MODIFICATION OF PLATINUM(II) ANTITUMOR COMPLEXES WITH SULFUR LIGANDS - 2 - REACTIVITY AND NUCLEOTIDE-BINDING PROPERTIES OF CATIONIC COMPLEXES OF THE TYPES [PTCL(DIAMINE)(L)]NO3 AND [(PTCL(DIAMINE))(2)(L-L)](NO3)(2) (L = MONOFUNCTIONAL THIOUREA DERIVATIVE, L-L = BIFUNCTIONAL THIOUREA DERIVATIVE) IN RELATION TO THEIR CYTOTOXICITY
U. Bierbach et al., MODIFICATION OF PLATINUM(II) ANTITUMOR COMPLEXES WITH SULFUR LIGANDS - 2 - REACTIVITY AND NUCLEOTIDE-BINDING PROPERTIES OF CATIONIC COMPLEXES OF THE TYPES [PTCL(DIAMINE)(L)]NO3 AND [(PTCL(DIAMINE))(2)(L-L)](NO3)(2) (L = MONOFUNCTIONAL THIOUREA DERIVATIVE, L-L = BIFUNCTIONAL THIOUREA DERIVATIVE) IN RELATION TO THEIR CYTOTOXICITY, Inorganic chemistry, 37(4), 1998, pp. 717-723
The reactions of [PtCl(en)(tmtu)]NO3 (1) and [PtCl(dach)(tmtu)]NO3 (2)
(en = 1,2-ethanediamine, dach = racemic trans-1,2-cyclohexanediamine,
tmtu = 1,1,3,3-tetramethylthiourea) and [{Pt(en)Cl}(2){mu-C2H4(NMeCSN
Me2)(2)-S,S}](NO3)(2) (3) and Pt(en)Cl}(2){mu-C6H12(NMeCSNMe2)(2-)S,S'
}](NO3)(2) . 0.5EtOH (4) with 5'-GMP and r(GpG) and their chemistry in
aqueous solution have been investigated by H-1 and Pt-195 NMR spectro
scopy. 1 and 2 only form the monofunctional adducts [Pt(en)(5'-GMP-N7)
(tmtu)] (I) and [Pt(dach)(5'-GMP-NT)(tmtu)] (II), irrespective of an e
xcess of free nucleotide. Pt-195 NMR chemical shifts of -3003 and -298
2 ppm, respectively, confirm a [N3S] mixed-donor environment of platin
um. The bulky tmtu ligand in 1 and 2 decreases the rate of hydrolysis
of the Pt-Cl bond and the rate of nucleotide binding compared to analo
gous reactions for cisplatin and structural analogues. The dinuclear c
omplexes 3 and 4 exhibit an unusual rapid intramolecular disproportion
ation in solution (t(1/2) = 2.5 and 12 h, respectively) which yields [
PtCl2(en)] and [Pt(en)(L-L)](2+) (L-L = chelating bifunctional thioure
a derivative; delta(Pt) -3454 with L-L = C2H4(NMeCSNMe2)(2)). Accordin
gly, 3 forms the mononuclear adducts [Pt(en)(5'-GMP-N7)(2)] (III) and
[Pt(en){r(GpG)-N7(1),N7(2)}] (IV). Due to the considerably slower rate
of decomposition, I gives both the dinuclear adduct 2){mu-C6H12(NMeCS
NMe2)(2)}{mu-r(GpG)-N7(1),N7(2)}] (V) (70%) and IV (30%). The 5' sugar
residue of r(GpG) in IV exhibits an N-type conformation, as commonly
observed in bifunctional adducts that are formed between Pt(II) antitu
mor complexes and dinucleotides. The absence of this structural featur
e in V supports the formation of a conformationally less restricted ma
crochelate. Cytotoxicity data for 1-4 in L1210 leukemia are in accorda
nce with the nucleotide-binding properties of 1 and 2 and the aqueous
solution chemistry of the dinuclear compounds 3 and 4. The results ind
icate that structurally modified thiourea ligands may be interesting f
or their use as alternative, strongly coordinating carrier groups in p
latinum(II) antitumor complexes.