Synthesis and antitumor activity of analogs of the antitumor antibiotic chartreusin

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Abstract
First isolated in 1953 from fermentation broth [Streptomyces chartreusis], chartreusin (1) has received renewed interest, as a result of substantial antitumor activities recently demonstrated in several murine test systems. Poor water solubility frustrated formulation attempts, and rapid biliary excretion observed in mice made 1 an improbable candidate for clinical development but an excellent candidate for an analogue synthesis program. From a common intermediate, which was prepared from 1, 3 analogues were synthesized; the disaccharide moiety of 1 was systematically replaced with fucose (6), glucose (7) and the disaccharide maltose (8). The analogues had a cytotoxic potency against cultured [mouse leukemia] L-1210 cells which was equal to, or better than, that shown by 1. Based on the structural similarity with the parent, an improved water solubility and a favorable accessibility through synthesis, maltoside 8 was chosen for further antitumor evaluation with an in vivo test system. Versus murine P-388 leukemia [cells], 8 showed reproducible activity comparable to chartreusin at similar dose levels. Although 8 caused no observable toxic effects at therapeutic dose levels when given i.p., neither 1 nor 8 produced active indications when administered s.c.