578 NEW AND UNIDENTIFIED GROWTH FACTORS 



out. Reports during the past year have been issued from f he Lederle Labor- 

 atories^^"^^ and jointly from the universities of Texas and Ilhnois and the 

 Eh Lilly Laboratories.^"'^^ These all point to the lipoic acids as a family of di- 

 thiooctanoic acids and their derivatives. The first synthesis of a pure com- 

 pound with lipoic acid activity was carried out by the Lederle group, who 

 prepared the cyclic 6,8-dithiooctanoic acid, which they called 6-thioctic 

 acid.^^ This was accomplished by condensing ethyl adipyl chloride with 

 ethylene to yield A^ , 6-ketooctenoate, and converting the latter in consecu- 

 tive steps to 8-thiol-6-hydroxyoctanoic acid (with thioacetic acid), 6,8- 

 dithioloctanoic acid (thiourea in HI), and finally the cyclic disulfide (l2in 

 KI). The product was confirmed as being identical with protogen A, after 

 earlier work had suggested the 5,8 ring structure for the factor. ^^ Syn- 

 thetic DL-6-thioctic acid appeared from the tabular data presented^^ to be 

 roughly half as active in pyruvate oxidation as the isolated lipoic acid of 

 Reed et al}^ Protogen B(/3-lipoic acid) may be presumed to be the corre- 

 sponding (mono) sulf oxide. ^^' ^^- ^^ This structure appears consistent with 

 the observed transformations (protogen A — > protogen B) during isolation, 

 and with the properties of the two compounds. 



The need for lipoic acid for the oxidation or dismutation of pyruvate 

 places this catalyst in the same particular area of metabolism as diphos- 

 phothiamine (DPT) and coenzyme A (CoA). The precise enzymatic role of 

 lipoic acid has not yet been determined, although important indications 

 were provided by the findings^®"^^ that "hpothiamide" (LT) and "lipothia- 



1" E. L. Patterson, J. A. Brockman, Jr., F. P. Day, J. V. Pierce, M. E. Macchi, C. E. 



Hoffmann, C. T. O. Fong, E. L. R. Stokstad, and T. H. Jukes, ./. .4w. Chem. Soc. 



73, 5919 (1951). 

 " J. A. Brockman, Jr., E. L. R. Stokstad, E. L. Patterson, J. V. Pierce, M. Macchi, 



and F. P. Day, J. Am. Chem. Soc. 74, 1868 (1952). 



18 M. W. Bullock, J. A. Brockman, Jr., E. L. Patterson, J. V. Pierce, and E. L. R. 

 Stokstad, /. Am. Chem. Soc. 74, 1868 (1952). 



19 M. W. Bullock, J. A. Brockman, Jr., E. L. Patterson, J. V. Pierce and E. L. R. 

 Stokstad, /. Am. Chem. Soc. 74, 3455 (1952). 



2" L. J. Reed, B. G. De Busk, I. C. Gunsalus, and G. H. F. Schnakenberg, J. Am. 

 Chem. Soc. 73, 5920 (1951). 



21 C. S. Hornberger, Jr., R. F. Heitmiller, I. C. Gunsalus, G. H. F. Schnakenberg 

 and L. J. Reed, /. Am. Chem. Soc. 74, 2.382 (1952). 



22 L. J. Reed, Q. F. Soper, G. H. F. Schnakenberg, S. F. Kern, H. Boaz, and I. C. 

 Gunsalus, /. Am. Chem. Soc. 74, 2383 (1952). 



23 L. J. Reed, I. C. Gunsalus, G. H. F. Schnakenl)erg, Q. F. Soper, H. E. Boaz, S. F. 

 Kern, and T. V. Parke, /. Am. Chem. Soc. 75, 1267 (1953). 



24L. J. Reed, B. G. DeBusk, C. S. Hornberger, Jr. and I. C. Gunsalus, ./. Am. 



Chem. Soc. 75, 1271 (1953). 

 25 C. S. HornbergcM-, Jr., R. F. Heitmiller, I. C. Gunsalus, G. H. F. Schnakenberg, 



and L. J. Reed, J. Am. Chem. Soc. 75, 1273 (19.53). 

 •^8 L. J. Reed and B. G. De Busk, ./. Am. Chew. Soc. 74, 3457 (1952). 



