Estimation of relationship between descriptors and cytotoxicity of newly synthesized 1,2,3,4-tetrahydroisoquinoline derivatives.

We recently demonstrated that the cytotoxicity of nineteen 1,2,3,4-tetrahydroisoquinoline derivatives depends on the molecular size (surface area, volume, width measured at 3-dimensional configuration), but not on most of the other electronic factors (Ishihara et al., Anticancer Res 29: 2265-2272, 2009). However, the information regarding cytotoxicity and molecular size in these compounds is limited. Here, a quantitative structure-activity relationship (QSAR) analysis using nineteen newly synthesized 1,2,3,4-tetrahydroisoquinoline derivatives was carried out. 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 the nineteen derivatives (TD1-19) against human promyelocytic leukemia HL-60 and human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4) cell lines and sixteen chemical descriptors determined by CONFLEX/PM5 method or the molecular weight. There was some correlation between the CC(50) and the dipole moment for HSC-4 cells (r(2)=0.273), between the CC and log P for HL-60 and HSC-3 cells (r(2) 50 =0.191-0.212), and between the CC(50) and distance of C-R(2) (at three dimensional configuration) (r(2)=0.394) and molecular weight (r(2)=0.292) for HL-60 cells. On the other hand, there was little or no correlation between the CC(50) and other descriptors. The present study demonstrated the dependency of the cytotoxicity of 1,2,3,4-tetrahydroisoquinoline derivatives on hydrophobicity and distance between C-R(2) in the 3-dimensional configuration. These descriptors obtained from the CONFLEX/PM5 method may be utilized as a tool to analyze the biological effect of 1,2,3,4-tetrahydroisoquinolines.