400 Colchicine 



workers, that happened to be widely separated by the e\ents of the 

 second World War. lire similar conclusions which were reached have 

 thus an added significance. The names of Gavaudan (Marseille, 

 France), ^i- *•■ Schmuck (U.S.S.R.) ,i^"- 1""' i""' and Levan and Oster- 

 Ostergren (Lund, Sweden) ""• "^- "^- •'- should be mentioned at this 

 point, lliis work began with the search for some i^olyploidizing agent 

 more eflfecti\e than colchicine and led to an intensive study of chemi- 

 cals and of the relation between their structure and their activity. One 

 of the first sulxstances demonstrated to be eflfcctive for the induction of 

 polyploidy in plants was acenaptJiene (I) . 1 his was discovered in 

 1938,i"'' '^•^- "•'■ -^^ and the simplicity of its chemical structure, ap- 

 parently without any relation to that of colchicine, quite naturally 

 led other authors to investigate various aromatic derivatives. 



In the following years, haloid derivatives of acenaphthene were 

 also found to be effective c-mitotic poisons, as well as later haloid 

 derivatives of other aromatic compounds, "i- ^'- i'-^- ^^^ and various de- 

 rivatives of benzene and naphthalene. All of these were soluble in 

 lipids and, contrary to colchicine, had low water solubility. In 

 France, mairy mono-substituted derivatives of benzene and naphtha- 

 lene were tested by the Gavaudans on Triticutn. This extensive work 

 can only be briefly reviewed here. It appeared that, Avhile benzene 

 was only weakly active, it was necessary only to add some side-chains 

 to obtain effective c-mitotic poisons. One exception was hexamethyl- 

 henzene, the inactivity of which was linked with its high degree of 

 symmetry. Nitro- and halo-derivatives of benzene and naphthalene 

 were studied, and many found to be mitotic ])oisons. Ho\\e\er, total 

 inactivation of the spindle was not always observed, and partial c- 

 mitosis (mero-stathmokinesis) or abnormalities of spindle (jricniation 

 (tropokinesis) were often the only cellular changes. C-mitosis was 

 also observed under the influence of anesthetic drugs, such as phenyl- 

 urethane, acetophenone, or anesthesine.^^- ^-^ 



It soon became evident that no definite chemical structure was 

 necessary, but that nearly all aromatic derivatives were c-mitotic 

 poisons under proper experimental conditions, except those Avith a 

 carboxyl, for instance, benzoic acid, or an amino-group. It ^^•as e\ i- 

 dent that an increased solubility in water was unfavorable for spindle 

 poisoning. More recently, however, amino-acenaplitJieue was demon- 

 strated to be a spindle poison for fibroblasts in tissue culture.''*'^- ^'^ 



In 1944, the French authors linked their observations with Fer- 

 guson's notion of tliennodynamic activity, which expressed the tend- 

 ency of a given substance to escape from the ])hase in which it is dis- 

 solved. It can be measured by the relation between the lowest active 

 concentrations of a sufjstance and its highest solubility in water. The 

 conclusion was reached that with only a few exceptions, all the chemi- 

 cals which had proved to arrest spindle activity acted like chemically 



