The steroid sex hormones are known to exhibit a multiplicity of physiological activities. In addition to their primary hormonal action of stimulating certain responsive tissues to grow or secrete, they show the ability to counteract some of the physiological effects of each other, as well as to inhibit the secretion of protein hormones by the pituitary. Consequently, sex hormones have found use as therapeutic agents for the regulation of endocrine balance and for the inhibition of various types of hormone-dependent cancers.

One limitation in the use of the active sex hormones as chcmotherapeu-tic agents is that the primary hormone action constitutes an undesirable side effect which often restricts the dose level or the duration of the treatment. In an effort to dissociate primary hormonal activity from secondary inhibitory actions, and with the further hope of finding substances more effective against endocrine cancers than the steroids heretofore employed, a number of structurally modified analogues of the active sex hormones have been synthesized and tested for biological activity. Most of these hormone analogues fall into four categories: (1) monofunctional steroids, (2) fluorinated steroids, (3) analogues of stilbestrol and hexestrol, and (4) derivatives of d,l-equilenin obtained by total synthesis.

Monofunctional Steroids

The great majority of the steroid sex hormones possess hydroxyl or ketone functions at two locations in the molecule, positions 3 and 17 in the estrogens and androgens, and positions 3 and 20 in the progestational hormones. In an effort to evaluate the contribution of the individual substituents to the primary hormonal activity of the molecule as compared to their importance in the secondary physiological activities, a number of steroids were prepared in which the oxygenated function at one or the other of the two critical positions is missing.

Of the 27 monofunctional steroids synthesized for physiological testing (Table 4), 14 were novel at the time of their preparation. These include substances in which the oxygen function has been replaced either by hydrogen or by an alkyl group. Compounds in which a hydroxyl group is replaced by fluorine are discussed below.

Table 4. Monofunctional Steroids

Many of these substances were prepared by the removal of a carbonyl group, either by Wolff-Kishner reduction or by desulfurization of the corresponding ethylene dithioketal, followed by appropriate standard transformations to obtain the desired compound. The 3-deoxyestrogens were prepared by the Raney nickel reduction of the phenolic p-toluene-sulfonate esters. The 3-methyl steroids were prepared by the addition of methyl magnesium iodide to the 3-ketosteroid followed by dehydration of the mixture of carbinols and hydrogenation of the resulting double bond.