DL-threo-beta-Fluoroaspartate and DL-threo-beta-fluoroasparagine: selective cytotoxic agents for mammalian cells in culture.
Absolute configuration assignments have been made for the diastereomers of DL-beta-fluoroaspartate by X-ray analysis. The cytotoxicity of these isomers against various mammalian cells was examined. DL-threo-beta-Fluoroaspartate shows selective cytotoxicity. Growth of the most sensitive cells is completely inhibited by 13 micrometers DL-threo-beta-fluoroaspartate in the presence of 100 micrometers L-aspartate, a component of the culture medium. A difference in the rate of transport of DL-beta-fluoroaspartate among the cells studied is an important factor determining cell specificity. For those cells that are sensitive to DL-beta-fluoroaspartate, the threo isomer is, in all cases, more potent than the erythro isomer. Radioactivity derived from L-threo-beta-fluoro[14C]aspartate is incorporated into proteins at a rate comparable to the rate of incorporation from L-[14C]aspartate. We synthesized DL-threo-beta-fluoroasparagine. This compound is also cytotoxic but less specific and less potent than DL-threo-beta-fluoroaspartate. However, the cell specificity can be enhanced in the presence of 1 mM L-aspartate, which can protect some cells but not others from the cytotoxic effects of DL-threo-beta-fluoroasparagine. Jensen sarcoma cells, which require asparagine, are not protected by L-aspartate. Therefore, a combination of L-aspartate and DL-threo-beta-fluroasparagine can be used to inhibit specifically the growth of asparagine-requiring tumors.
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001216:Asparagine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002478:Cells, Cultured; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000503:physiopathology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000596:Amino Acids; D000970:Antineoplastic Agents; D001224:Aspartic Acid; C023463:beta-fluoroaspartic acid; D001216:Asparagine; C023464:beta-fluoroasparagine