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Comparative Molecular Field Analysis-based Predictive Model of Structure-Function Relationships of Polyamine Transport Inhibitors in L1210 Cells¹

Department of Pharmaceutical Sciences, School of Pharmacy [Y. L., A. D. M., Y-Y. W., D. A. B., P. S. C.]; Division of Developmental Therapeutics [M. J. E., M. F. B., D. M. R.] and Oncology Program [M. J. E., P. S. C.], University of Maryland Cancer Center; and Division of Hematology-Oncology, Department of Medicine, School of Medicine [M. J. E.], University of Maryland, Baltimore, Maryland 21201

Maintenance of intracellular polyamine concentrations necessary for cell growth and proliferation is regulated in part by an energy-dependent polyamine uptake system. To obtain information on the characteristics of the polyamine uptake system in L1210 leukemia cells, we have applied computational chemistry techniques to the study of relationships between structure and function of 57 polyamine analogues. K_i values of polyamine analogues, derived from competitive inhibition of [³H]spermidine transport into L1210 cells, were chosen as the measure of biological activity. Using comparative molecular field analysis (CoMFA), a model was constructed to relate molecular structure with biological activity. The model was based on 4 monocationic, 8 dicationic, 14 tricationic, and 20 tetracationic polyamine analogues with a range of K_i values for the inhibition of [³H]spermidine uptake of 0.97–521 µM. The CoMFA model successfully predicted the inhibitory potency of 11 polyamines that had not previously been tested for polyamine uptake inhibitory activity. The 11 values predicted were within 33 ± 62% of the actual K_i values. The test group included aziridinyl diamines, acetylated spermidines, two new oxazolidinonyl spermidines, monoaziridinyl spermidines, and a diaziridinyl spermine. Several of the compounds from this test group have been shown to have anticancer activity in mice. Consistent with the CoMFA model, certain basic functional groups, such as aziridines that have pK_a values in the range of 6–7, seem to interact with the polyamine transporter in a cationic form. The results suggest that the CoMFA model is useful in drug design strategies as a predictive tool for the discovery of new anticancer agents that utilize a polyamine transporter for cellular uptake.

¹ Supported in part by the Mildred Mindell Cancer Foundation and a H. A. B. Dunning Graduate Fellowship (Y. L.).

² To whom requests for reprints should be addressed, at Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N. Pine Street, Baltimore, MD 21201.

Received 6/ 7/96. Accepted 11/14/96.