SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL CYCLIC ENEDIYNE COMPOUNDS RELATED TO DYNEMICIN-A AS ANTITUMOR AGENTS

Novel cyclic enediyne compounds, which are simple functional analogs o f dynemicin A (1) having the bicyclo[7.3.1]tridec-4-ene-2,6-diyne syst em, were synthesized and evaluated for the DNA-cleaving ability, in vi tro cytotoxicity and in vivo antitumor activity. All of the sulfones 1 9-24, which were equipped with a 2-(arylsulfonyl)ethoxycarbonyl group or the 2-(methylsulfonyl)ethoxycarbonyl group as a triggering device, showed both potent DNA-cleaving activity and cytotoxicity against vari ous tumor cell lines. However, these compounds were entirely inactive or only slightly active against murine P388 leukemia in mice, On the o ther hand, the enediyne 2a having a phenyl carbamate moiety as a stabl e N-protecting group showed effective antitumor activity both in vitro and in vivo. In particular, it exhibited significant antitumor activi ty against Lewis lung carcinoma in mice, These results show that the c haracter of the carbamate moiety of the cyclic enediynes strikingly af fects their biological activities, that is, the sulfonylethyl carbamat e moiety is an effective triggering device for both DNA-cleaving activ ity and cytotoxicity, and the phenyl carbamate moiety is significant f or antitumor activity in vivo. As part of a mechanistic study, the rea ctivities of 2a and 21 were examined under a weakly basic condition (p H 9.3); both compounds failed to give the Bergman cycloaromatization p roduct.