STUDIES ON THE SYNTHESIS AND BIOACTIVITY OF 5,5'-VAL(2)-AMD AND 2,2'-PHE(2)-AMD

Actinomycin D(AMD) contains a planar phenorazone ring as well as two c yclic depsipeptides and is best known for its effectiveness as an inhi bitor of transcription. It has been used clinically for treating Wilm' s tumor, gestational chriocarcinoma. Although it possesses valuable bi ological activities its high cytotoxity and inactivities toward some t umors have prompted the search for modified AMD. On the basis of the r esult of AMD-DNA binding model proposed by Takusagawa, we designed and synthesized 5,5'-Val(2)-AMD and 2,2'-Phe(2)-AMD. The title compounds were synthesized from 3 in 13 steps with overall yield of 27%, 17%, re spectively. The structures were identified with H-1 NMR, 2D NMR, MS an d HRMS. The biological activities of two analogs were carried out in c omparison with those of AMD. The order of antitumor activity was 2,2'- Phe(2)-AMD>AMD>5,5'-Val(2)-AMD.