Estimation of relationship between the structure of 1,2,3,4-tetrahydroisoquinoline derivatives determined by a semiempirical molecular-orbital method and their cytotoxicity.

A semiempirical molecular-orbital method (CAChe 4.9, PM5) was applied to delineate the relationship between the cytotoxicity (evaluated by 50% cytotoxic concentration, CC(50)) of nineteen 1,2,3,4-tetrahydroisoquinoline derivatives, their molecular weight and the sixteen chemical parameters (descriptors) determined by CONFLEX/PM5 method. There was little or no correlation between the CC(50) in HL-60 cells and the heat of formation, stability of hydration (DeltaH), dipole moment, electron affinity, ionization potential, highest occupied molecular orbital energy (E(HOMO)), lowest unoccupied molecular orbital energy (E(LUMO)), absolute hardness (eta, softness and hardness of the molecule) or molecular weight (r(2)<0.312). On the other hand, there was a good correlation between the CC(50) and the hydrophobicity (log P) (r(2)=0.503), and the descriptors for the molecular size such as surface area (r(2)=0.771), volume (r(2)=0.805) and width (r(2)=0.757). Similar, but not so clear-cut correlation was found in HSC-2, HSC-3 and HSC-4 human oral squamous cell carcinoma cell lines. The present study demonstrates that the cytotoxicity of 1,2,3,4-tetrahydroisoquinoline derivatives depends more on the descriptors for molecular size rather than the physicochemical descriptors.