ANTIMITOTIC ACTIONS 531 



(D) Hydroxylation. Both lawsone and juglone are presumably less potent 

 than 1,4-naphthoquinone (this quinone was not tested but is probably of 

 comparable potency to the corresponding hydroquinone), but the addition 

 of a hydroxy group to menadione to form phthiocol somewhat increases 

 the potency, although it weakens the ability to produce metaphase arrest, 

 an effect attributed by Mitchell and Simon-Reuss (1952 b) to the electron- 

 repelling inductive property of the hydroxy group. 2,3-Dihydroxy-l,4- 

 naphthoquinone produces metaphase block but has lost the capacity for 

 inhibiting the entry into prophase. 



(E) Carboxylation. The introduction of carboxyl groups reduces the po- 

 tency somewhat more than do methyl or bromo groups, but the differences 

 are not as much asinight be expected from the increased negative charge.* 

 The 2,3-dicarboxyl-l,4-NQH2-diP type of action resembles that of the di- 

 methyl derivative, although metaphase effects and spindle abnormalities 

 are not so common, indicating either the relative unimportance of these 

 groups in the over-all action, or the oxidation of methyl to carboxyl groups 

 in the cell. 



(F) Cyclic versus acyclic compounds. In discussing structure-action re- 

 lations, one must also consider the early hypothesis of Friedmann et cd. 

 (1948a) that perhaps only the — CO — CH = CH — CO — grouping is respon- 

 sible for the antimitotic effects, since maleate and some related compounds 

 exert effects similar to those discussed above. Maleate at 0.002 mM in- 

 hibits mitoses almost 70% and alters the phase distribution (see page 322), 

 with clumped metaphases, undivided telophases, and chromosomal frag- 

 mentation. The concentration for 50% mitotic inhibition is given as 

 0.0005 mM, so that it is certainly of comparable potency with the quinones. 

 If this hypothesis is valid, it implies that the quinonoid structure is not 

 necessary, the active grouping being the conjugated double-bond system 

 which reacts with SH or other groups in the cell. This problem will be 

 taken up in more detail in the discussion of the possible mechanisms in- 

 volved (page 533). 



Further information on the actions of menadiol-diP may be found in 

 the work of Richard et al. (1954) on fibroblast cultures from embryonic 

 mouse heart. These cells seem to be at least 10 times more sensitive than 

 chick fibroblasts, but the important additional fact emerging is the critical 



* The effects of phosphorylation and carboxylation of the hydroquinones lead to 

 the question whether these compounds must get into the cells or whether they can 

 exert their antimitotic actions on the cell membrane. On the other hand, possibly 

 fibroblasts are not so impermeable to anions as are most cells, or possess mechanisms 

 for the uptake of such substances, either intact or metabolically altered. The surface 

 motility evident in time-lapse studies of fibroblasts in culture may indicate that 

 pinocytosis occurs and accounts for the uptake of these anions. 



