322 2. MALE ATE 



EFFECTS ON MITOSIS AND GROWTH 



Many naphthoquinones are potent antimitotic agents and react readily 

 with thiols. Friedmann et al. (1948 a) reasoned that since many of the 

 chemical properties of the naphthoquinones relate to the nonbenzenoid 

 part of the molecule, the antimitotic activity might also, and so they inves- 

 tigated maleate (which is 1,4-naphthoquinone with the benzene ring re- 

 placed by two hydroxylate groups), using chick fibroblast cultures. The 

 shift in the phase distribution produced by 0.002 mM maleate (see ac- 

 companying tabulation) points to a metaphase-type inhibition. This is 



substantiated by the cytological changes observed: clumped metaphases, 

 fragmentation of chromosomes, undivided telophases, and, in higher con- 

 centrations, exploded cells. There is a linear relationship between log(in- 

 hibition) and log(maleate), 50% inhibition being given by 0.0005 raM. 

 The potency of maleate here is remarkably high and it is difficult to at- 

 tribute the antimitotic action to an effect on enzymes or metabolism. 



o o o 



II II II 



CH O CH O C 



II II II 



C X^ ^C^ 



II II 



o o 



« 



\~. ~ Maleate Citraconate 



quinone 



Fumarate produces some abnormal cells but does not inhibit mitosis, while 

 methylmaleate (citraconate) and methylfumarate (mesaconate) are com- 

 pletely inactive, indicating effective blocking of the double bond by the 

 methyl group. Is reaction with SH groups involved in the antimitotic ac- 

 tion of maleate? Friedmann et al. (1948 b) prepared and examined the ad- 

 dition compounds of maleate with glutathione, thiolacetate, and cysteine, 

 and showed them to be antimitotic, although less potent than maleate; 

 e. g., maleate is 14 times more active than the product with glutathione. 

 These results are puzzling and seem to argue against an SH group reaction, 



