Nagamura S, Kobayashi E, Gomi K, Saito H
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co, Ltd., Japan.
Bioorg Med Chem. 1996 Aug;4(8):1379-91. doi: 10.1016/0968-0896(96)00132-0.
A series of the eight-substituted A-ring pyrrole derivatives of duocarmycin B2 were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the analogues in aqueous solution was examined. The 8-H and the 8-CN compounds which cannot structurally release the cyclopropane compound (DU-86), exhibited extremely diminished anticellular activity compared with duocarmycin A (1a) or DU-86. The ethers and the sulfonates which were not converted to DU-86 under usual conditions (35 degrees C, pH 7), showed almost equal in vivo activities to that of 1a. However, their optimal doses were significantly higher than that for 1a. Most of the A-ring pyrrole analogues which can be chemically or enzymatically converted to DU-86, displayed remarkably superior in vivo antitumor activity to 1a. These results suggest that the A-ring pyrrole analogues need to chemically or enzymatically release DU-86 as an active metabolite to exhibit potent in vivo antitumor activity.
合成了一系列多卡霉素B2的八取代A环吡咯衍生物，并对其进行了体外抗HeLa S3细胞活性和体内抗小鼠肉瘤180活性的评估。此外，还检测了类似物在水溶液中的稳定性。不能在结构上释放环丙烷化合物（DU-86）的8-H和8-CN化合物，与多卡霉素A（1a）或DU-86相比，其抗细胞活性极低。在通常条件（35℃，pH 7）下不能转化为DU-86的醚类和磺酸盐类，其体内活性与1a几乎相当。然而，它们的最佳剂量明显高于1a。大多数可通过化学或酶促转化为DU-86的A环吡咯类似物，其体内抗肿瘤活性明显优于1a。这些结果表明，A环吡咯类似物需要通过化学或酶促方式释放DU-86作为活性代谢物，以展现出强大的体内抗肿瘤活性。
