530 5. QUINONES 



duces the activity, sometimes quite markedly. It is interesting to compare 

 the compounds in the following tabulation: 



Concentration (mM) for 

 50% mitotic inhibition 



(I) l,4-NQH2-diP 0.000003 



(II) Menadiol-diP 0.0038 



(III) 3-Methylmenadiol-diP 0.007 



Although (I) is much more potent than (II), it does not exhibit such selec- 

 tivity; (II) produces few mitotic abnormalities and does not alter the phase 

 distribution, whereas (I) causes many abnormalities and metaphase ac- 

 cumulation. Compovmd (III) differs from the others in that it blocks the 

 entrance of the cells into mitosis at higher concentrations, but at very low, 

 not antimitotic, concentrations it causes metaphase accumulation, which 

 increases with the concentration. Compound (III) brings about spindle 

 abnormalities such as are induced by colchicine, and causes marked chro- 

 mosome fragmentation and anaphasic bridging. It was postulated that the 

 two methyl groups sterically hinder the free rotation of the ijhosphate 

 groups, imposing a distance between them comparable to the repeating 

 distan cealong a polypeptide chain. These three substances were compared 

 on cultures of chick osteoblasts by Hughes and Simon-Reuss (1953). Here 

 the basic action of the three is metaphase arrest, due primarily to a fail- 

 ure in the formation of the spindle, or its disorientation if already formed, 

 the chromosomes clumping secondarily. There is no effect on the entry 

 into prophase. All cause cellular edema. After exposure to (I) at 0.000001 

 mM for 6 hr there are a number of binucleate cells, indicating a primary ef- 

 fect on cytoplasmic cleavage mechanisms. That the penetration of such 

 substances into cells is possibly quite slow was pointed out, since some 

 actions appear only after many hours, but it is more likely that such lag 

 periods are dependent on delay in the cellular response. 



(C) Bromination. Introduction of a bromine atom in the 2-position of 

 1,4-naphthoquinone reduces the antimitotic activity much as does a methyl 

 group. MDHg-diP and 2-Br-l,4-NQH2-diP have essentially the same po- 

 tency, but the latter is more toxic and induces metaphase accumulation 

 in a higher concentration range. 3-Methyl-MDII.3-diP and S-Br-MDHg-diP 

 also are equally potent but the patterns of action are somewhat different. 

 As Mitchell and Simon-Eeuss (1952 b) pointed out, the methyl and bromine 

 groups have about the same radii but the inductive effects are different, 

 bromine being more electronegative, so that the differences in action may 

 be related to alterations in the rest of the naphthoquinone structure (e. g., 

 as manifested by different redox potentials or reactivities with thiols). 



