Di Marco A, Casazza A M, Soranzo C, Pratesi G
Cancer Chemother Pharmacol. 1978;1(4):249-54. doi: 10.1007/BF00257158.
Previous studies on structure-activity relationships of anthracycline antitumor antibiotics have shown that removal of the methoxyl group at position 4 of the aglycone causes a marked increase in the potency of the compounds: 4-demethoxydaunorubicin and 4-demethoxyadriamycin had an antitumor effect similar to that of the parent compound at doses five to eight times lower, and they were active even when administered orally. This paper reports the effects of further substitutions at positions 1, 2, 3, and 4 of 4-demethoxy aglycone. The introduction of methyl groups at positions 2 and 3, or 1 and 4 resulted in decreased cytotoxicity and biological activity. The addition of a benzoyl ring at positions 2 and 3 decreased the activity further. 1,4-Dichloro-4-demethoxydaunorubicin and 2,3-dichloro-4-demethoxydaunorubicin were respectively as active and 2.5 times less active than was daunorubicin against HeLa cells in vitro while they were inactive against P388 and L1210 leukemias in vivo. 2,3-Dimethyl-4-demethoxyadriamycin showed an antitumor activity against mouse leukemias that was slightly higher than was that of adriamycin.
先前关于蒽环类抗肿瘤抗生素构效关系的研究表明，糖苷配基4位上甲氧基的去除会使化合物的效力显著增加：4-去甲氧基柔红霉素和4-去甲氧基阿霉素在剂量降低五到八倍时具有与母体化合物相似的抗肿瘤效果，并且即使口服给药也具有活性。本文报道了在4-去甲氧基糖苷配基的1、2、3和4位进行进一步取代的效果。在2和3位或1和4位引入甲基会导致细胞毒性和生物活性降低。在2和3位添加苯甲酰环会进一步降低活性。1,4-二氯-4-去甲氧基柔红霉素和2,3-二氯-4-去甲氧基柔红霉素在体外对HeLa细胞的活性分别与柔红霉素相同和比柔红霉素低2.5倍，而它们在体内对P388和L1210白血病无活性。2,3-二甲基-4-去甲氧基阿霉素对小鼠白血病的抗肿瘤活性略高于阿霉素。
