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 derivati

摘要

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(NMeCSNMe2)(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 spectroscopy. 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 excess of free nucleotide. Pt-195 NMR chemical shifts of -3003 and -2982 ppm, respectively, confirm a [N3S] mixed-donor environment of platinum. 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 analogous reactions for cisplatin and structural analogues. The dinuclear complexes 3 and 4 exhibit an unusual rapid intramolecular disproportionation 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 thiourea derivative; delta(Pt) -3454 with L-L = C2H4(NMeCSNMe2)(2)). Accordingly, 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 [{Pt(en)}(2){mu-C6H12(NMeCSNMe2)(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) antitumor complexes and dinucleotides. The absence of this structural feature in V supports the formation of a conformationally less restricted macrochelate. Cytotoxicity data for 1-4 in L1210 leukemia are in accordance with the nucleotide-binding properties of 1 and 2 and the aqueous solution chemistry of the dinuclear compounds 3 and 4. The results indicate that structurally modified thiourea ligands may be interesting for their use as alternative, strongly coordinating carrier groups in platinum(II) antitumor complexes. [References: 41]