844 X. THE VITAMIN K GROUP 



7. Chemical Structure of the K Vitamins and Vitamin -K-Like 

 Compounds in Relationship to Biological Activity 



A very large number of substances, other than the natural K vitamins, 

 possess antihemorrhagic activity. Many of these are equally potent, or 

 even more potent than the naturally occurring vitamins. This is be- 

 cause their relative effectiveness seems to be related to their capacity for 

 conversion into 2-methyl-l,4-naphthoquinone in the animal organism. 



A large number of compounds with structures related to that of vitamin 

 K have been investigated to determine their ability to promote prothrom- 

 bin production. This was especially studied by Fieser et al.,^^ who em- 

 ployed a modification of the 18-hour test of Thayer et alJ^''"^ for prothrombin 

 formation in chicks. The minimum amounts necessary to produce an ef- 

 fect comparable with that brought about by 0.3 jug- of 2-methyl-l,4-naph- 

 thoquinone were determined. When no appreciable effect results at a dos- 

 age of 1000 jug- (1 rng.), it is considered that the substance possesses little 

 importance as an antihemorrhagic agent. The effects of variations within 

 each group have been systematically investigated. 



(1) Effect of Substitution of 2-Methyl-l ,4-naphthoquinone in Position 3 



The side chain on position 3 of the naturally occurring K vitamins has 

 been found to be of no value in contributing to prothrombin production, 

 although it is important in augmenting the solubility of these vitamins in 

 organic solvents. In fact, the hydrocarbon side chains in this position re- 

 duce the potency of the vitamins in accordance with the proportion to 

 w^hich they contribute to the increase in molecular weight over that of 

 menadione. 



The greatest biological effectiveness is obtained with menadione. The 

 generally accepted minimal dose of this quinone, using deficient chicks, is 

 0.3 jug.^* By a similar test, the dose of vitamin Ki which gives the same 

 activity is 1 ;ug. Thus, menadione is 3.3 times as active as is vitamin 

 Ki,2' which corresponds to a ratio of activity of 3.8:1 reported by Alm- 

 quist and Klose,^^ one of 2.2:1 by Emmett, Brown, and Kamm,^'' one of 

 2.1:1 by Dam et al.,''^ and finally a ratio of 4:1 given by Ansbacher, Fern- 

 holz, and MacPhillamy.^'' 



The antihemorrhagic effect of a large number of compounds structurally 



" S. A. Thayer, R. W. MoKee, S. B. Binkley, D. W. MacCorquodale, and E. A. Doisy. 

 Proc. Soc. Exptl. Biol. Med., 40, 478-481 (1939). 



^4 S. A. Thayer, R. W. McKee, S. B. Binkley, D. W. MacCorquodale and E. A. Doisy, 

 Proc. Soc. Exptl. Biol. Med., 41, 194-197 (1939). 



^5 H. J. Almquist and A. A. Klose, /. Biol. Chem., 130, 787-789 (1939). 



7« A. D. Emmett, R. A. Brown, and O. Kamm, /. Biol. Chem., 132, 467-468 (1940). 



" S. Ansbacher, E. Fernholz, and H. B. MacPhillamy, Proc. Soc. Exptl. Biol. Med., 42, 

 655-658 (1939). 



