Enantiomers of 7-(2,3-epoxypropoxy)actinomycin D as dual-action DNA-acting antitumor agents

Enantiomeric forms of (+/-)-EPA [racemic 7-(2,3-epoxypropoxy)actinomycin D] have been synthesized; these are (R)-(+)- and (S)-(-)-EPA, which are active against a range of actinomycin resistant and marginally responsive tumors. The R-(+) enantiomer is uniformly superior to the other forms in all the tumor lines tested. These enantiomers act by binding to DNA, both by intercalation and alkylation at the guanine base of DNA. They are superior to actinomycin D in their in vitro activity against mouse leukemias (L1210 and P388/ADR) and mouse melanoma B16. This superior activity is also evident against all the preceding mouse leukemias and against solid tumors B16 and C26 in vivo. In biochemical action, the enantiomers behave similarly and act primarily by inhibiting DNA synthesis in tumor cells; the only difference found was in their preference for sites in DNA bases during alkylation. The R-(+) enantiomer generates an adduct that is believed to be bonded to the N7-site of guanosine; conversely, the S-(-) isomer forms two adducts with DNA that are different from the preceding one by HPLC and are tentatively assigned O6-guanosine-substituted structures on the basis of their UV, CD, and other chemical behaviors.