Actinomycin D(AMD), containing a planar phenoxazone ring and two cyclic pentapeptides, is well known for its specific inhibition of DNA transcription and the clinical use in the treatment of highly malignant tumors. On the basis of the crystal structure of the DNA-AMD complex and structure-activity relationships of AMD analogs, two types of AMD analogs were designed and total chemically synthesized. Three novel analogs were designed to study the effect of lengthening and shortening the side chains of L-Me-Val, in which amino acid replacements were made by D-Me-Leu, Me-Ile and Sar, discussed with L-Me-Leu analog which has been reported. A serial [D-Phe2]AMD analogs in which L-Me-Val was replaced with Sar, D-Me-Ala, D-Me-Val, L-Me-Leu, D-Me-Leu, Me-Ile, L-Me-Phe, D-Me-Phe were designed. All analogs were prepared from C terminal to N terminal to form linear pentapeptides, then cyclized, and condensed with BMNBCA, followed by catalytic reduction, controlled oxidation and purification, and afforded as red solid. The spectrum data of all analogs including HR-MS, 1H NMR and [α]D were given. In vitro antitumor effects of all analogs against SGC-7901, BEL-7402, TB, HepG-2 and MCF-7 cell lines were tested. The results show that analogs retaining D-Val2 but with long side chains at the 5th position play more powerful in vitro antitumor activity than AMD itself, though the in vitro antitumor activities of [D-Phe2]AMD analogs are generally reduced.
