J. S. MITCHELL 



tetra-sodium 2-methyl-l : 4-naphthohydroquinone diphosphate (Com- 

 pound I) by nucleotides, nucleosides, purines and pyrimidines and some 

 other compounds by Mitchell"' in 1950 and 1951. The report by 

 MitchelF has been criticized by Gellhorn and Gagliano^- (1950). 

 Berkmax" (1951, 1953} published clinical results similar to those of 

 Mitchell. Clinical and laboratory studies have been published by 

 Jolles^^ (1952). Experiments on the Ehrlich mouse carcinoma have been 

 described by Dittrich and Schmermund" (1953). An account of six 

 years' clinical studies and attempts at quantitative clinical assessment of 

 Compound I as a radio-sensitizer in the radiotherapy of malignant tumours 

 has been published (Mitchell, 1953). Recently, oxidation-reduction 

 potential and pH measurements have been made m vivo using the Walker rat 

 carcinoma 256 and the Jensen sarcoma to study the effects of oxygen, 

 Synkavit and X-rays alone and in combination (Cater and Phillips 2*5). 



J^ew Compounds 



The attempt to devise compounds which incorporate radioactive atoms and 

 may concentrate in malignant tumours has led to the development of tetra- 

 sodium 6-iodo-2-methyl-l : 4-naphthohydroquinone diphosphate ('6-iodo 

 Synkavit 'j. The synthesis of this compound was carried out by Dr. K.J. M. 

 Andrews, of Roche Products, Welwyn Garden City, by the kind arrange- 

 ment of Dr. A. L. Morrison. The tissue-culture studies made on chick fibro- 

 plasts by Mrs. Simon-Reuss show that as expected the introduction of the iodine 

 atom in the 6-position slightly reduces the activity as measured in terms of the 

 concentration producing 50 per cent mitotic inhibition by a factor of about 1 -5 

 but otherwise produces cytological effects very similar to those of Compound I. 

 The idea which I had of incorporating a ' radio-mimetic ' group and a 

 radio-sensitizer in the same molecule as a related method of improvement 

 upon Synkavit, has led to the development of 2-ethylenimino- 1 : 4-naphtho- 

 quinone. After reading the paper by Domagk, Petersen and Gauss" 

 (1954), this seemed a natural step. 



O 



O 



2-ethylenimino- 1 : 4-naphthoquinone 



The compound 2-ethylenimino- 1 : 4-naphthoquinone and the corre- 

 sponding known open-chain compound 2-^-hydroxyethylamine-l : 4- 

 naphthoquinone (Fieser, L. F. et al'-^, 1948), have been synthesized in this 

 Department by Mr. D. R. Maxwell, with the advice of Dr. D. H. Marrian. 

 Animal experiments in progress using the Walker rat carcinoma suggest 

 that 2-ethylenimino- 1 : 4-naphthoquinone has some action in producing 

 tumour retrogression by itself, in addition to radio-sensitization when used 

 in combination with therapeutic doses of X-rays. The tissue-culture studies 

 by Mrs. Simon-Reuss using chick fibroblasts show that 2-ethylenimino- 1 : 4- 

 naphthoquinone produces 50 per cent mitotic inhibition after 24 hours in 

 concentration approximately 4 X 10^ M with a striking accumulation of 



171 



