Synthesis and Screening of Substances acting by Alkylation and Metabolic Inhibition

Summary

Molecular carriers with alkylating sites and sites endowed with antimetabolic activity were synthesized.

Phenylalanine and hydroxyphenylalanine having a dichlorodiethylamino group in the benzene ring were chosen as alkylating agents because of their capability to form peptides with natural and antagonist aminoacids.

The chemotherapeutic screening was carried out according to CCNSG rules with the only variant that the determination of the weight of the tumors of the treated mice was carried out on the day subsequent to that indicated by the CCNSC, i.e. at the 9^th day after tumor implantation. In this same day the spleen weight was determined also. On the previous day, the white cell count was carried out and in way it was allowed an evaluation of the hemotoxicity.

The optical isomerism of the compounds plays a fundamental rôle in the chemotherapeutic activity.

Examples of different isomers of the tripeptide phenylalanyl-ethionyl-m-sarco-lysine and of the tetrapeptide arginyl-p-fluorophenyl-alanyl-glycyl-m-sarcolysine, endowed with markedly different chemotherapeutic activities (from o to 90) in relation to the different stereochemical configuration are reported.

Oxidative phosphorylation, ATPase, glycolysis, Nadase, succinic dehydrogenase, cytochrome-oxidase, glutamic dehydrogenase, lactic dehydrogenase amino acid oxidase, proteolysis were studied in biochemical pharmacology investigations.

The active compounds bring the phosphorylation ratio to zero in Sarcoma 180 mitochondria at doses reducing the P/O by 40-50% in normal liver mitochondria.

Interesting observations are pointed out for other enzyme systems, showing the specificity of the activity of some peptides at the biochemical level on tumor enzyme systems in comparison with the same enzyme systems of normal tissues.