Steroid Transformations 123 



In 1949, Hench et al. (10) observed the dramatic clinical 

 effects of cortisone (VIII), and later hydrocortisone (IX), 

 in the treatment of rheumatoid arthritis. These observa- 

 tions opened the way for one of the most fascinating epi- 

 sodes in the history of medicine and chemistry. The inten- 

 sive and widespread study that followed was surpassed only 

 by the investigations on penicillin. Although the brilliant 

 work of the organic chemist played an important role in 

 this development, the work reported here on the cortisone 

 and hydrocortisone problem is restricted to the microbio- 

 logical aspects. 



Clinicians were able to show that the 11 -oxygen atom 

 in cortisone (VIII) and hydrocortisone (IX) was essential 

 for the biological activity in the treatment of this disease.^ 

 Unfortunately, chemical introduction of an oxygen atom 

 at position 1 1 in the steroid nucleus is effected only with 

 great difficulty. In early chemical work, desoxycholic acid 

 (X) from cattle bile was used to make cortisone (VIII), 



IX 



Hydrocortisone 



and it required approximately ten chemical steps to shift 

 the oxygen from position 12 to 11. A total of approxi- 

 mately 37 steps was required to make cortisone from this 

 bile acid. 



The major problem, however, was that of introducing 

 oxygen at carbon 1 1 . This necessarily meant that the cost 



2 The structures of cortisone (VIII) and hydrocortisone (IX) are identical 

 except that cortisone contains an 11-keto group, and hydrocortisone an 

 llp-hydroxyl group. A solid line indicates a p-hydroxyl group lying on 

 a plane facing the reader; a dotted line indicates an a-hydroxyl group 

 lying behind the molecule. The lla-hydroxy epimer epihydrocortisone 

 (XV) is biologically inactive by the rat liver glycogen assay. (5, 27) 



