In the search for new anticancer drugs. X. N,N; N',N'-bis(1,2-ethanediyl)-N''-(1-oxyl-2,2,6,6-tetramethyl- 4-piperidinylaminocarbonyl) phosphoric triamide--a new potential anticancer drug of high activity and low toxicity.
A new nitroxyl labeled TEPA derivative 5 containing the urea bridge between the phosphorus and the nitroxyl moiety, and the congeners containing the NOH and NH groups instead of the nitroxyl function were synthesized, and tested in vivo on CD2F1 mice for anticancer activity against P388 and L1210. The nitroxyl compound is more active than the reduced forms. The nitroxyl compound 5 elicits 170% ILS at 90 mg/kg after 30 days and 439% ILSmax after 60 days against P388, and has a higher therapeutic ratio (26.4) than the clinically used Thio-TEPA (2.75). The LD50 of 5 is 270 mg/kg, while that of Thio-TEPA is 18 mg/kg. Consequently, the nitroxyl compound 5 is a promising new anticancer drug.
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000633:toxicity; D001389:Azirines / Q000138:chemical synthesis*; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship; D013852:Thiotepa / Q000627:therapeutic use; D013721:Triethylenephosphoramide / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
D000970:Antineoplastic Agents; D001389:Azirines; D013852:Thiotepa; C045031:N,N,N',N'-bis(1,2-ethanediyl)-N''-(1-oxyl-2,2,6,6-tetramethyl-4-piperidinylaminocarbonyl)phosphoric triamide; D013721:Triethylenephosphoramide