Quantitative Structure-cytotoxicity Relationship Analysis of Coumarin and its Derivatives by Semiempirical Molecular Orbital Method

Abstract

A semiempirical molecular orbital method (CAChe) was applied to delineate the relationship between cytotoxicity against the human squamous cell carcinoma line HSC-2 (evaluated by 50% cytotoxic concentration, CC₅₀) of 20 coumarin (2H-pyran-2-one) derivatives and twelve physical parameters (descriptors) calculated by the CONFLEX/PM3 method. There was a highly significant correlation between the CC₅₀ and ionization potential, highest occupied molecular orbital (HOMO) energy, difference between electron energy of HOMO and electron energy of lowest unoccupied molecular orbital (LUMO), or absolute hardness (r²=0.756~0.802). On the other hand, there was no significant correlation between the CC₅₀ and heat of formation, stability of hydration, dipole moment, electron affinity, or LUMO energy (r²=0.13~0.36). When the CC₅₀ was plotted vs. log P, a parabolic curve was produced, with a maximum cytotoxicity (or the least CC₅₀ value) at log P of 2.5. The present study demonstrated that hardness and softness, other than the electron accepting and donating properties, are important factors in estimating the cytotoxic activity of coumarin derivatives.