COMPARATIVE MOLECULAR-FIELD ANALYSIS-BASED PREDICTIVE MODEL OF STRUCTURE-FUNCTION-RELATIONSHIPS OF POLYAMINE TRANSPORT INHIBITORS IN L1210 CELLS

Maintenance of intracellular polyamine concentrations necessary for ce ll growth and proliferation is regulated in part by an energy-dependen t polyamine uptake system, To obtain information on the characteristic s of the polyamine uptake system in L1210 leukemia cells, we have appl ied computational chemistry techniques to the study of relationships b etween structure and function of 57 polyamine analogues, K-i values of polyamine analogues, derived from competitive inhibition of [H-3]sper midine transport into L1210 cells, were chosen as the measure of biolo gical activity, Using comparative molecular field analysis (CoMFA), a model was constructed to relate molecular structure with biological ac tivity, The model was based on 4 monocationic, 8 dicationic, 14 tricat ionic, and 20 tetracationic polyamine analogues with a range of K-i va lues for the inhibition of [H-3]spermidine uptake of 0.97-521 mu M. Th e CoMFA model successfully predicted the inhibitory potency of 11 poly amines that had not previously been tested for polyamine uptake inhibi tory activity, The 11 values predicted were within 33 +/- 62% of the a ctual K-i values, The test group included aziridinyl diamines, acetyla ted spermidines, two new oxazolidinonyl spermidines, monoaziridinyl sp ermidines, and a diaziridinyl spermine, Several of the compounds from this test group have been shown to have anticancer activity in mice, C onsistent with the CoMFA model, certain basic functional groups, such as aziridines that have pK(a) values in the range of 6-7, seem to inte ract with the polyamine transporter in a cationic form, The results su ggest that the CoMFA model is useful in drug design strategies as a pr edictive tool for the discovery of new anticancer agents that utilize a polyamine transporter for cellular uptake.