Fransson Rebecca, McCracken Alison N, Chen Bin, McMonigle Ryan J, Edinger Aimee L, Hanessian Stephen
Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, Que., H3C 3J7, Canada.
ACS Med Chem Lett. 2013 Oct 10;4(10):969-73. doi: 10.1021/ml4002425.
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 anti-neoplastic actions. Our published work suggests that at least some of FTY720's anti-cancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective anti-tumor 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 anti-leukemic activity.
FTY720因其对1-磷酸鞘氨醇受体的作用而作为一种免疫抑制剂发挥作用。在远高于免疫抑制所需剂量时，FTY720也具有抗肿瘤作用。我们已发表的研究表明，FTY720的抗癌活性至少有一部分与其对S1P受体的作用无关，而是由于其诱导营养转运蛋白下调的能力。能够引发营养转运蛋白缺失但缺乏FTY720与S1P受体相关的剂量限制性毒性的化合物，有可能成为有效的选择性抗肿瘤药物。在本研究中，合成了一系列对映体纯且立体化学多样的吡咯烷O-取代苄基醚，并测试了它们杀死人白血病细胞的能力。发现羟甲基的立体化学是化合物活性的关键决定因素。此外，该基团的磷酸化对于抗白血病活性并非必需。
