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 the ligand L=NH(2)C(CH(2)CH(2)COOH)(3) were prepared: cis-PtCl(2)L(2) and cis-PtCl(2)L(NH(3)). The starting compound for the syntheses was NH(2)C(CH(2)CH(2)COOtBu)(3), also known as a building block for dendrimers. cis-PtCl(2)L(2) was prepared from K(2)PtCl(4) in an unusual two-phase reaction in water-chloroform, followed by deprotection of the tert-butyl protective groups with formic acid to yield a water-soluble complex. The mixed-ligand compound cis-PtCl(2)L(NH(3)) was prepared from [PPh(4)][PtCl(3)(NH(3))] in methanol, with subsequent deprotection in formic acid. DNA-binding properties of the two compounds were investigated using the model base guanosine-5'-monophosphate (5'-GMP) and pBR322 plasmid DNA. While cisplatin [cis-PtCl(2)(NH(3))(2)] induced an unwinding of 12 degrees in pBR322 plasmid DNA, cis-PtCl(2)L(NH(3)) induced only 3 degrees unwinding, which is indicative of a monofunctional binding mode. Remarkably, cis-PtCl(2)L(2) did not induce any distortion in plasmid DNA, which strongly suggests that the compound does not bind to DNA. Test reactions with 5'-GMP, monitored by 1H and 195Pt NMR, confirmed that cis-PtCl(2)L(2) is unable to bind to DNA, whereas cis-PtCl(2)L(NH(3)) binds only one nucleotide. Apparently, binding of platinum to nucleotides at the coordination site cis with respect to the ligand L is prevented by steric crowding. Thus, cis-PtCl(2)L(NH(3)) must bind DNA monofunctionally at the trans position. Besides, both compounds have a chloride replaced by one of the carboxylate arms, forming a a seven-membered chelate ring. In theory, cis-PtCl(2)L(2) could also form a second chelate ring, but this was not observed.
Jansen
B A
BA
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, NL-2300 RA Leiden, The Netherlands.
Pérez
J M
JM
Pizarro
A
A
Alonso
C
C
Reedijk
J
J
Navarro-Ranninger
C
C
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D004247:DNA / Q000378:metabolism / Q000648:ultrastructure; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010957:Plasmids / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D008024:Ligands; D006157:Guanosine Monophosphate; D004247:DNA; D002945:Cisplatin