Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Eur J Med Chem. 2011 Jan;46(1):433-8. doi: 10.1016/j.ejmech.2010.10.012. Epub 2010 Oct 15.
Complex mechanisms of prostate cancer progression prompt to novel therapeutic strategies concerning a combination of drugs or of single molecules able to interact with more crucial targets. Histone deacetylase inhibitors and sigma ligands with mixed σ(1) antagonist and σ(2) agonist properties were proposed as new potential tools for treatment of prostate cancer. (±)-MRJF4 was synthesized as phenylbutyrate ester of haloperidol metabolite II, which is a molecule consisting of a histone deacetilase inhibitor (4-phenylbutyric acid) and a sigma ligand (haloperidol metabolite II). Antiproliferatives activities of 4-phenylbutyric acid, haloperidol metabolite II, equimolar mixture of both compounds and (±)-MRJF4 were evaluated in vitro on LNCaP and PC3 prostate cancer cells. Preliminary binding studies of (±)-MRJF4 for σ(1), σ(2), D(2) and D(3) receptors and inhibition HDAC activity were reported. MTT cell viability assays highlighted a notable increase of antiproliferative activity of (±)-MRJF4 (IC(50) = 11 and 13 μM for LNCaP and PC3, respectively) compared to 4-phenylbutyric acid, haloperidol metabolite II and the respective equimolar pharmacological association. (±)-MRJF4 was also used in combination with σ(1) agonist (+)-pentazocine and σ(2) antagonist AC927 in order to evaluate the role of σ receptor subtypes in prostate cancer cell death.
前列腺癌进展的复杂机制促使人们寻求新的治疗策略，包括药物联合治疗或使用能够与更关键靶点相互作用的单一分子。组蛋白去乙酰化酶抑制剂和具有混合 σ(1)拮抗剂和 σ(2)激动剂特性的 sigma 配体被提议作为治疗前列腺癌的新潜在工具。(±)-MRJF4 是作为氟哌啶醇代谢物 II 的苯丁酸钠酯合成的，它是一种由组蛋白去乙酰化酶抑制剂（4-苯丁酸）和 sigma 配体（氟哌啶醇代谢物 II）组成的分子。体外评估了 4-苯丁酸、氟哌啶醇代谢物 II、两者等摩尔混合物和 (±)-MRJF4 对 LNCaP 和 PC3 前列腺癌细胞的抗增殖活性。报告了 (±)-MRJF4 对 σ(1)、σ(2)、D(2)和 D(3)受体的初步结合研究和抑制 HDAC 活性。MTT 细胞活力测定突出显示 (±)-MRJF4 的抗增殖活性显著增加（对 LNCaP 和 PC3 的 IC(50)分别为 11 和 13 μM）与 4-苯丁酸、氟哌啶醇代谢物 II 和各自的等摩尔药理学联合相比。还将 (±)-MRJF4 与 σ(1)激动剂 (+)-戊苯嗪和 σ(2)拮抗剂 AC927 联合使用，以评估 σ 受体亚型在前列腺癌细胞死亡中的作用。
