Chemical Compounds as Carcinogenic Agents

Abstract

Chemical Relationships Group I: Cholanthrene Derivatives The carcinogenic compounds of the cholanthrene group merit separate consideration on account of their chemical relationship to the cholane (bile acid) class of naturally occurring substances. They are, however, of essentially the same type as the benzanthracene derivatives (see p. 222). Methylcholanthrene was prepared independently by Wieland and Dane (125) and by Cook and Haslewood (35) by dehydrogenation of dehydronorcholene, a pentacyclic hydrocarbon obtained in 1925 by Wieland and Schlichting (126) from the bile acid, deoxycholic acid, by simple chemical transformations. The molecular structure of methylcholanthrene was proved by its degradation by Cook and Haslewood (36) to 5:6-dimethyl-1:2-benzanthraquinone, identical with a specimen prepared synthetically by a method which established its constitution. The synthesis of methylcholanthrene by Fieser and Seligman (51) is in complete harmony with this structure, and the conversion of cholic acid into methylcholanthrene has been reported by Fieser and Newman (48). Cholic acid and deoxycholic acid are the two principal acids of human bile, so that in these reactions we have a comparatively simple chemical transformation of important constituents of the human body into a cancer-producing hydrocarbon related in structure to those already known. The interest of these relationships needs no further emphasis. So far it has not been possible to secure evidence that the production in the body of methylcholanthrene or a related compound is an aetiological factor in human cancer. The parent pentacyclic aromatic hydrocarbon, cholanthrene, has also been synthesised, both in London and at Harvard (38, 53). The biological testing of cholanthrene and methylcholanthrene has shown that these two hydrocarbons are carcinogenic agents of greater potency than any compounds hitherto investigated (7, 33, 122). When painted on the skin of mice in 0.3 per cent benzene solution they produce epitheliomas, the first tumours making their appearance after an average period of 70 to 80 days; on subcutaneous injection into rats and mice (results with mice only have been reported with cholanthrene) sarcomas are produced. Tumours are induced by cholanthrene in a comparatively short time, and it appears that the methyl group of methyl-cholanthrene is of no great significance in determining its carcinogenic potency. The essential structural feature is the pentacyclic system in the molecule.