Hydroxyl-substituted double Schiff-base condensed 4-piperidone/cyclohexanones as potential anticancer agents with biological evaluation

Lianshuang Zhang,Qin Chen,Guige Hou,Wei Zhao,Yun Hou

doi:10.1080/14756366.2018.1501042

Abstract

Novel hydroxyl-substituted double Schiff-base 4-piperidone/cyclohexanone derivatives, 3a–e, 4a–e, 5a–d, and 6a–c, were synthesized and fully characterized by 1H NMR, IR and elemental analysis. The cytotoxicity against human carcinoma cell lines A549, SGC7901, HePG2, HeLa, K562, THP-1 and non-malignant LO2 cell lines were evaluated. The results showed 4-piperidinone derivatives displayed better cytotoxicity than cyclohexanone derivatives, especially for 3,4,5-trihydroxyphenyl-substituted BAP 5c. The western blot and flow cytometry results proved 5c can effectively promote cell apoptosis through up-regulating Bax protein and down-regulating Bcl-2 protein expression. Molecular docking modes showed that 5c could reasonably bind to the active site of Bcl-2 protein through strong intermolecular hydrogen bonds and significant hydrophobic effect. In vivo, 5c can effectively suppress the growth of HepG2 xenografts without apparent body weight changes. This study indicates that 5c can be a potential anticancer agent for early treatment of liver cancers.

Highlights

Curcumin (Figure 1), a major active component of the food flavor turmeric, has anti-inflammatory, antibacterial, anticancer and antioxidant activities[1]
Some 2,6-dibenzylidenecyclohexanone and 3,5-bis(arylidene)-4-piperidone derivatives (BAPs) were synthesized and evaluated bioactivity. These compounds generally possess the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore into their structures to form one or more a,b-unsaturated keto groups, which can react preferentially or exclusively with thiols in contrast to amino and hydroxy groups resulting in a greater chemosensitivity to tumors rather than with normal cells[7,8]
Schiff-base compounds with active –C 1⁄4 N group can be a good donor site or an active ligand, which exhibits a range of biological activities, including antifungal, antiviral, anticancer, antibacterial and anti-inflammatory properties[21–26]

Summary

Introduction

Curcumin (Figure 1), a major active component of the food flavor turmeric, has anti-inflammatory, antibacterial, anticancer and antioxidant activities[1]. Curcumin and its analogues containing the pharmacophore of 1,5-diaryl-3-oxo-1,4-pentadienyl, are thought to interact at the primary binding site, bio-thiols from susceptible neoplasms Another pharmacophore of methoxyphenol groups at an auxiliary site can influence their bio-activities. Some 2,6-dibenzylidenecyclohexanone and 3,5-bis(arylidene)-4-piperidone derivatives (BAPs) were synthesized and evaluated bioactivity These compounds generally possess the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore into their structures to form one or more a,b-unsaturated keto groups, which can react preferentially or exclusively with thiols in contrast to amino and hydroxy groups resulting in a greater chemosensitivity to tumors rather than with normal cells[7,8]. Some symmetric or dissymmetric N-substituted-3,5bis(arylidene)-4-piperidone derivatives as anticancer agents were reported by our group[15,16]. Schiff-base compounds with active –C 1⁄4 N group can be a good donor site or an active ligand, which exhibits a range of biological activities, including antifungal, antiviral, anticancer, antibacterial and anti-inflammatory properties[21–26]. Interests lie in incorporation of amino-substituted 3,5-bis(arylidene)-4-piperidone derivatives and phenolic hydroxyl-substituted aromatic aldehydes to construct phenolic hydroxyl-substituted double Schiff-base 4-piperidone/cyclohexanone derivatives with desired antitumor activity

Materials and methods

ZHANG ET AL

Results and discussion

Conclusions