Sterically hindered cisplatin derivatives with multiple carboxylate auxiliary arms: synthesis and reactions with guanosine-5 '-monophosphate and plasmid DNA
Baj. Jansen et al., Sterically hindered cisplatin derivatives with multiple carboxylate auxiliary arms: synthesis and reactions with guanosine-5 '-monophosphate and plasmid DNA, J INORG BIO, 85(2-3), 2001, pp. 229-235
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.