An internally consistent set of evaluations was made of inhibition constants of a large number of a-(A)-formylheteroaromatic thiosemicarbazones against the enzyme ribonucleoside diphosphate reductase (RDR) of human tumor origin (H.Ep.-2 cells) in vitro and as inhibitors of the growth of three mouse neoplasms, L1210 leukemia, sarcoma 180 ascites, and the Lewis lung carcinoma in vivo. The in vivo doses tabulated are those which gave maximum antitumor effect without toxic signs. Of 27 compounds which were highly active inhibitors of RDR (-log C5o > 6.0) 25 were active against one or more mouse tumors in vivo. Of 51 compounds of intermediate activity as inhibitors of RDR [6.0 > (-log C) > 4.0] 33 were active in vivo against one or more experimental neoplasms. Of compounds of low inhibitory activity against RDR (-log C < 4.0) only 2 out of 19 showed in vivo activity. These data affirm the general utility of enzyme studies as one of the guides in designing these drugs. In vitro activities of thiosemicarbazones and their relation to in vivo antitumor results and to toxicity data are discussed. Physicochemical parameters, structure-activity relationships, and enzyme interaction models are explored. The outlook is optimistic for the development of compounds more useful in vivo and as potential candidates as anticancer agents.developed methods of isolation and partial purification of mammalian RDR.27 The RDR system is responsible for the conversion (CDP, UDP, ADP, GDP) -(dCDP, dUDP, dADP, dGDP), respectively, and hence ultimatelv to DNA.The basic work on RDR, especially the highly purified system from Escherichia coli B which is Fe dependent, is described by Reichard.28 This pure enzyme consists of two EtOH CsHioNíS C, , N, S 7 4'-j>C4H96 145-146 MeOH CnHieN^C, , N, S 9 4'-(2-Pyridyl)' 193-194 EtOH CiíHuNsS C, , N, S 10 4',4'-(CH3)2°121-122 EtOH C9H12N4S
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