Synthesis, Structure, Biological Activity, and DNA Binding of Platinum(II) Complexes of the Type trans-[PtCl(2)(NH(3))L] (L = Planar Nitrogen Base). Effect of L and Cis/Trans Isomerism on Sequence Specificity and Unwinding Properties Observed in Globally Platinated DNA.
In order to establish fundamental structural requirements for the antitumor activation of the trans-platinum geometry, complexes of the general formulas [PtCl(2)(NH(3))L] (L = planar N donor) have been synthesized. The trans isomers, trans-[PtCl(2)(NH(3))(quinoline)] (3), trans-[PtCl(2)(NH(3))(thiazole)] (5), trans-[PtCl(2)(NH(3))(benzothiazole)] (7), and trans-[PtCl(2)(NH(3))(isoquinoline)] (8) and the cis isomers cis-[PtCl(2)(NH(3))(quinoline)] (4) and cis-[PtCl(2)(NH(3))(thiazole)] (6) were characterized by (1)H NMR and analytical data. In addition, the crystal structures of 3, 5, 7, and 8 were determined: 3, monoclinic, P2(1)/c, with a = 8.414(1) Å, b = 12.373(3) Å, c = 21.266(3) Å, beta = 96.78(1) degrees, V = 2198.3(6) Å(3), and Z = 8; 5, monoclinic, P2(1)/n, with a = 8.815(4) Å, b = 19.917(8) Å, c = 14.498(5) Å, beta = 103.30(3) degrees, V = 2477(2) Å(3), and Z = 12; 7, monoclinic, P2(1)/c, with a = 8.150(4) Å, b = 23.196(9) Å, c = 11.297(7) Å, beta = 90.94(4) degrees, V = 2135.3(2) Å(3), and Z = 8; 8, monoclinic, C2/c, with a = 19.043(4) Å, b = 8.570(2) Å, c = 29.127(6) Å, beta_ = 111.59(2) degrees, V = 4420(2) Å(3), and Z = 16. In all cases, the Pt coordination plane and L are mutually twisted with angles between planes of 50-68 degrees. Bulky quinoline in 3 produces intramolecular steric strain as evidenced by a short, nonbonding Pt.H8(quin) contact of 2.77 Å and concomitantly distorted Pt-N(quin)-C bond angles. The trans complexes 3, 5, 7, and 8 showed a significantly higher cytotoxicity in cisplatin-sensitive L1210 leukemia than trans-[PtCl(2)(NH(3))(2)] (2), with 3 and 5 being as potent as the corresponding cis isomers 4 and 6. In addition, the presence of the planar ligand greatly enhanced the activity of all of the compounds in cells resistant to cisplatin, cis-[PtCl(2)(NH(3))(2)] (1). Complex geometry and L play an important role in the binding of 1-7 to DNA. For synthetic poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) the order of binding affinities (r(b), drug-to-nucleotide ratio) was 2 > 1 > 6 > 5 > 4 > 7 > 3 and 5 > 6 > 7 > 3 > 2 > 1 > 4, respectively. Furthermore, 3 and 7, carrying large planar ligands, were remarkably effective at unwinding negatively supercoiled, closed circular pUC19 DNA (phi = 15 degrees and 17 degrees, respectively). The consequences of structural effects caused by L on target DNA with respect to possible biological consequences are discussed.
Bierbach
Ulrich
U
Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia 23284-2006, and School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia.
Qu
Yun
Y
Hambley
Trevor W.
TW
Peroutka
John
J
Nguyen
Holly L.
HL
Doedee
Marijo
M
Farrell
Nicholas
N