type. The specific goal is to test a novel and previously undescribed mechanism by which Beta-carotene acts as an anticancer agent. In essence, Beta-carotene is hypothesized to exist as a stable diradical and, as such, would be eminently suited to trap the free radicals that are widely accepted to be major contributors to aging, mutagenesis, and the development of cancer. The hypothesis finds tentative support in a quantum mechanical theory of polyenes and polyenic radicals, but requires experimental unification before it can guide a pharmacological program. The immediate aim is the examination of polyenes containing five and seven double bonds. They have been selected to bridge the gap between the well-studied polyenes with three double bonds and Beta-carotene with eleven. From their behavior in a thermal rearrangement involving the diradical form, a reliable estimate of the accessibility of the diradical of Beta-carotene will be made. This examination projects the synthesis of eight polyenes of a novel, semi-rigid structure, the determination of their thermochemistry by heat of hydrogenation, and the identification of their related diradicals by kinetic study over a range of temperatures. The quantitative validity of the quantum mechanical theory will be determined, as will be viability of the new diradical mechanism for the anticancer action of Beta-carotene.