Synthesis and characterization of new platinum(II) complexes with cyclic iminoether-type ligands having the azomethine group out of cycle

Abstract The trans isomer of cisplatin, transplatin, is an inactive platinum drug; however, a number of analogues, such as trans complexes with iminoether, thiazole and isopropylamine ligands, demonstrate promising antitumor activity in vitro and in vivo. In the particular case of iminoether ligands, HN=C(R)OR’, due to the presence of a double bond, two configurations, E and Z, can exist and isomerization between the two forms has been observed sometime in solution. An attempt to stabilize the ligand configuration was to block the geometry of the ligand by inserting the iminic double bond into a cycle; this led to the synthesis of platinum complexes with 5-methoxy-3,4-dihydropyrrole, {N=C(OCH3)CH2CH2CH2}, and 2-methyl-4,5-dihydro-1,3-oxazole, {N=C(CH3)OCH2CH2}, in which, however, the ligand is deprived of a proton on the coordinating iminic nitrogen considered to be a key feature for the interaction of the platinum drug with target DNA. In this paper we describe the synthesis and characterization of platinum complexes with the 2-iminotetrahydrofuran ligand, {HN=COCH2CH2CH2}, where the iminic nitrogen is outside the cycle and can keep its proton. Apart from the isolation of the pure E and Z isomers (compounds 2-E and 2-Z) we also prepared the diiodido derivative (compound 1) and the cis isomer (compound 3).