Quantitative Structure-Cytotoxicity Relationship Analysis of 3-Formylchromone Derivatives by a Semiempirical Molecular-orbital Method with the Concept of Absolute Hardness

Abstract

A semiempirical molecular-orbital method (CAChe) was applied to delineate the relationship between the cytotoxicity (evaluated by 50% cytotoxic concentration, CC₅₀) of 11 3-formylchromone derivatives and 15 chemical parameters (descriptors). The most stable conformation of all these compounds was exhibited by the planar structure. Compounds [2], [3], [4] and [9] had additionally protruding branches from the coplanar. In HSG cells, the best correlation coefficient was observed between CC₅₀ and stability of hydration (ΔH), followed by electron affinity, lowest unoccupied molecular orbital energy (E_LUMO), highest occupied molecular orbital energy (E_HOMO), ionization potential, absolute electron negativity (χ) and reactivity index (ω). When the value for [1], which was off from the regression line, was omitted, higher correlation coefficients were obtained between CC₅₀ and electron affinity, E_LUMO, χ and ω. When CC₅₀ value was plotted vs. log P, a parabolic curve was produced, under the condition that the data for [5] were omitted. In HL-60 cells, moderate correlation was found between CC₅₀ and ΔH, electron affinity, E_LUMO, χ and ω. When the values for [1] and [6], which were off the regression line, were omitted, higher correlation coefficients were obtained between CC₅₀ and these five descriptors. In HSC-3 cells, there was moderate correlation between CC₅₀ and the dipole moment, but not with other descriptors. In HSC-2 and MT-4 cells, there was no clear-cut correlation between CC₅₀ and any of these descriptors. The present study indicates the applicability of HSG cells in searching for more active 3-formylchromone derivatives, using QSAR with the concept of absolute hardness.