The synthesis of the following thioethers of 2-chloro-6-mercaptopurine is described: 2-chloro-6-[4-phenyl-imidazole-2-thio] purine; 2-chloro-6-[4-guanidopropyl-imidazole-2-thio] purine; 2-chloro-6-[4-t.butyl-thiazole-2-thio] purine;2-chloro-6-[4-phenyl-thiazole-2-thio] purine; 2-chloro-6-[4-methylthiazole-2-thio] purine;2-chloro-6-[4-carbethoxymethyl-thiazole-2-thio] purine; 2-chloro-6-[4-carboxamido-5-amino-thiazole-2-thio] purine; 2-chloro-6-[5-phenyl-thiadiazole (1,3,4) -2-thio] purine; 2-chloro-6-[5-t.butyl-thiadiazole (1,3,4) -2-thio] purine; 2-chloro-6-[tetrazole-5-thio] purine. The thioether bond of these compounds is cleaved by nucleophilic agents especially by mercaptanes under mild conditions. The compounds are not metabolized by ascites cells and preferentially bound to the cell surface. They are inhibitors of DNA-, RNA-, and proteinsynthesis and of proliferation of Ascites cells in a different degree; the ascites carcinoma of mice was not influenced. A possible mechanism of action of their metabolic effects is discussed.
In the presence of 150(μ/ml of chloramphenicol, viability (dye exclusion test) of Ehrlich ascites tumor cells is not severely affected within 48 h; however the number of dead cells increases above this concentration; more than 10 mg/ml render all of the cells dye-positive within a culture period of 24 h. With the highest concentration tested (25 mg/ml) cells begin to lose viability 8 h after beginning of treatment.
In the first passage in the presence of the antibiotic, proliferation of the cells is reduced by about 50%; in the second passage cell growth was about 65% that of controls. As is shown by flow cytometric analysis and BrdU-H33258 technique of flow cytometry, the reduction of proliferation in the second passage is caused by retardation of cell cycle progression of about 8 h; in the third passage the cell cycle is delayed by further 8 h as compared to controls. On recultivation in the third passage in the absence of the inhibitor an increase of cell number of about 75% of controls was observed.
Lactate production and glucose uptake of the cells were stimulated by the inhibitor by about 20%; oxygen consumption was 60% that of controls after 24 h; however the ATP/ADP ratio of chloramphenicol treated cells was in the range of controls.
Over a time period of 24 h the incorporation of [2-14C]thymidine is reduced to 34 ± 3%, incorporation of [2-14C]uridine was 88 ± 4% that of controls, incorporation of [U-14C]lysine was not significantly affected by 150 μg/ml of chloramphenicol; the same was found for the uptake of [2-14C]-α-aminoisobutyric acid.
Electron micrographs of chloramphenicol treated cells reveal a high amplitude of swelling of all mitochondria with a translucent appearance of the inner compartment. The mitochondrial membranes remain largely intact but the number of cristae is drastically reduced.
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