E. Kendall
Jun 1, 1949
Citations
0
Influential Citations
17
Citations
Journal
Annals of the New York Academy of Sciences
Abstract
It is just ten years since Steiger and Reichsteinl prepared desoxycorticosterone by partial synthesis. It is fortunate that the yield of this steroid and the supply of starting material were sufficient to permit preparation of large amounts of this hormone so that its physiological activity could be determined both in experimental animals and in patients who had Addison's disease. These studies soon indicated that, although there was a marked effect on the metabolism of sodium, potassium, chloride, and water, desoxycorticosterone produced but little effect on the metabolism of fat, carbohydrate, and protein. It did not markedly increase the resistance of animals to stress, toxic compounds, and infections. There was a wide discrepancy between the physiological effect of extracts of the adrenal cortex and that of desoxycorticosterone. At the same time, it was shown that the crystalline hormones of the adrenal cortex with an atom of oxygen a t Cll, in experimental animals, did influence the metabolism of fat, carbohydrate, and protein, and also increased the resistance to stress, toxic compounds, and infections. However, the amounts of material available were insufficient to extend these observations to a clinical study of patients who had Addison's disease. I n 1940, since it seemed probable that the hormones of the adrenal cortex would be useful therapeutic agents in the treatment of shock and trauma encountered in military operations, several laboratories throughout the world started investigations with the objective of preparing these hormones by partial synthesis. A survey of available starting material indicated that plant steroids could not readily be used, since oxygen could not be added a t Cll. However, the bile acids provided a source of steroids which theoretically could be rearranged with an atom of oxygen a t Cn. Desoxycholic acid appeared to be a practical starting material, and experience has shown that this conclusion was correct. The conversion of desoxycholic acid to hormones of the adrenal cortex involves four changes, each one of which is composed of from two to twelve steps. These changes are: (1) introduction of oxygen at C11; (2) removal of the side chain a t Czo; ( 3 ) elaboration of the ketol group a t Czo:Czl; and (4) formation of an unsaturated ketone in ring A. The sequence of the steps which have been used in the conversion of desoxycholic acid to the hormones of the adrenal cortex is as follows: I n the preparation of dehydrocorticosterone, Lardon and Reichstein2 (1) removed the side chain; ( 2 ) introduced oxygen a t Cll; (3) elaborated the ketol group a t Czo,:Czl; and (4) formed a double bond ketone in ring A. Von Euw, Lardon, and Rei~hstein,~ in the partial synthesis of corticosterone, (1) reDiz'isiolt of Biochemistry, M a y o Foundation, Zocliester, Minnesota