Design, Synthesis, and Anti leukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)
Design, Synthesis, and Anti leukemic Activity of Stereochemically Defined Constrained Analogues of FTY720 (Gilenya)
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DOI：
10.1021/ml4002425
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发表时间：
2013-10-01
影响因子：
4.2
通讯作者：
Hanessian, Stephen
中科院分区：
文献类型：
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作者：
Fransson, Rebecca;McCracken, Alison N.;Hanessian, Stephen
FTY720由于其对鞘氨醇-1-磷酸受体的作用而发挥免疫抑制剂的作用。当剂量远高于免疫抑制所需的剂量时，FTY720也具有抗肿瘤作用。我们发表的研究表明，FTY720的抗癌活性至少部分独立于其对SIP受体的作用，而是由于其诱导营养转运蛋白下调的能力。触发营养转运体损失但缺乏FTY720的SIP受体相关的剂量限制性毒性的化合物有可能成为有效和选择性的抗肿瘤药物。本研究生成了一系列对映体纯度高、立体化学结构多样的吡咯烷类o取代苯醚，并对其杀伤人白血病细胞的能力进行了测试。羟基甲基的立体化学被发现是化合物活性的关键决定因素。此外，抗白血病活性并不需要这一组的磷酸化。
FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has antineoplastic actions. Our published work suggests that at least some of FTY720's anticancer activity is independent of its effects on SIP receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's SIP receptor-related, dose-limiting toxicity have the potential to be effective and selective antitumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for antileukemic activity.