In other studies, we tried to introduce sulfur into the fatty acid molecule, this time changing the polar group itself. With the sulfhydryl replacing the hydroxyl of the carboxyl group, a bivalent negative sulfur was introduced, thus realizing a thionic group. (R COSH)

We prepared several members of this thionic acid series corresponding to various saturated, polyunsaturated and even conjugated fatty acids. We studied in particular the effect of hexylthionic acid, corresponding to caproic acid. The results observed were essentially the same as those seen with the other bivalent sulfur containing lipoids mentioned previously. In addition to influencing pain and systemic changes, hexylthionic acid produced some interesting effects upon experimental tumors, reducing the growth of a few of them. However, there were no important differences from the effects of the other sulfolipoids.

Another entire series of products was prepared by introducing a thiol group at the C2, or alpha position, of various fatty acids, with the intention of creating a more complex polar group similar to that present in alpha hydroxy or alpha amino compounds. Alpha thio fatty acids were thus obtained for the entire homologous series of saturated, and for many of the nonsaturated, fatty acids. Some members of this series of alpha thio fatty acids, such as caproic, caprylic and myristic, were studied extensively both in animals and humans. From the biological point of view, however, they showed no manifest differences over the thiolipoids previously discussed.

Thioglycolic Series

All these researches with limited biological results brought us to the study of lipoids in which the thiol represents a polar group but in which a secondary polar center is present in the molecule. Many such synthetic thiolipoids were prepared in our laboratory with the hope that they would prove biologically more effective and would have alkylating activity as well. Two series appeared to be interesting, since they were being active particularly at lower levels of organization. This led us to utilize them also on a larger scale in clinical work. While consistent results were obtained on pain and systemic changes, the influence upon animal tumors was erratic and no different from that of other preparations with thiol groups or the sulfur compounds mentioned above. There were marked effects in some animals with tumors; in others with the same tumor treated identically, there were no effects at all. In humans the effects on pain, tissular, organic and systemic levels were similar to those of many other sulfolipoids.

Starting with these substances, derivatives were prepared. One group comprised derivatives with a special character. In order to have only one active polar group, one of the two polar groups had to be blocked. For thioglycolic acid which we studied, either the thiol or the carboxyl group could be blocked, leaving the uncombined radical as the active polar group. Since we were interested in substances having the thiol group as active polar radical, the carboxyl group was blocked by replacing its hydrogen with a methyl group. Methylthioglycolate has been thoroughly studied in our laboratory. Its pharmocological activity is similar to that of the other thiol preparations mentioned above.

Other thioglycolate esters with ethyl, propyl or butyl instead of methyl, were prepared and studied but showed no advantage over the methyl ester. We tried to obtain the allyl ester in order to have a more potent secondary center but we were unable to synthesize it.

In the same group of agents we studied another substance, beta mer captopropanoic acid, having a thiol and a carboxyl as polar groups. Used uncombined, it could be seen that here again, as with thioglycolic acid, it is the carboxyl that acts as active polar group while the thiol acts as a secondary energetic center at the nonpolar group. This acid is very toxic in animals, producing as a peculiar effect, manifest muscular spasms. The compound also produced abnormal muscular rigidity, seen immediately after death. In nontoxic doses, it showed a marked influence upon tumor growth. Many tumors disappeared; in many others, a reduction in size occurred. Impressive results were obtained in spontaneous mammary carcinoma in mice where a fairly high proportion of tumors disappeared (28/ 40). Repeated injections into these animals gave good results if the growth was slow enough to permit treatment for a period of at least a month. The preparation, however, showed toxic effects in animals with tumors, producing weight loss similar to that produced by the thioglycolic series. To change the polar group and have the thiol act as such, we blocked the carboxyl with a methyl in some experiments and with an allyl group in others. But the influence upon tumors in animals was reduced through these changes.