STRUCTURE-ACTIVITY-RELATIONSHIPS OF CYCLIC ENEDIYNES RELATED TO DYNEMICIN-A .1. SYNTHESIS AND ANTITUMOR-ACTIVITY OF 9-ACETOXY ENEDIYNES EQUIPPED WITH ARYL CARBAMATE MOIETIES

A series of the 9 acetoxy enediyne compounds, 6a-k which were simplifi ed from natural dynemicin A, and designed to be equipped with various aryl carbamate moieties, was synthesized and evaluated for DNA-cleavin g ability, in vitro cytotoxicity, and in vivo antitumor activity. As a result of this study of the structure-activity relationships (SAR) wi th regard to the R-1 substituent, both compounds 6a and 6f with the ph enyl carbamate and 4-chlorophenyl carbamate moiety, respectively, were found to exhibit significant activity (T/C > 200%) against murine P38 8 leukemia in mice, in spite of having IC50 values in the micromolar r ange. In particular, compound 6f showed the most potent activity with a maximum T/C of 256% at a daily dosage of 4.0 mg/kg for four days. Fu rthermore, both compounds 6a and 6f were effective against Meth A sarc oma in mice and inhibited 71 and 77% of the tumor growth at 2.0 and 3. 0 mg/kg dosages, respectively. In contrast to 6f, compound 6i possessi ng the 2-nitrophenyl carbamate moiety showed only a slight in vivo act ivity, while it had about one order of magnitude higher in vitro cytot oxicity than 6f. For the stereochemistry-activity relationships at the C9 position, the (9R)-isomers of 6c, 6g, and 6j were found to show h igher in vitro and in vitro potencies than the corresponding (9S)-iso mers. (C) 1997 Elsevier Science Ltd.