The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells

A number of thiosemicarbazones have been tested previously and herein are i ncluded three bis(thiosemicarbazones) for comparison to the previous deriva tives. In general the uncomplexed thiosemicarbazones were more potent in th e cytotoxic screens than the bis(thiosemicarbazone) except in the murine L 1210 and the human colon SW480 screens. Mode of action studies have only de monstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemic arbazones) complexes of copper, nickel, zinc, and cadmium have been examine d to compare them to the heterocyclic N(4)-substituted thiosemicarbazones m etal complexes. These new derivatives demonstrated excellent activity again st the growth of suspended lymphomas and leukemias although it should be po inted out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemica rbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breas t MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cel ls the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase , appeared to he a major tal get of the complexes. However, minor inhibitio n of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonu cleotide reductase, and nucleoside kinases occurred over the same time peri od. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical acid unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the hete rocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, t heir metabolic effects in the turner cell were more focused on a single syn thetic pathway.