A COMPARATIVE MOLECULAR-FIELD ANALYSIS OF PROPAFENONE-TYPE MODULATORSOF CANCER MULTIDRUG-RESISTANCE

The presented 3D-QSAR is based on literature data of daunomycin MTT cy totoxicity and rhodamine-123 efflux inhibition activity in CCRF-CEMvcr 1000 multidrug resistant (MDR) tumor cell line of 28 compounds from th e propafenone and benzofuran classes. A systematic conformational sear ch of the most active compounds in their classes was performed and the resulting minimum energy conformations were used in the further analy sis. The structures were superimposed according to two different align ment rules using both, rms and field fit alignment techniques. A numbe r of ComFA models were derived using the standard CoMFA steric and ele ctrostatic fields as well as hydrophobic fields. Most of the models we re statistically significant and highly predictive. Better CoMFA model s were obtained for MTT cytotoxicity assay than for rhodamine-123 effl ux inhibition assay activity data. The hydrophobic fields alone and in combination with the steric and both, (steric and electrostatic) fiel ds yielded the models with the highest cross-validated coefficients of explained variance. The results show that the differences in MDR-modu lating activity of the compounds of different classes can be explained if based on hydrophobicity as a space directed molecular property.