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
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.