IT. CHEMISTRY 491 



the oily li(iiiid (//-acetate originally proposed,^' 1 mg. of which was one 

 international unit (I.U.)- In terms of this unit, the biological equivalents 

 of (//-a-tocopherol, d-a-tocopherol, and c?-a-tocopheryl acetate are 0.68, 

 0.92, and 1.36 I.U. per milligram, respectively .^^ 



Sul)stitution of etliyl for one or two methyl groups lessened the activity 

 slightly, but compounds obtained l)}^ replacement of the two o-methyl 

 groups (7, 8) in a-tocopherol by tri- or tetramethylene rings were inactive 

 in 50-mg. doses. ^'^ When the 2-methyl group was replaced by an ethyl or a 

 propyl group, biological activity was slightly reduced.**"* Of several methoxy- 

 tocols, only the 5 , 7-dimethyl-8-methoxy tocols had any biological activity 

 (60 mg. was completely protective), and this was less than that of 5,7- 

 dimethyltocol.^^ 



The character of the side chain is highly specific; reduction of the number 

 of isoprene units, even by one, is inactivating, but the four units may be of 

 natural or S3'nthetic origin; the asymmetry of the phytol residue is unim- 

 portant.*^ 



An aminotocopherol (NHo in place of OH) was biologically equivalent 

 to the hydroxyl-containing compound,*^ w^hether as such or after biological 

 replacement is not knowni. Methyl and ethyl ethers and the allophanates 

 are inactive. ^^ 



A naphthotocopherol obtained as a by-product in the synthesis of vita- 

 min K has the biological properties of both the vitamins, the adequate rat 

 dose exceeding that of jS-tocopherol.^^' ^^ 



Many of the compounds described in the comprehensive review of vita- 

 min E (up to 1940)^° were demonstrated to have biological activity in 

 massive doses, 50 to 100 mg.^^ Not only are such amounts unphysiological, 

 but the results may be suspect, because the control of the bioassay was 

 inadequate according to present practice. Recently some of these com- 

 pounds were shown to be inactive biologically. ^- 



*i E. M. Hume, Xature 148, 472 (1941); Quart. Bull. Health Organisation League Na- 

 tions 9, 436 (1940-1941). 

 8= P. L. Harris and M. I. Ludvvig, /. Biol. Chem. 179, 1111 (1949); 180, 611 (1949). 

 83 P. Karrer and A. Kugler, Helv. Chim. Acta 28, 436 (1945). 

 8< P. Karrer and H. Stahelin, Helv. Chim. Acta 28, 438 (1945). 

 85 P. Karrer and K. Diirr, Helv. Chim. Acta 32, 1361 (1949). 

 8« P. Karrer and H. Rentschler, Helv. Chim. Acta 26, 1750 (1943). 

 8' L. I. Smith, W. B. Renfrew, and J. W. Opie, ./. Am. Chem. Sac. 64, 1082 (1942). 



88 M. Tishler, L. F. Fieser, and N. L. Wendier, J. Am. Chem. Soc. 62, 1982 (1940). 



89 M. Tishler and H. M. Evans, J. Biol. Chem. 139, 241 (1941). 

 »« L. I. Smith, Chem. Revs. 27, 287 (1940). 



9' H. M. Evans, O. H. Emerson, G. A. Emerson, L. I. Smith, R. E. Ungnade, W. W. 



Prichard, F. L. Austin, H. H. Hoehn, J. W. Opie, and S. Wawzonek, ./. Org. Chem. 



4, 376 (1939). 

 '2 P. D. Boyer, M. Rabinovitz, and E. Liebe, /. Biol. Chem. 192, 95 (1951). 



