Structure-activity relationships of anthracyclines relative to cytotoxicity and effects on macromolecular synthesis in L1210 leukemia cells.

Abstract

The effects of 92 anthracycline compounds on the growth and DNA, RNA and protein synthesis of L1210 leukemia cells were studied in relationships to their structures and antitumor activity. The following structure-activity relationships were observed: 1) The hydroxyl groups at C-1, C-2, C-4, C-6 and C-11 on aglycones have significant relationships to the in vitro potency. Compounds lacking the hydroxyl group at C-6 (an anthracycline containing α2-rhodomycinone) or containing the methoxyl group at C-6 (6-O-methylaclacinomycin A) are lower in their cytotoxicity and RNA and DNA synthesis-inhibiting activity than those containing the C-6 hydroxyl group. The hydroxyl group at C-2 did not influence the in vitro potency, but the hydroxyl group at C-1 and/or C-11 enhanced the potency. The activity which prolongs the life span of L1210-bearing mice was decreased by an hydroxyl group at C-1 or C-11, although the effective doses were lowered. In compounds which are different at C-4, in vitro potency increased in the following series: deoxy>hydroxy>methoxy. 2) The side chain at C-9 in aklavinone- and daunomycinone-glycosides produced slight influence on cytotoxicity and on the activity which inhibits RNA and DNA synthesis in intact cells. Ethyl, isopropyl and acetonyl derivatives at C-9 had an equal potency. The methyl derivative had the least activity. 3) A 10-carbomethoxy group in the S-configuration decreased the inhibitory activity on RNA synthesis. The removal of this group at C-10 resulted in a marked reduction in cytotoxicity and in the activity which inhibits nucleic acid synthesis. 4) The amino function either on the aglycone or on the sugar moiety was essential for in vitro activity. Compounds having an alkylamino group at C-3' were more potent in vitro than those with a primary amino group, although these groups produced different effects in in vivo activity, depending on each anthracycline. 5) Disaccharides and trisaccharides were more potent in vitro than monosaccharides. This was reflected in the ratios for the IC50 values of DNA and RNA synthesis. The ratio of the concentration to inhibit DNA synthesis to that for RNA synthesis was 1-4 in monosaccharides (group I), while in trisaccharides (group II). the ratio was 7-10. In disaccharides the ratio was 5-6. The length of the sugar chain did not correlate with in vivo antitumor activity.