Sterically hindered cisplatin derivatives with multiple carboxylate auxiliary arms: synthesis and reactions with guanosine-5 '-monophosphate and plasmid DNA

Two novel sterically hindered cisplatin derivatives with tile Ligand L=NH2C (CH2CH2COOH)(3) were prepared: cis-PtCl2L2 and cis-PtCl2L(NH3). The startin g compound for the syntheses was NH2C(CH(2)CH(2)COOtBu)(3), also known as a building block for dendrimers. Lis-PtCL2L2 was prepared from K2PtCL4 in an unusual two-phase reaction in water-chloroform, followed by deprotection o f the tert-butyl protective groups with formic acid to yield a water-solubl e complex. The mixed-ligand compound cis-PtCl2L(NH3) was prepared from [PPh 4][PtCl3(NH3)] in methanol, with subsequent deprotection in formic acid. DN A-binding properties of the two compounds were investigated using the model base guanosine-5 ' -monophosphate (5 ' -GMP) and pBR322 plasmid DNA. While cisplatin [cis-PtCl2(NH3)(2)] induced an unwinding of 12 degrees in pBR322 plasmid DNA, cis-PtCl2L(NH3) induced only 3 degrees unwinding, which is in dicative of a monofunctional binding mode. Remarkably, cis-PtCl2L2 did not induce any distortion in plasmid DNA, which strongly suggests that the comp ound does not bind to DNA. Test reactions with 5 ' -GMP monitored by H-1 an d Pt-195 NMR, confirmed that cis-PtCl2L2 is unable to bind to DNA, whereas cis-PtCl2L(NH3) binds only one nucleotide. Apparently, binding of platinum to nucleotides at the coordination site cis with respect to the ligand I, i s prevented by steric crowding. Thus, cis-PtCl2L(NH3) must bind DNA monofun ctionally at the trans position. Besides, both compounds have a chloride re placed by one of the carboxylate arms, forming a a seven-membered chelate r ing. In theory, cis-PtCl2L2 could also form a second chelate ring, but this was not observed. (C) 2001 Elsevier Science B.V. All rights reserved.