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.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D001578:Benzopyrans; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006027:Glycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D012995:Solubility
D000903:Antibiotics, Antineoplastic; D001578:Benzopyrans; D006027:Glycosides; C002185:chartreusin