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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Purified adenosine kinase from L1210 cells displayed substrate inhibition by high concentrations of adenosine (Ado), ATP, and MgCl2. When incubated with ATP and MgCl2, the enzyme was phosphorylated, and the phosphorylated kinase transferred phosphate to adenosine in the absence of ATP and MgCl2. Substrate binding, isotope exchange, and kinetic studies suggested that the enzyme catalyzes the reaction by means of a two-site ping-pong mechanism with the phosphorylated enzyme as an obligatory intermediate. Among many possible pathways within this mechanism probably a random-bi ordered-bi route is the preferred sequence in which the two substrates, adenosine and MgATP, bind in a random order to form the ternary complex MgATP . E . Ado followed by the sequential dissociation of MgADP and AMP. Dissociation constants of various enzyme-substrate and enzyme-product complexes and the first-order rate constant of the rate-limiting step were estimated.

Several nitrosoureidonucleosides (9a, 9b, 11a, 11b, 18 and 20) designed as inhibitors of enzymes that metabolize purine and pyrimidine nucleotides have been prepared and their chemical and biological properties studied. The low level of biological activity observed may be due to the unexpected stability of these nitrosoureas compared to biologically active compounds such as N-methyl-N-nitrosourea (MNU), N,N'-bis(2-chloroethyl)-N'-nitrosourea (BCNU), and N,N'-dicyclohexyl-N-nitrosourea (DCyNU).

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