Abstract:
In this paper, we have established methylenebis (4-hydroxy-2H-chromen-2-one) as a promising anticancer
scaffold with kinesin spindle protein (KSP) inhibitory activity under malignant condition. A series of biscoumarin
derivatives (MN1 to MN30) with different substituent were synthesized, and their anticancer activity was
explored. Six biscoumarin derivatives that were found active were further selected to formulate organic nanoparticles
(ONPs). Anticancer activity of both the forms (viz conventional and ONPs) was compared. MN30 was
found most potent whereby MN10 showed good anticancer activity in both, i.e., conventional and ONP form; the
structural activity relationship (SAR) study has been established. Computational investigation revealed biscoumarin
scaffold as a suitable pharmacophore to bind against KSP protein. Molecular dynamics simulation
studies revealed protein-ligand stability and dynamic behavior of biscoumarin-KSP complex. Finally, accruing
signal transduction model was formulated to explain the observed MTT trend of conventional and ONP form.
The model seems useful towards solving population specific varied results of chemotherapeutic agents.
According to the model, MN10 and MN30 derivatives have good pharmacodynamics inertia and therefore, both
the molecules were able to provide dose-dependent cytotoxic results.
