title: N2- and C-7 substituted actinomycin D analogues: synthesis, DNA-binding affinity, and biochemical and biological properties. Structure-activity relationship.
abstract: N2-n-Alkyl- and omega-amino-n-alkylactinomycin D and 7-alkoxy-, 7-aralkoxy-, and 7-(acyloxy)actinomycin D were synthesized by modification of the parent actinomycin D molecule at the N2 and C-7 positions of the phenoxazinone moiety. The intermediate for N2 substitution was 2-deamino-2-chloroactinomycin D. For C-7 substitution, 7-hydroxyactinomycin D was used as the intermediate. Treatment of 2-deamino-2-chloroactinomycin D with an excess of the appropriate amine produced the N2-substituted derivatives. Condensation of the required alkyl or acyl halides with 7-hydroxyactinomycin D, aided by solid anhydrous potassium carbonate, yielded the C-7-substituted analogues. Calf thymus DNA-binding affinity was determined by equilibrium binding and also by thermal denaturation of DNA techniques, inhibitory activity of nucleic acid synthesis was examined using P388 cells in vitro, cytotoxicity measurements to tumor cells in vitro employed human lymphoblastic leukemic cells (CCRF-CEM), and antitumor activity was assayed against P388 mouse leukemia in CDF1 mice. Synthesis of a number of new analogues in each series and determination of the biophysical, biochemical, and biological properties established a more thorough structure-activity relationship in these analogues. These results establish that with the selection of omega-(n-alkylamino) groups at the N2 site or O-n-alkyl or O-acyl groups at the C-7 site a variety of modifications can be carried out on the actinomycin molecule while preserving biological activity. N2-3'-Amino-n-propyl- and N2-10'-amino-n-decylactinomycin D, 7-methoxy- and 7-ethoxyactinomycin D, and the 7-O-(1'-adamantoyl) ester of 7-hydroxyactinomycin D were found to be the most effective antitumor agents in vivo and in vitro. They also strongly inhibit cellular RNA and DNA synthesis and, with the exception of the ester, retain high DNA-binding affinity.
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007941:Leukemia P388 / Q000378:metabolism; D008297:Male; D051379:Mice; D009691:Nucleic Acid Denaturation; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D003609:Dactinomycin; D012313:RNA; D004247:DNA