olivomycins and Leukemia-P388

A novel way of chemical modification of the antibiotic olivomycin I at the 2'-keto group of the side chain of the aglycone moiety was developed. Reaction of olivomycin I with the carboxymethoxylamine hemihydrochloride gave the key intermediate, 2'-carboxymethoxime-olivomycin I, which was further reacted with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate to give the corresponding amides. The antiproliferative and topoisomerase I (Topo-I)-poisoning activities of the novel derivatives were examined. One of the novel derivatives showed a marked inhibitory activity against Topo-I, a pronounced antitumor activity in in vivo experiments on mice bearing leukemia P-388 and lower toxic side effects compared with the parent olivomycin I.

Topics: Animals; Antibiotics, Antineoplastic; Carbohydrate Sequence; Cell Line, Tumor; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Ketones; Leukemia P388; Male; Mass Spectrometry; Mice; Molecular Sequence Data; Olivomycins; Topoisomerase I Inhibitors

Novel analogues of olivomycin A were prepared by selective reactions involving the carbonyl and hydroxyl groups of the aglycon moiety. Electrophilic substitution of the aglycon also was successful. Of 11 analogues, all but two were active in the P-388 murine leukemia assay. One compound, the 2'-methoxime, showed superior activity to olivomycin A based on its wider dose range and greater potency. The methyl imine and the 8-O-methyl ether were equal to olivomycin A in potency and efficacy. Most of the other analogues were slightly less potent or effective.

Topics: Animals; Antibiotics, Antineoplastic; DNA; Female; Leukemia P388; Mice; Olivomycins; Structure-Activity Relationship