408 



Colchicine 



66 



colchicine have also proved to be without action against neoplasms. 



It is premature to discuss the reasons for the weak activity of the 

 iso- compounds. One reason which has been jnit forward is the forma- 

 tion of hydrogen bonds between the side-chains of ring C and ring B, 

 because of the closeness of the methyl groups of these chains in the 

 iso- forms. (VII) It has been suggested that the weak antimitotic 

 activity of colchiceine may be the consequence of the iso- form of this 

 molecule.*'-^ Other data prove that the activity of colchicine on mitosis 

 is related to both these side-chains. 



The substances to be studied now can all be considered as de- 

 rivatives of trimeUiylcokhicinic acid (III) . This compound was dem- 

 onstrated in some of the first work on colchicine derivatives and 

 mitotic cells in mammals, to be inactive. In cultures of fibroblasts 

 and of neoplastic cells also, no activity could be detected (Table 



17.1).^^ 



Substitution on ring B alone does not yield effective mitotic poi- 

 sons. On tissue cultuies, Is-acetyl-colchicol and its methyl ether (VIII) 

 have only slight activity. Tables 17.1 and 17.2 give further evidence 



TABLE 17.1 

 LD 50's OF Colchicine Derivatives in mg kg 

 (After Goldberg et al.**) 



* TMCA = trimethvlcolchicinic acid. 



of this. I he activity of this derivative is comparable to that of col- 

 chiceine. 



However, when ring C remains as in colchicine, it is evident that 

 A^-substitution in ring B is not of great importance for activity. In 

 tissue cultures, desacetylcolchicine, trimetliyh olchicinic acid methyl 

 ether (IX) , is an effective spindle poison, while the parent substance, 

 desacetylcolchiceine (=TMCA) , is almost inactive. N-betizoyl-tri- 



