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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.

The preparation of 16β-piperidino- and -morpholino-17-ketones of C18- and C19-steroids from 16α-bromo-17-ketones is described; reduction gives the corresponding cis-16β-amino-17β-ol the structure of which is confirmed by preparation from the trans-16α-bromo-17β-ol and by infrared spectroscopy. trans-16-Amino-17ols were prepared from cis-16-bromo-17-ols and a 16α,17α-epoxide.

The very rapid progress which has been made recently in the chemistry of the œstrogenic hormones, of which an excellent has been given by Girard (1933) has established that these substances are hydrogenated phenanthrene derivatives containing oxygen in the molecule ( cf . Butenandt, Weidlich, and Thompson, 1933). On the assumption of a biological relationship between these hormones and the sterols and bile acids, an assumption which seems justifiable, although it cannot yet be regarded as rigidly proved, œstrone (= ketohydroxyœstratriene) is probably represented by formula I or II. The present communication describes the examination for œstrogenic properties of a number of condensed carbon-ring compounds of somewhat analogous structure in an attempt to elucidate the molecular conditions necessary for œstrogenic activity. A preliminary account of some of these experiments has already been given (cook, Dodds, and Hewett, 1933; cook and Dodds, 1933). Our investigations have brought to light a number of pure synthetic compounds, of known molecular structure, which show this physiological activity, and in some of the compounds studied the activity is of a very high order. It will be observed that one of two oxygen atoms in œstrone is ketonic and the other hydroxylic. Girard (1933) has suggested that these two types of oxygen-containing groups are biologically equivalent, and our own experiments group but no hydroxyl group, whereas others contain only hydroxyl groups in a similar type of molecule.

Condensation of 2α,3α- and 2β,3β-epoxy-5α-androstanes with secondary cyclic amines gives 2β-amino-3α-ols and 3α-amino-2β-ols respectively; reaction of a 2β-bromo-3α-hydroxy-5α-androstane with the same cyclic amines gives the 2α,3α-epoxide in contrast to the 3α-bromo-2β-hydroxy-isomer, which undergoes substitution without inversion to give the corresponding 3α-amino-2β-ol. The mechanisms of these reactions are discussed. The preparation of 2-morpholino-5α-androst-1-ene-3,17-dione is also described.

Condensation of a 17β-acetoxy-16α,17α-epoxy-5α-androstane with morpholine yields a 17β-morpholino-16-ketone as the major product, contaminated with some isomeric 16β-morpholino-17-ketone; in the presence of water the condensation yields the latter isomer as the major product. An intermediate in these reactions was shown to be a 16α-hydroxy-17-ketone. The mechanisms of these reactions are discussed and also those of the condensations of 16α-acetoxy-17-ketone, 17β-acetoxy-16-ketone, and 17β-hydroxy-16-ketone systems with morpholine to give 16β-morpholino-17-ketones.

IN conformity with the hypothesis, for which there is at present no experimental basis, that the ovarian hormones are formed by degradation of sterols, and in the light of recent developments in the chemistry of the sterols, ketohydroxy-oestrin is possibly represented by formula (i).

THE nature of the cancer-producing constituent (or constituents) of coal tar has been under investigation in this and other laboratories for some years past, but hitherto no known constituent of tar has been found to have definite cancer-producing properties, and no new carcinogenic constituent has been isolated. The isolation has now been accomplished by concentrating active fractions of coal-tar pitch, making use of the method of fluorescence spectroscopy introduced here by W. V. Mayneord. This brought to light a spectrum which was found to be common to many carcinogenic mixtures.1 The methods adopted have included fractional distillation, solvent extraction, and crystallisation of picrates and of the products of their decomposition with alkali.

Condensation of 3β-acetoxy-5α,6α-epoxy-androstanes and -pregnanes with ammonia and primary and secondary amines, and subsequent alkaline hydrolysis, gives 6β-amino-3β,5α-dihydroxy-steroids; water catalyses the epoxide cleavage. When condensation with ammonia is carried out in aqueous dioxan solution a 6β-acetamido-5α-hydroxy-steroid is obtained. Condensation of a mixture of 5α,6α- and 5β,6β-epoxides with aqueous morpholine at 115° gives the cleavage product of the α-oxide only and the β-oxide is recovered unchanged. Condensation of 5β,6β-epoxy-3β-hydroxyandrostan-17-one with piperidine and morpholine at 190° gives abnormal ring opening to the diequatorial 6α-amino-3β,5β-dihydroxyandrostan-17-one, the infrared spectra of which show intramolecular hydrogen bonding between the 3β-hydroxyl group and the oxygen atom of the 5β-hydroxyl group, which in turn bonds to the 6α-nitrogen atom. Oxidation of 3β,5α-dihydroxy-6β-piperidinoandrostan-17-one or the 5β,6α-epimer, and subsequent dehydration of the product, gives 6α-piperidinoandrost-4-ene-3,17-dione.