Synthesis and in vitro anti-proliferative evaluation of naphthalimide-chalcone/pyrazoline conjugates as potential SERMs with computational validation

Abstract

A series of naphthalimide-chalcone/pyrazoline conjugates was prepared and evaluated for their anti-breast cancer potential against estrogen responsive, i.e. MCF-7 (ER+), and triple-negative, i.e. MDA-MB-231 (ER-), cell lines. The structure-activity-relationship (SAR) was deduced based on the influence of linker length, substituents on the phenyl ring and the generated functionalities, on anti-proliferative activities. Docking simulations further delineate the type of interactions of the designed molecules with the selected targets. This report discloses the scope of triazole tethered naphthalimide-chalcone/pyrazoline conjugates as anti breast cancer agents.

Scheme 1. Reagents and conditions: (a) ethanol amine (n = 2)/propanol amine (n = 3), ethanol, reflux, 1 h (b) mesyl chloride, Et₃N, dry CHCl₃, RT, 3 h (c) NaN₃, DMF, 60 °C, 2 h.

Scheme 2. Reagents and conditions: (a) NaOH (40% w/v), ethanol, RT, 1 h (b) hydrazine hydrate, acetic acid, 130 °C, reflux, 2 h.

Scheme 3. Reagents and condition: (a) CuSO_4, sodium ascorbate, EtOH : H₂O (90 : 10), RT, 10 h.

Fig. 1. Representative graphs comparing the percentage growth inhibition of MCF-7 and MDA-MB-231 cells at selected concentrations of test compounds. 40 μM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D (n = 3), where *p < 0.05, **p < 0.01 and ***p < 0.001 significant difference to untreated control.

Fig. 2. Generalized SAR of the synthesized compounds.

Fig. 3. Representative graph comparing the percentage growth inhibition of HEK-293 cells at selected concentrations of test compounds 13f and 13g. 40 μM Plumbagin was used as a positive control. Data are mean ± standard deviation S.D (n = 3), where *p < 0.05, **p < 0.01 and ***p < 0.001 significant difference to untreated control.

Fig. 4. The docked binding modes of (a) 13f and (b) 13g in the binding site of ERα (PDB:3ERT).

Fig. 5. The docked binding modes of (a) 13f and (b) 13g in the binding site of ERβ (PDB:3LOS).

Fig. 6. The docked binding modes of 13h in the binding site of (a) ERα and (b) ERβ.