Curcumin mimics of potential chemoprevention with NQO1 induction properties

Abstract

Chemoprevention is one of the accessible strategies for preventing, delaying or reversing cancer processing utilizing chemical intervention of carcinogenesis. NAD(P)H quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing cytosolic enzyme/protein with important functional properties towards oxidation stress, supporting its ability in detoxification/chemoprotective role. A set of 3,5-diylidene-4-piperidones (as curcumin mimics) bearing alkyl sulfonyl group were synthesized with potential NQO1 induction properties. Compounds 5ab (R = 2-MeOC₆H₄, R' = Me) and 5ac (R = 2-MeOC₆H₄, R' = Et) are the most promising agents synthesized (% induction of NQO1 = 51.562, 45.793) relative to that of 4'-bromoflavone (4'-BF, reference standard) at 10 µM. LPS-induced iNOS production in RAW264.7 macrophages of the most promising agents discovered (5ab and 5ac) displayed concentration-dependent with comparable activities to the reference anti-inflammatory drug indomethacin. Molecular modeling studies (including QSAR, molecular docking and molecular dynamics) were accessed supporting the observed biological profiles.

Keywords: Cancer; Chemoprevention; Curcumin mimic; Molecular modeling; NQO1; Piperidone; iNOS.

Fig. 1

Design of the targeted 1-sulfonyl-3,5-ylidene-4-piperidones (curcumin mimics) with NQO1 induction properties.

Fig. 2

Synthetic route towards 5a-5ah.

Fig. 3

Western blotting of NQO1 induction by the synthesized piperidones 5w, 5x, 5ab, 5ac and 5ae. Hepa1c1c7 cells were treated for 48 h with vehicle (0.1% DMSO) or 10 µM of the tested compounds. 4’-BF was used as reference NQO1 inducer. Cell lysates were prepared and NQO1 expression was detected as mentioned in the experimental section.

Fig. 4

Western blotting showing NQO1 induction by 2.5 and 5 µM of compounds 5ab and 5ac.

Fig. 5

Densitometric analysis of the observed NQO1 induction of protein expression by compounds 5ab and 5ac at 2.5 and 5 µM.

Fig. 6

Concentration-dependent inhibition of LPS-induced NO production by 5ab and 5ac in RAW264.7 macrophages.

Fig. 7

Western blot showing concentration-dependent inhibition of LPS-induced iNOS expression by 5ab and 5ac in RAW264.7 macrophages.

Fig. 8

Densitometric analysis of Western blot of LPS-induced iNOS protein expression by 5ab and 5ac in RAW264.7 macrophages.

Fig. 9

(A), (B) docking poses (3D and 2D) of 5ab; (C), (D) docking poses (3D and 2D) of 5ac; (E) docking pose (2D) of the co-crystallized ligand in the active site of PDB: 4IQK. Figs were obtained due to docking studies and drawn by Biovia Discovery Studio Visualizer (https://discover.3ds.com/discovery-studio-visualizer-download).

Fig. 10

Total energy vs. time in production step during interaction of; (A): protein of PDB: 4IQk, (B): best conformation pose of compound 5ab in PDB: 4IQK, (C): best conformations pose of compound 5ac in PDB: 4IQK.

Fig. 11

(A): RMSD, (B): RMSF of the protein and best conformation pose of compounds 5ab and 5ac in PDB: 4IQK.