Synthesis of novel platinum oxadiazoline complexes with potential anti-tumour activity.

Abstract

In the framework of this project, a series of platinum 4-1,2,4-oxadiazoline complexes was produced. These complexes were tested in vitro for anti-tumour effect and have been found to exhibit anti-tumour activity in ovarian, testicular-and colon cell cultures. One complex, JS5, trans-dichlorobis{2-methyl-3- phenyl-5-(4-hydroxyphenyl)-4-1,2,4-oxadiazoline}platinum(II), trans-[PtCl2{N=C(p-HO-C6H4)-0-N(Me)-CH(Ph)}2] (product 45), proved to be twice as effective as carboplatin and also showed good activity in carboplatin resistant cell lines. Another complex JS6, trans-dichloro(4-(2-methoxyethoxy)benzonitrile){2- methyl-3-phenyl-5-(4-(2-methoxyethoxy)phenyl)-4-1,2,4-oxadiazoline}platinum(II), trans-[PtCl2(p-Me0C2H40-C6H4CN){N=C(p-Me0C2H40-C6H4)-0-N(Me)-CH(Ph)}] (product 41), proved to be more effective in carboplatin resistant cell lines than platinum sensitive ones. This suggests a binding mode different to the accepted one exhibited by cisplatin, which is to the N7 nitrogen of guanine. The synthetic strategy employed was the [2+3] cycloaddition of platinum nitrile complexes to nitrones. This method was chosen as it is a straight forward route to the platinum heterocycles, using relatively mild conditions. Also, properties such as solubility of the platinum oxadiazoline in polar solvents can easily be modified by using starting nitrones and platinum nitriles that contain polar substituents. The stalling reagents for these compounds are commercially available, simplifying the overall synthesis. In this way the ligand is constructed in the coordination sphere and subtle changes are effected without altering the basic skeleton of the complex. Nitrones of the type RC6H4CH=NOCH3 (R= OH, CO2H, 2-CH3OC2H4O, N(Me)2, N+(Me)3, and sodium sulphonate salt), were prepared from the corresponding aldehydes via the condensation of an aldehyde with N-methyl-hydroxylamine method. Novel platinum complexes of the type PtX2(RC6H4CN)2, (X= halogen, R = OH, 2- CH3OC2H4O, were also prepared by a modification of the Kharasch route. Both mono and bis 4-1,2,4-oxadiazolme platinum complexes were produced that were more soluble in polar solvents than previously known similar complexes. Substitution and oxidative addition reactions of the said oxadiazoline platinum complexes were also studied and are discussed. The synthesis of analogous ruthenium complexes was attempted, but ruthenium did not behave in the same way as platinum