Umezawa K, Takeuchi T, Komuro K, Nosaka C, Kunimoto S, Tsuchiya T, Takagi Y, Umezawa S, Umezawa H
Institute of Microbial Chemistry, Tokyo, Japan.
Drugs Exp Clin Res. 1988;14(7):429-34.
The authors have synthesized 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) adriamycinone (FT-ADM) which exhibited strong antitumour activity and weak toxicity. These characteristics of FT-ADM are partly due to the presence of a 2'-fluoro atom which strengthens the glycoside bond. FT-ADM, however, is sparingly soluble in water because of lack of the 3'-amino group of adriamycin. To increase the solubility of FT-ADM, a hydrophilic group was added at the 14-OH group. Then, the 14-hemisuccinate, 14-hemiglutarate, 14-hemiadipiate, 14-hemipimelate and 14-hemisuberate derivatives of FT-ADM were synthesized. Among them, the 14-hemipimelate derivative (FAD-104) was selected for further development because of its potent antitumour activity and weak toxicity. When drugs were injected intraperitoneally every day from day 1 to 9, FAD-104 showed an apparently stronger antitumour effect against mouse L-1210 leukaemia than adriamycin with lower toxicities. FAD-104 was also more effective than adriamycin on L-1210 using other administration schedules. A characteristic feature is that FAD-104 is effective over a very broad range, which will be advantageous for safe clinical use. FAD-104 also showed marked antitumour effect against L-1210 when it was injected intravenously either once on day 1 or three times on days 1, 5 and 9. Thus, FAD-104 may be a more potent antitumour anthracycline than adriamycin.
作者合成了7-O-(2,6-二脱氧-2-氟-α-L-塔罗吡喃糖基)阿霉素酮(FT-ADM)，其显示出强大的抗肿瘤活性和较弱的毒性。FT-ADM的这些特性部分归因于2'-氟原子的存在，该原子增强了糖苷键。然而，由于阿霉素缺乏3'-氨基，FT-ADM在水中的溶解度很低。为了提高FT-ADM的溶解度，在14-OH基团处添加了一个亲水基团。然后，合成了FT-ADM的14-半琥珀酸酯、14-半戊二酸酯、14-半己二酸酯、14-半庚二酸酯和14-半辛二酸酯衍生物。其中，14-半庚二酸酯衍生物(FAD-104)因其强大的抗肿瘤活性和较弱的毒性而被选择进一步开发。当从第1天到第9天每天腹腔注射药物时，FAD-104对小鼠L-1210白血病显示出比阿霉素更强的抗肿瘤作用，且毒性更低。使用其他给药方案时，FAD-104对L-1210的效果也比阿霉素更好。一个特征是FAD-104在非常广泛的范围内有效，这将有利于安全的临床应用。当在第1天静脉注射一次或在第1、5和9天静脉注射三次时，FAD-104对L-1210也显示出显著的抗肿瘤作用。因此，FAD-104可能是一种比阿霉素更有效的抗肿瘤蒽环类药物。
