Peter B. Russell

Studies on analogs of purines and pyrimidines.

A study was begun in these laboratories, in 1942, of the relationship between chemical structure and the ability of certain pyrimidine* derivatives to serve as precursors for or to modify nucleic acid synthesis. Since only brief accounts of small portions of this work have been published to the present paper is to be regarded as a preliminary report of the work as n whole. It was felt that such studies might lead to fundamental knowledge of the roles of pyrimidine and purine bases in growth, and of the part played by folk acid in the synthesis of these bases. It was felt also that new chemotherapeutic agents might be discovered by this means since, it was argued, parasitic tissues in general depend for survival on a more rapid growth, hence a more rapid synthesis of nucleic acid, than that of the host tissues. This argument applies equally well to bacterial, viral, rickettsial, and neoplastic diseases, so that, in a sense, one might say we have been searching for the philosopher’s stone, the universal panacea, of the ancients. A distinct advantage of antipurines and antipyrimidines as chemotherapeutic agents seemed to lie in the fact that the requirements of bacteria, at least, appeared to be qualitatively different from those of mammalian tissues. A considerable number of microorganisms6 were known to require preformed pyrimidines and/or purines for growth, whereas the evidence available a t that time indicated that purine and pyrimidine bases played no role in mammalian nucleic acid synthesis.6 In the interim, of course, it has become known that two purines, adenine7rR and 2,6-diaminop~rine,~ do contribute to the nucleic acid purine of mammalian tissues, and the hypothesis becomes subject to modification on this account. The effect of thymine in nutritional macrocytic anemia, sprue, and pernicious anemialo indicates that some metabolic role may have to be postulated for this pyrimidine base in the face of the studies with isotopically tagged thymine, which indicated only a catabolic elimination and no retention of exogenous thymine.6 It is conceivable that guanine, uracil, and cytosine may have metabolic roles which remain undetected in similar studies because of low turnover rates or for other reasons. The choice of Lactobacillus casei as a model biological system for the study of pyrimidine analogs was based on the known requirement of this microorganism for folk acid and the role of thymine and guanine in the satisfaction of this growth requirement:‘ This allows a study of the activity of each substance in a number of different ways in the same microorganism. TABLE 1 shows the six media used for study and the effects of various substances in each of the media. The media contain thymine or

Effect of Aliphatic Oxime and Isatin Thiosemicarbazones on Vaccinia Infection in the Mouse and in the Rabbit

Summary 1. Serial passage of vaccinia virus intracerebrally in mice treated with isatin thiosemicarbazone results in a gradual diminution in the amount of virus demonstrable in the brain. 2. Treatment with isatin thiosemicarbazone fails to protect rabbits inoculated intracerebrally with vaccinia virus. 3. Aliphatic oxime thiosemicarbazones may be as effective as benzene or heterocyclic derivatives as chemoprophylactic agents against vaccinia virus in mice.

The Virostatic and Virucidal Action of α-Haloacylamides on Vaccinia Virus in Vitro.

Summary Several chloro- and bromoacylamides were demonstrated to inhibit multiplication of the vaccinia virus in chick embryonic tissue. 5-Dichloroamidouracil was found to be inhibitory whereas 5-fluoroacetamidouracil was inactive.