Glutathione and mercapturic acid conjugates of sulofenur and their activity against a human colon cancer cell line
Glutathione and mercapturic acid conjugates of sulofenur and their activity against a human colon cancer cell line
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DOI：
10.1124/dmd.30.3.331
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发表时间：
2002-03-01
影响因子：
3.9
通讯作者：
Pellegrini, J
中科院分区：
文献类型：
--
作者：
Guan, XM;Hoffman, BN;Pellegrini, J
舒降之是作为抗癌剂开发的二芳基磺酰脲类药物之一。Sudurur在几种实体瘤模型中具有广泛的活性，并基于其令人印象深刻的临床前活性进行了广泛的临床试验。然而，由于其贫血的副作用，其临床疗效一直令人失望。此外，sucrosurur及其二芳基磺酰脲类似物的抗癌机制仍不清楚。阐明硫代嘌呤的代谢命运有助于阐明其作用机制，并为指导结构修饰以获得更有效且副作用更小的抗癌药物提供信息。我们已经确定了谷胱甘肽共轭物和巯基尿酸共轭物与液相色谱/质谱法的帮助下，从successur-closed大鼠。在给药大鼠胆汁中，5 h内谷胱甘肽结合物的硫柳汞剂量分数为0.12 +/-0.03%，24 h内尿液中巯基尿酸结合物的分数为1.4 +/-0.7%。谷胱甘肽缀合物和巯基尿酸缀合物的蛋白结合分别测定为20 +/-3和84 +/-2%，而硫代尿酸的蛋白结合>99%。硫糖铝的高蛋白结合需要高于体外剂量，这被认为会引起贫血的副作用。这一代谢途径的重要性在于，发现两种缀合物均为谷胱甘肽还原酶抑制剂，并且对人结肠腺癌GC（a）/c1细胞（一种硫柳汞敏感细胞系）具有与硫柳汞相当的抗癌活性。这些偶联物可作为开发新型抗癌药物的新线索。
Sulofenur is one of the diarylsulfonylureas developed as an anticancer agent. Sulofenur possesses a broad spectrum of activity in several solid tumor models and has undergone extensive clinical trials based on its impressive preclinical activity. However, the clinical response of sulofenur has been disappointing because of the side effect of anemia. Furthermore, the anticancer mechanism of sulofenur and its diarylsulfonylurea analogs still remains unknown. Elucidation of the metabolic fates of sulofenur may help to delineate the mechanism and provide information to guide the structural modification for more potent anticancer agents with less side effects. We have identified a glutathione conjugate and a mercapturic acid conjugate from sulofenur-closed rats with the aid of liquid chromatography/mass spectrometry. The fraction of the dose of sulofenur as the glutathione conjugate in the dosed-rat bile over 5 h was 0.12 +/- 0.03%, and the mercapturic acid conjugate in urine over 24 h was 1.4 +/- 0.7%. Protein binding of the glutathione conjugate and mercapturic acid conjugate was determined to be 20 +/- 3 and 84 +/- 2%, respectively, as opposed to >99% of sulofenur. The high protein binding of sulofenur requires a higher than in vitro dose, which is believed to cause the side effect of anemia. The significance of this metabolic pathway is that both conjugates were found to be glutathione reductase inhibitors and to possess anticancer activity comparable to sulofenur against human colon adenocarcinoma GC(a)/c1 cells, a sulofenur-sensitive cell line. These conjugates may serve as new leads for the development of novel anticancer agents.