Dipartimento di Farmacia, Università degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 W 168th St., New York, NY 10032, USA.
Eur J Med Chem. 2015 Jan 27;90:1-9. doi: 10.1016/j.ejmech.2014.11.012. Epub 2014 Nov 6.
In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuation of this work, here we report the asymmetric synthesis of compounds (R)-(+)-MRJF4 and (S)-(-)-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastoma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(+)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy.
在之前的工作中，我们报道了（±）-MRJF4 的抗增殖作用，（±）-MRJF4 是一种新型氟哌啶醇代谢物 II（HP-mII）（一种sigma-1 拮抗剂和 sigma-2 激动剂）前药，通过酯键与 4-苯丁酸（PhBA）[组蛋白去乙酰化酶抑制剂（HDACi）]连接得到。作为这项工作的延续，我们在这里报告了化合物（R）-（+）-MRJF4 和（S）-（-）-MRJF4 的不对称合成，并评估了它们在源自多形性胶质母细胞瘤（GBM）的大鼠 C6 神经胶质瘤细胞中的生物活性，GBM 是最常见和最致命的中枢神经系统（CNS）侵袭性恶性肿瘤。有利的物理化学性质、在平行人工膜透过性测定（PAMPA）中的高通透性、良好的酶和化学稳定性、体内抗癌活性，以及降低细胞活力和通过细胞凋亡增加细胞死亡的能力，使化合物（R）-（+）-MRJF4 成为开发用于神经胶质瘤治疗的有用治疗药物的有前途的候选药物。
