Synthesis and biological properties of actinomycin D chromophoric analogues substituted at the 7-carbon with aziridine and aminopropoxy functions.
The growing importance of functionalized aziridines in numerous organic biomolecules led us to develop syntheses of novel actinomycin D (AMD) analogues substituted with an aziridine. Reaction of 7-hydroxyactinomycin D with 2-(iodomethyl)aziridine produced the desired 7-(2-aziridinylmethoxy)actinomycin analogue. In an attempt to develop an alternate route to this analogue, 7-(2-azido-3-iodopropoxy)actinomycin was subjected to reduction with dimethylamine-borane complex; the reaction did not produce the three-membered aziridine; instead the reaction product was found to be linear 7-(2-aminopropoxy)actinomycin D. Calf-thymus-DNA binding of these analogues was comparable to that of AMD as examined by UV-visible difference spectral measurements, thermal denaturation of DNA, and CD techniques. The analogues were found to be about 1/4 to 1/30 as cytotoxic to human lymphoblastic CCRF-CEM leukemia and B16 melanoma cells in vitro as AMD.
D002460:Cell Line; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D013329:Structure-Activity Relationship
D003609:Dactinomycin; D004247:DNA