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

Citation
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
Citations number
41
Categorie Soggetti
Chemistry Inorganic & Nuclear
Journal title
ISSN journal
00201669
Volume
37
Issue
4
Year of publication
1998
Pages
717 - 723
Database
ISI
SICI code
0020-1669(1998)37:4<717:MOPACW>2.0.ZU;2-5
Abstract
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.