Structure Based Design of Tubulin Binding 9-Arylimino Noscapinoids: Chemical Synthesis and Experimental Validation Against Breast Cancer Cell Lines

Abstract

A novel class of noscapine derivatives known as 9-arylimino noscapinoids was designed by substituting arylimino groups (Schiff bases) at the C-9 position. These molecules were docked with αβ-tubulin complex and a panel of three top scoring molecules, 4-6 based on docking score were screened out. These molecules bind tubulin with robust predicted binding energy of -37.24 kcal/mol and -45.41 kcal/mol for 4, -39.73 kcal/mol and -47.74 kcal/mol for 5, and -43.62 kcal/mol and -49.72 kcal/mol for 6 respectively compared to noscapine (-34.47 kcal/mol and -40.27 kcal/mol) using molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA). These three molecules were chemically synthesized and demonstrated experimentally to bind tubulin with high affinity compared to noscapine. The anti-proliferative activity of 4-6 revealed inhibitory concentration (IC50 value) in between 3.6 to 32.6 µM using MCF-7 and MDA-MB-231 human breast cancer cell lines and a group of primary breast tumor cells. All three molecules were shown to inhibit the mitotic progression at the G2/M phase and induce apoptosis to cancer cells at a different level. Thus, we conclude that 9-arylimino noscapinoids 4-6 have tremendous potential as chemotherapeutic agents for the treatment of breast cancer.