Synthesis and antitumor activity of analogues of the antitumor antibiotic chartreusin

First isolated in 1953 from a fermentation broth, 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, three analogues were synthesized wherein the disaccharide moiety of 1 was systematically replaced with fucose (6), glucose (7), and the disaccharide maltose (8). Each of the three analogues had a cytotoxic potency against cultured L1210 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 choe P388 leukemia, 8 showed reproducible activity comparable to chartreusin at similar dose levels. Although 8 caused no observable toxic effects at therapeutic dose levels when given ip, neither 1 nor 8 produced active indications when administered subcutnaeously.