ESSENTIAL FEATURES OF THE P-GLYCOPROTEIN PHARMACOPHORE AS DEFINED BY A SERIES OF RESERPINE ANALOGS THAT MODULATE MULTIDRUG RESISTANCE
ESSENTIAL FEATURES OF THE P-GLYCOPROTEIN PHARMACOPHORE AS DEFINED BY A SERIES OF RESERPINE ANALOGS THAT MODULATE MULTIDRUG RESISTANCE
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DOI：
10.1073/pnas.86.13.5128
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发表时间：
1989-07-01
影响因子：
11.1
通讯作者：
BECK, WT
中科院分区：
文献类型：
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作者：
PEARCE, HL;SAFA, AR;BECK, WT
我们之前已经证明，利血平是 P-糖蛋白相关多药耐药性 (MDR) 的有效“调节剂”。除了增强我们的多重耐药人白血病细胞系 CEM/VLB100 中的药物细胞毒性外，利血平还与长春花碱的光活化类似物 N-(p-叠氮基-3-[125I]碘水杨基)-N''-(β-氨乙基)长春地辛强烈竞争与 P-糖蛋白的结合。我们之前还证明，调节 P-糖蛋白相关 MDR 的许多化合物中存在三个亚结构域：一个碱性氮原子和两个平面芳环。在本研究中，我们希望更严格地测试以下假设：这些结构域不仅是 MDR 调节剂所必需的，而且它们必须以适当的构象存在。利血平是 MDR 的调节剂，其中这些结构域以明确的构象存在。因此，我们使用天然存在的利血平或育亨宾作为化学模板，制备了八种改变这些结构域空间方向的化合物。当测试其在 CEM/VLB100 细胞中增强天然产物抗肿瘤药物的细胞毒活性的能力时，以适当的空间方向保留苯甲酰基功能的五种化合物均调节 MDR。相比之下，缺乏该部分的化合物则无法做到这一点。这些活性调节剂与 125I 标记的长春花碱类似物强烈竞争与由这些细胞制备的质膜囊泡中的 P-糖蛋白的结合。使用分子力学的构象分析揭示了活性调节剂的结构相似性。我们的结果支持这样的假设：芳香环和碱性氮原子的相对配置对于 P-糖蛋白相关 MDR 的调节剂很重要，并且它们表明这些药物存在配体-受体关系。这些结果也为 MDR“药效团”的定义提供了方向。
We have shown previously that reserpine is an effective "modulator" of P-glycoprotein-associated multidrug resistance (MDR). In addition to enhancing drug cytotoxicity in our multidrug-resistant human leukemia cell line, CEM/VLB100, reserpine strongly competes with a photoactivatible analog of vinblastine, N-(p-azido-3-[125I]iodosalicyl)-N''-(.beta.-aminoethyl)vindesine, for binding to P-glycoprotien. We also demonstrated previously that there are three substructural domains present in may compounds that modulate P-glycoprotein-associated MDR: a basic nitrogen atom and two planar aromatic rings. In the present study, we wished to test more rigorously the hypothesis that not only are these domains necessary for modulators of MDR but also they must exist in an appropriate conformation. Reserpine is a modulator of MDR in which these domains are present in a well-defined conformation. Accordingly, we prepared eight compounds that vary the spatial orientation of these domains, using either naturally occurring reserpine or yohimbine as chemical templates. When tested for their ability to enhance the cytotoxic activity of natural product antitumor drugs in CEM/VLB100 cells, five compounds that retained the pendant benzoyl function in an appropriate spatial orientation all modulated MDR. By contrast, compounds lacking this moiety failed to do so. These active modulators competed strongly with the 125I-labeled vinblastine analog for binding to P-glycoprotein in plasma membrane vesicles prepared from these cells. Conformational analysis using molecular mechanics revealed the structural similarities of the active modulators. Our results support the hypothesis that the relative disposition of aromatic rings and basic nitrogen atom is important for modulators of P-glycoprotein-associated MDR, and they suggest a ligand-receptor relationship for these agents. These results also provide direction for the definition of an MDR "pharmacophore.".