Untersuchungen zum cytostatischen Wirkungsmechanismus der Methylhydrazine, III

Abstract

Hydrazine, Natulan (4-[2-methyl-hydiazinomethyl]-N-isopropyl-benzamide) and Azo-Natulan (4-[methylazomethyl]-N-isopropyl-benzamide) inhibit the incorporation of [14C]thymidine and -leucine both "in vitro" and "in vivo" in Ehrlich ascites-turnour cells of the mouse. Furthermore, the incorporation of [14C]uridine is specifically inhibited by Natulan, by dehydrogenated and by demethylated Natulan (4-[hydrazinomethyl]-N-isopropyl-benzamide). This is due to the substituent, N-isopropyl-carbonamide in the p-position on the benzene ring. N-Isoproypl-4-formylbenzamide and 4-hydroxymethyl-N-isopropylbenzamide also inhibit the incorporation of uridine. In the presence of NADPH by liver microsomes, Natulan is split to give formaldehyde. The biosynthesis of proteins in a cell-free system is not inhibited by the hydrazine compounds tested. The degradation product of Natulan, N-isopropyl-4-formyl-benzamide spontaneously reacts with amino acids to produce Schiff bases. The inhibition of leucine incorporation, which is caused by the Natulan group, could result from the removal of amino acids from protein synthesis by this production of Schiff bases. The synthesis of DNA and RNA was affected in the following manner: Hydrazine inhibits the formation of purine-deoxynucleosides. The formaldehyde resulting from the CH3-group of the methyl-hydrazine inhibits the formation of the di- and tri-phosphates of deoxynucleosides. The substituent N-isopropyl-carbonamide in the p-position on the benzene ring inhibits the entrance of nucleosides and purines into the cell, resulting in a general lowering of the intracellular content of nucleosides and purines, as shown by a decrease in uridine incorporation. In addition to the condensation with amino acids, the aldehyde group of the N-isopropyl-4-formyl-benzamide inhibits the formation of the di- and tri-phosphates of nucleosides. All of these effects can be demonstrated simultaneously for Natulan and Azo-Natulan.