Quantitative structure-cytotoxicity relationship analysis of 3-formylchromone derivatives by a semiempirical molecular-orbital method with the concept of absolute hardness.

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 (DeltaH), followed by electron affinity, lowest unoccupied molecular orbital energy (ELUMO), highest occupied molecular orbital energy (EHOMO), ionization potential, absolute electron negativity (chi) and reactivity index (omega). When the value for [1], which was off from the regression line, was omitted, higher correlation coefficients were obtained between CC50 and electron affinity, ELUMO, chi and omega. 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 DeltaH, electron affinity, ELUMO, chi and omega. 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.