Terpene conjugates of diaminedichloridoplatinum(II) complexes: Antiproliferative effects in HL-60 leukemia, 518A2 melanoma, and HT-29 colon cancer cells

Twenty-eight [6-(aminomethyl)nicotinate]dichloridoplatinum (II) complexes 1 esterified with various terpene alcohols either directly or via alkyl spacers were tested for antiproliferative activity in human 518A2 melanoma and HL-60 leukemia cells. Generally, conjugates with menthanes and polycyclic sesquiterpenes attached via propane-1,2-diyl spacers were most active. In the melanoma cells, the propane-12-diyl-spacered conjugates of (-)-menthol (1a(2')), (+)-neomenthol (1b(2')), (-)-carvomenthol (1h(2')), and (-)-isolongifolol (1n(2')) displayed growth inhibition at IC(50 <)4 mu M which is ten times smaller than that of cisplatin. The stationary diamino ligand was also crucial. The (-)-menthyl ester complexes with 23-diaminopropanoate (9a) and 2.4-diaminobutanoate (10a) ligands caused a greater and persistent growth inhibition in HT-29 colon cancer Cells upon long-term exposure when compared to the 6-(aminomethyl)nicotinate analogue 1a. The cedrenyl ester II and the menthoxyisopropyl ester 1a(2') proved most efficacious in all three tumor cell lines. The DNA binding of complexes 1 was assessed by electrophoretic band-shift experiments and found correlated to the terpene structure but not to the observed antiproliferative activities.