Department of Chemistry and Biochemistry, ‡Skaggs School of Pharmacy and Pharmaceutical Sciences, §Moores Cancer Center, and ⊥School of Medicine, University of California, San Diego , 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
J Med Chem. 2014 Jun 26;57(12):5085-93. doi: 10.1021/jm4016922. Epub 2014 Jun 10.
Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds.
慢性淋巴细胞白血病（CLL）是西方社会最常见的淋巴肿瘤，目前无法治愈。目前有多种治疗方法，但现有的小分子药物存在剂量限制毒性和不良副作用。因此，需要开发新的、毒性更小的治疗方法。在这里，我们证明了从海绵中提取的吡咯-咪唑生物碱（-）-agelastatin A（1a）对 CLL 的原代细胞系具有很强的体外活性，并披露了几种类似物的合成，这些类似物具有与天然产物相当或超过其效力的活性。在针对相同细胞系的测试中，新型合成类似物 13-脱溴-13-三氟甲基 agelastatin A（1j）的活性高于天然产物，是迄今为止报道的最有效的 agelastatin 衍生物。本文还详细描述了 1a 在 CLL 中的体外构效关系，并与 22 种合成类似物进行了比较，同时对最有效的化合物进行了初步的体内药代动力学和代谢研究。
