A study on structure-activity relationships of nucleoside analogues.

A selected series of nucleoside analogues were tested for inhibitory activity vs DNA and/or RNA synthesis at L1210 cells. The structure-activity relationship was studied among derivatives of 5-fluorouracil and arabinosylcytosine (araC), compounds clinically used in cancer chemotherapy. 5-Fluorouridine was found to be a selective, most potent inhibitor of RNA synthesis. Arabinosylcytosine was the most potent selective inhibitor of DNA synthesis. Only cyclocytidine stands very close to the carcinostatic antibiotics in its strong simultaneous inhibition of both DNA and RNA synthesis. A biologically interesting new group of 5'-deoxy derivatives of arabinosylcytosine was investigated. The inhibitory activity vs DNA and/or RNA synthesis is compared with the activity against growth of E. coli and against herpes simplex virus type I (HSV). The system for inhibition of NA synthesis is proposed as a preliminary first step: an in vitro screening method promising for the discovery of new types of potential carcinostatic agents. Both transport and biotransformation processes of nucleoside analogues were studied in the isolated everted rat jejunum with a continuous perfusion technique. The 5'-substituted derivatives of araC and 5'-chloro-5-fluorouridine exhibited higher transport rates and higher metabolic stability during intestinal penetration than the parent nucleosides. There was found to be no correlation between lipophilicity and transport rate, but there is a correlation between lipophilicity and metabolic alterations among the nucleoside derivatives studied.