SEMI-RIGID CONJUGATED POLYENES AS MODEL ANTICARCINOGENS

点击翻译按钮获取中文摘要

Beta-Carotene is a ubiquitous plant polyene and a normal component of the human diet. It has been established in several epidemiological studies to be a potent protective agent against lung cancer, among other forms. The long-range goal of this project is the creation of more effective anticarcinogens of the fat-soluble polyene type. The near-range goal is a chemical mechanism for the anticarinogenticity of beta-carotene that may serve as the rational basis for achieving the long-range goal. In general, substituents on a double bond (ene) are arranged in cis or trans forms (isomers) that can suffer cis-trans interconversion on being heated. In this process, a diradical exists fleetingly at the half-way stage. But for its far too short lifetime, the diradical would function as a very effective trap for the free radicals that are now widely accepted to be major contributors to aging, mutagenesis and carcinogenesis. As the number of double bonds joined together increases in polyenes, the number of cis-trans isomers increases as 2n and cis-trans interconversion occurs more rapidly and at lower temperatures. Beta-Carotene, a polyene of eleven double bonds, has in theory 256 isomer, but is commonly available as all-trans beta-carotene. A specific goal is to discover at how low a temperature the many cis, trans forms of beta-carotene can be interconverted. If these changes can occur at physiological temperature, then one (or more) of the cis beta-carotenes, and not the all-trans isomer, as is generally believed, may be their true anticarcinogenic agent. If they occur at even lower temperature, the fleeting diradicals may take on a life of their own in the membrane of a cell and serve as highly effective traps for free radicals. The immediate goal is the synthesis of semi-rigid polyenes with seven and nine double bonds, the study of kinetics of their cis-trans interconversion and the determination of their thermochemistries by heat of hydrogenations with a view to bridging the gap between the well-studied systems with three and five double bonds and the beta-carotenes with eleven. Three results can be expected: a much more precise estimate of the accessibility of the critical diradical trapping capabilities of beta-carotene; a testing of the hypothesis that all-trans beta-carotene may be isomerizing to cis isomers at body temperature; and, depending on the outcome, an alert to investigate the question of which isomer or isomers are in fact the active anticarcinogenic agents. A second goal is to facilitate the testing of the known cis isomers of beta-carotene.