Background: Prostate cancer is still one of the serious causes of mortality and morbidity in men. Despite recent advances in anticancer therapy, there is a still need of novel agents with more efficacy and specificity in the treatment of prostate cancer. Because of its function on angiogenesis and overexpression in the prostate cancer, methionine aminopeptidase-2 (MetAP-2) has been a potential target for novel drug design recently.

Objective: A novel series of Flurbiprofen derivatives N-(substituted)-2-(2-(2-fluoro-[1,1'- biphenyl]-4-il)propanoyl)hydrazinocarbothioamide (3a-c), 4-substituted-3-(1-(2-fluoro-[1,1'-biphenyl]- 4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (4a-d), 3-(substitutedthio)-4-(substituted-phenyl)- 5-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4H-1,2,4-triazole (5a-y) were synthesized. The purpose of the research was to evaluate these derivatives against MetAP-2 in vitro and in silico to obtain novel specific and effective anticancer agents against prostate cancer.

Methods: The chemical structures and purities of the compounds were defined by spectral methods (1H-NMR, 13C-NMR, HR-MS and FT-IR) and elemental analysis. Anticancer activities of the compounds were evaluated in vitro by using MTS method against PC-3 and DU-143 (androgenindependent human prostate cancer cell lines) and LNCaP (androgen-sensitive human prostate adenocarcinoma) prostate cancer cell lines. Cisplatin was used as a positive sensitivity reference standard.

Results: Compounds 5b and 5u; 3c, 5b and 5y; 4d and 5o showed the most potent biological activity against PC3 cancer cell line (IC50= 27.1 μM, and 5.12 μM, respectively), DU-145 cancer cell line (IC50= 11.55 μM, 6.9 μM and 9.54 μM, respectively) and LNCaP cancer cell line (IC50= 11.45 μM and 26.91 μM, respectively). Some compounds were evaluated for their apoptotic caspases protein expression (EGFR/PI3K/AKT pathway) by Western blot analysis in androgen independent- PC3 cells. BAX, caspase 9, caspsase 3 and anti-apoptotic BcL-2 mRNA levels of some compounds were also investigated. In addition, molecular modeling studies of the compounds on MetAP-2 enzyme active site were evaluated in order to get insight into binding mode and energy.

Conclusion: A series of Flurbiprofen-thioether derivatives were synthesized. This study presented that some of the synthesized compounds have remarkable anticancer and apoptotic activities against prostate cancer cells. Also, molecular modeling studies exhibited that there is a correlation between molecular modeling and anticancer activity results.

背景：前列腺癌仍然是男性死亡和发病的严重原因之一。尽管抗癌疗法方面有最新进展，但仍需要在前列腺癌治疗中具有更高功效和特异性的新型药物。由于其对前列腺癌中血管生成和过度表达的功能，蛋氨酸氨基肽酶-2（MetAP-2）最近已成为新药设计的潜在目标。

目的：一系列新型的氟比洛芬衍生物N-（取代的）-2-（2-（2-氟-[[1,1'-联苯] -4-il）丙酰基）肼基碳硫代酰胺（3a-c），4-取代的- 3-（1-（2-氟-[[1,1'-联苯] -4-基）乙基）-1H-1,2,4-三唑-5（4H）-硫酮（4a-d），3- （取代的硫代）-4-（取代的苯基）-5-（1-（2-氟-[1,1'-联苯] -4-基）乙基）-4H-1,2,4-三唑（5a- y）被合成。该研究的目的是在体外和计算机上评估这些针对MetAP-2的衍生物，以获得针对前列腺癌的新型特异性和有效抗癌药。

方法：通过光谱方法（1 H-NMR，13 C-NMR，HR-MS和FT-IR）和元素分析确定化合物的化学结构和纯度。通过使用MTS方法体外评估PC-3和DU-143（雄激素非依赖性人前列腺癌细胞系）和LNCaP（雄激素敏感性人前列腺腺癌）前列腺癌细胞系的化合物的抗癌活性。顺铂用作阳性灵敏度参考标准。

结果：化合物5b和5u。3c，5b和5y；4d和5o显示出对PC3癌细胞系（IC50 = 27.1μM和5.12μM），DU-145癌细胞系（IC50 = 11.55μM，6.9μM和9.54μM）和LNCaP癌症的最强生物学活性细胞系（IC50分别为11.45μM和26.91μM）。通过蛋白质印迹分析在雄激素非依赖性PC3细胞中评估了某些化合物的凋亡胱天蛋白酶蛋白表达（EGFR / PI3K / AKT途径）。还研究了某些化合物的BAX，胱天蛋白酶9，胱天蛋白酶3和抗凋亡BcL-2 mRNA水平。此外，对化合物在MetAP-2酶活性位点上的分子建模研究进行了评估，以深入了解结合模式和能量。

结论：合成了一系列氟比洛芬-硫醚衍生物。这项研究表明，某些合成的化合物对前列腺癌细胞具有显着的抗癌和凋亡活性。此外，分子模型研究显示分子模型与抗癌活性结果之间存在相关性。