Estimation of Relationship between the Structure of Trihaloacetylazulene Derivatives Determined by a Semiempirical Molecular–Orbital Method (PM5) and their Cytotoxicity

We have previously reported the cytotoxicity and type of cell death induced by twenty trihaloacetylazulenes in human tumor cell lines. We determined for the first time the most-stable chemical structures from their reported structures, using the semiempirical molecular—orbital method (CONFLEX/PM5), and then delineated the relationship between their cytotoxicity (evaluated by 50% cytotoxic concentration, CC 50 ) and a total of twelve parameters. The parameters used are the molecular weight and eleven chemical descriptors: the heat of formation (COSMO, non-COSMO), stability of hydration (=COSMO -nonCOSMO (ΔH)), dipole moment (D), hydrophobicity (log P), highest occupied molecular orbital energy (E HOMO ), lowest unoccupied molecular orbital energy (E LUMO ), absolute hardness [η=(E LUMO -E HOMO )/2], absolute electron negativity [χ=-(E LUMO +E HOMO )/2], reactivity index (ω=χ 2 /2η) and surface area (A 2 ), and volume of the molecule (A 3 ). There was good correlation between the CC 50 value and all descriptors except for absolute hardness in HL-60 cells. There was also a good correlation between the CC 50 value and EHOMO, χ, ω, surface area, volume and molecular weight in HSC-2, HSC-3 and HSC-4 cells. The descriptors determined by the present method are useful in evaluating the biological activity of trihaloacetylazulenes.