Carbon-7 Substituted Actinomycin D Analogues as Improved Antitumor Agents: Synthesis and DNA-Binding and Biological Properties

Article abstract of DOI:10.1021/jm00352a023

7-(2,3-Epoxypropoxy)actinomycin D has been synthesized along with its major companion product, 7-(2,3-dihydroxypropoxy)actinomycin D.They were characterized by UV-visible and CD spectra and by NMR studies.According to UV-visible absorptiometry, circular dichroism, and thermal denaturation studies, they bind to DNA in a manner that is comparable to actinomycin D.The analogues are, like actinomycin D, extremely cytotoxic to human lymphoblastic leukemic cells (CCRF-CEM) in vitro but are significantly less toxic than actinomycin D to normal CDF1 mice in vivo.Unlike actinomycin, these analogues are metabolised in rats, and the methabolite are excreted in rat urine at a rapid rate.Compared to actinomycin D, the antitumor activity of the 7-(2,3-epoxypropoxy)actinomycin analogue against P-388 leukemia in mice is decidedly superior, and the therapeutic index is improved several fold.