ANTIMITOTIC ACTIONS 533 



summarized in Table 5-8. Compounds III and IV are at least 100 times 

 more potent than the others and one must concede the marked structural 

 requirements and the inactivating effects of certain groups; e. g., the losses 

 of activity when a 2-methyl group is substituted for a 2-hydroxy group, 

 or methyl groups are put on the mercaptoacetic side chains, or these side 

 chains are slightly lengthened. Compounds III and IV cause metaphase 

 accumulation at low concentrations and simultaneously produce cell edema 

 and occasionally cytolysis. Compound VII actually accelerates mitosis, 

 while it has no effect on the phase distribution and does not produce 

 mitotic abnormalities. It is interesting to note that the addition of the 

 mercaptoacetic group to lawsone to give Compound III increases the po- 

 tency well over 100-fold. 



One must consider several possibilities in attempting to interpret the 

 results of such studies. (1) The compounds are unstable within the cell and 

 split off the mercaptoacetic group to form the active parent quinone. This 

 explanation is very unlikely for several reasons: as far as is known these 

 groups are not easily split off, it is difficult to understand why Compound 

 III is more potent than lawsone, and it is not clear why Compound I is not 

 the most active since removal of the mercaptoacetic group would produce 

 the active 1,4-naphthoquinone. (2) The compounds such as III and IV 

 are directly active. If this is so, one might propose that the quinones enter 

 the cells and form toxic conjugates with soluble thiols, an interesting pos- 

 sibility for which there is no experimental evidence. (3) These compounds 

 may be metabolized to toxic products within the cells. It is known that the 

 mercaptoacetic derivatives are easily oxidized to sulfoxides (Friedmann 

 and Simon-Reuss, 1956 b). The conjugates with mercaptoacetate and other 

 thiols are thioethers, and the actions of certain thioethers (e. g. ethionine) 

 are antagonized by other thioethers (e. g. methionine). It was found that 

 the mitotic inhibition produced by Compound IV could be effectively 

 counteracted by methionine. Methionine forms an energy-rich complex 

 with adenosine (/S-adenylmethionine) and it was suggested that the sul- 



+ coo 



CH— CHOH)j— CHCHj— S— CHjCHj— CH^ 

 O O I O 1 CH3 



Sulfoxide of Compound in S -Adenylmethionine 



foxides of Compounds III and IV might compete with this onium complex, 

 possibly to interfere with methyl transfers. If this were true, it would 

 be an entirely new type of action unassociated with the quinone structure, 

 and would explain the actions of the quinones only if thiol conjugates 



