Rational design of N3-Bromo benzyl noscapine as a promising derivative of the natural lead molecule, noscapine with improved cytotoxicity effects on breast cancer cell lines

<p>We present a new derivative of a natural lead molecule, noscapine by coupling the 3-bromo benzyl functional group with the ‘N’ atom in the scaffold to develop N3-Bromo benzyl noscapine (N3-Br-Benzyl-Nos) on the basis of our in silico efforts. On the basis of the combination of molecular docking and molecular dynamics simulation studies, N3-Br-Benzyl-Nos was found to have better binding affinity towards tubulin, with a docking score of -6.727 kcal/mol, than did noscapine (-4.080 kcal/mol), and with an improved binding free energy (ΔGbinding) of -25.50 kcal/mol, than noscapine (ΔGbinding was -22.93 kcal/mol). Inspired by our in silico calculation, N3-Br-Benzyl-Nos was chemically synthesized, and its anticancer activity was validated based on cellular studies using two human breast cancer cell lines, MCF-7 and MDA-MB-231 and a normal healthy cell line (HEK). The compound N3-Br-Benzyl-Nos revealed IC50 values of 7.51 μM and 12.12 μM, respectively, without causing any toxicity to normal cells (IC50 value is 215 μM). The induction of apoptosis was analysed via FACS. Moreover, the onset of apoptosis in MDA-MB-231 cells by the treatment of N3-Br-Benzyl-Nos revealed morphological changes such as cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic body formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting the induction of cancer cell apoptosis. Additionally, N3-Br-Benzyl-Nos significantly inhibited the growth of the spheroids. These results imply that the newly designed N3-Br-Benzyl-Nos has impressive anticancer activity against breast cancer cell lines and has possible therapeutic option for the treatment of breast cancer.</p>