SYNTHESIS OF CONGENERS AND PRODRUGS .3. WATER-SOLUBLE PRODRUGS OF TAXOL WITH POTENT ANTITUMOR-ACTIVITY
SYNTHESIS OF CONGENERS AND PRODRUGS .3. WATER-SOLUBLE PRODRUGS OF TAXOL WITH POTENT ANTITUMOR-ACTIVITY
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DOI：
10.1021/jm00124a011
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发表时间：
1989-04-01
影响因子：
7.3
通讯作者：
ZALKOW, LH
中科院分区：
文献类型：
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作者：
DEUTSCH, HM;GLINSKI, JA;ZALKOW, LH
紫杉醇在许多测试系统中显示出良好的体内抗肿瘤活性。用于抗肿瘤试验的紫杉醇的配方一直很困难。C-2‘’或C-7的外化会导致体外微管蛋白组装活性的丧失，但不会产生细胞毒性。这些观察结果表明，C-2‘’和/或C-7上的酯可能是紫杉醇的有用前体药物，它们往往会促进水的溶解。紫杉醇在室温下与丁二酸酐或戊二酸酐在吡啶溶液中反应，分别得到结晶的单2‘-加合物1b和1f。这些酸(1b、1f、1i)的盐是通过加入1当量的相应碱，然后蒸发和/或冷冻干燥溶剂形成的(S)。与游离酸相比，这些盐具有更好的抗肿瘤活性。三乙醇胺和N-甲基葡萄糖胺盐在水中的溶解度大大提高，且比钠盐更具活性。戊二酸系列由于具有较高的活性和较高的产率而被优先考虑。2‘’-戊二酰紫杉醇(1f)与3-(二甲氨基)-1-丙胺在CDI作用下发生偶联反应，合成了氨基紫杉醇(1f)。盐酸盐(1P)具有良好的溶解性，具有极强的药效和活性。在10 mg/kg的B16筛选中，1P的T/C为352，10个疗程中有5个。在MX-1乳腺移植试验中，该前药在剂量为40 mg/kg和20 mg/kg时给出-100的值，所有活体动物都没有肿瘤。
Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Exterification at either C-2'' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2'' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2''-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2''-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.