In this study, (S)-naproxen thiosemicarbazides (3a-d), 1,2,4-triazoles (4a-c), triazole-thioether hybride compounds (5a-p) were synthesized and their structures (3a, 3d, 4a and 5a-p) were confirmed by FT-IR, ¹H NMR,¹³C NMR, HR-Mass spectra and elemental analysis. These compounds are designed to inhibit methionine amino peptidase-2 (MetAP2) enzyme in prostate cancer. These compounds (3d, 5a-p) evaluated against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using MTS method. Compounds 5a, 5b, 5d and 5e showed 14.2, 5.8, 10.8 and 8.4 μM anticancer activity against PC-3 cell lines, compounds 5e, 5g and 5n presented anticancer activity against DU-145 cell lines 18.8, 12.25 and 10.2 μM, and compounds 5g, 5m and 5n exhibited anticancer activity against LNCaP cell lines 12.25, 22.76 and 2.21 μM, respectively. Consequently, of these results, compounds 5e and 5n showed the highest activities against androgen dependent and independent prostate cancer cell lines, so these compounds could be potent small molecules against prostate cancer. Furthermore, mitogen-activated protein kinase (MAPK) pathway activation, AKT (protein kinase B) phosphorylation and androgen receptor activation of compound 5n (SGK636) were investigated in LNCaP cells by using Western blot method. Compound 5n (SGK636) was also tested against mRNA expression analysis of the Bax, Bcl-2, Caspase 3, Caspase 9 by using real-time PCR analysis. Compound 5n was given to nude male mice with cancer in comparison to the control group. Compound 5n was found to reverse the malignant phenotype in the nude male mice, whereas the prostate cancer progressed in the control group. Analysis of some blood parameters in the study showed that they were within the normal values with respect to the control. The blood values of the animals treated according to the control group also exhibited compliance with the blood limit values. Molecular docking and dynamics simulation of compound 5n binding to Methionine Aminopeptidase 2 (MetAP2) enzyme rationalized its potential activity. In addition, inhibition assay MetAP2 enzyme of compound 5n was evaluated. Taken together, we suggest compound 5n to be a potential candidate for prostate cancer therapy.

在这项研究中，合成了（S）-萘普生硫代氨基脲（3a-d），1,2,4-三唑（4a-c），三唑-硫醚杂化化合物（5a-p）及其结构（3a，3d，4a和图5a-p ）通过FT-IR，确认¹ H NMR，¹³ C NMR，HR-质谱和元素分析。这些化合物旨在抑制前列腺癌中的蛋氨酸氨基肽酶2（MetAP2）酶。通过使用MTS方法评估了这些化合物（3d，5a-p）对雄激素非依赖性前列腺腺癌（PC-3，DU-145）和雄激素非依赖性前列腺腺癌（LNCaP）细胞系的影响。化合物5a，图5b，5d和5e显示了对PC-3细胞系的14.2、5.8、10.8和8.4μM抗癌活性，化合物5e，5g和5n表现出对DU-145细胞系18.8、12.25和10.2μM的抗癌活性，以及​​化合物5g，5m 5n和5n分别对LNCaP细胞系12.25、22.76和2.21μM具有抗癌活性。因此，在这些结果中，化合物5e和5n在对雄激素依赖性和非依赖性前列腺癌细胞系具有最高的活性，因此这些化合物可能是对抗前列腺癌的有效小分子。此外，使用蛋白质印迹法研究了LNCaP细胞中化合物5n（SGK636）的有丝分裂原活化蛋白激酶（MAPK）途径活化，AKT（蛋白激酶B）磷酸化和雄激素受体活化。还通过使用实时PCR分析，针对Bax，Bcl-2，Caspase 3，Caspase 9的mRNA表达分析测试了化合物5n（SGK636）。与对照组相比，将化合物5n给予患有癌症的裸性雄性小鼠。复合5n发现前列腺癌可逆转裸鼠的恶性表型，而对照组则进展为前列腺癌。对研究中某些血液参数的分析表明，相对于对照，它们在正常值范围内。根据对照组治疗的动物的血液值也显示出符合血液极限值。化合物5n结合蛋氨酸氨基肽酶2（MetAP2）酶的分子对接和动力学模拟合理化了其潜在活性。另外，评价了化合物5n的抑制试验MetAP2酶。两者合计，我们建议化合物5n是前列腺癌治疗的潜在候选者。