Antitumor activities of newly synthesized 5-carbamoyl-1 H-imidazol-4yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4yl piperonylate.
In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.
Significance of Furine Salvage in Circumventing the Action of Antimetabolites in Rat Hepatoma Cells1
The flux activities of de novo and salvage purine synthesis were compared in rat hepatoma 3924A cells in various growth phases. The initial rate assays of [I4C]adenine, ("C]hypoxanthine, and |"C]guanine incorporation yielded Michaelis-Menten kinetics with A'msof 5, 7, and 7 #tM,respectively. After replating plateau phase cells in lag and log phases the activity of purine de novo pathway increased 4.5to 8-fold with a preferential rise in guanylate synthesis, whereas purine salvage activities increased only 1.6to 2.1-fold. However, for the syntheses of IMP, AMP, and GMP, the activities of purine salvage pathways were 2to 7-fold, 5to 28-fold, and 2to 32-fold higher than those of the de novo purine pathway. Treatment of cells with acivicin, an inhibitor of the activity of amidophosphoribosyltransferase, phosphoribosylformylglycinamidine synthase, and GMP synthase, inhibited the flux activities of de novo purine, adenylate, and guanylate syntheses to 37, 73, and 3% of the controls and decreased the concentration of GTP to 42%; the concentra tion of ATP did not change and that of 5-phosphoribosyl 1-pyrophosphate increased 3.1-fold. Under these conditions the activities of salvage syn thesis from hypoxanthine and guanine were enhanced 2.5-fold. Treatment of hepatoma cells with IMP dehydrogenase inhibitors, tiazofurin, ribavirin, and 4-carbamoylimidazolium 5-olate, to block de novo guanylate synthesis accelerated the flux activity of guanine salvage pathway. The higher capacity of purine salvage pathway than that of the de novo one and the further rise of the activity in response to the drugs targeted against the de novo pathway highlight the important role salvage synthe sis might play in circumventing the impact of antimetabolites of de novo purine synthesis in cancer chemotherapy.
Spin label motion in fatty acids.
Spin labels dissolved in highly purified fatty acid systems exhibit nearly identical tumbling rates in liquid and solid phases. Even though the spin labels do not have the same molecular geometry as the lipid matrix the melting point of the matrix can be inferred by measurements of the temperature dependency of molecular motion.