Mononuclear Platinum(II) Complex with 2-Phenylpyridine Ligands Showing High Cytotoxicity against Mouse Sarcoma 180 Cells Acquiring High Cisplatin Resistance

Abstract

Mouse sarcoma 180 cell with a 25-fold higher cisplatin (CDDP) resistance, termed S-180cisR, is newly established. S-180cisR cells grow quite slowly in the presence of CDDP with high concentration. This may show that S-180cisR cells modulate the cell cycle to acquire CDDP resistance. P-Glycoprotein is selectively expressed on the surface of S-180cisR, which is not on CDDP-sensitive S-180 parent cells. In an experiment using an inhibitor (verapamil) of P-glycoprotein, cytotoxicity of CDDP against S-180cisR is significantly increased (viz., IC(50) value is decreased) and accumulation of CDDP in S-180cisR cells is also increased. These results indicate that enhanced pumping-out of CDDP by P-glycoprotein should be one of the reasons for the CDDP resistance of S-180cisR. A platinum(II) complex with a cyclometalated 2-phenylpyridine ligand and a nonchelated one (complex 5) is synthesized, and its structure is determined by X-ray structural analysis. Complex 5 has a cyctotoxicity against S-180cisR higher than that of CDDP and its derivatives with 2- or 3-substituted pyridine ligands (complexes 2-4, 6, 7). Complex 5 is incorporated in S-180cisR to an enormously greater extent than CDDP; that is, the ratio of accumulated platinum amount after 3 h is 61.9. In S-180 parent cells, on the other hand, the ratio remains 8.1. This high accumulation of complex 5 into S-180cisR must account for the higher activity of complex 5 against S-180cisR compared to CDDP.

Ruthenium (II)-Derived Organometallic Compounds Induce Cytostatic and Cytotoxic Effects on Mammalian Cancer Cell Lines through p53-Dependent and p53-Independent Mechanisms

“…At this stage, we formulated a different approach. Examples can be found in the literature of antitumoral cycloplatinated (Okada et al, 2001) or cyclopalladated (Rodrigues et al, 2003) compounds. In this respect, we tested cycloruthenated phenylpyridine RDC-8 and benzylpyridine RDC-10 with a lack of success (IC 50 Ͼ 50 M).…”

1H, 13C, 15N and 195Pt NMR studies of Au(III) and Pt(II) chloride organometallics with 2‐phenylpyridine

“…[13,32] However, the respective 1 H and 13 C signals usually remained unassigned or were assigned inconsistently by various authors. The 195 Pt NMR spectra were described for cis-[Pt(2ppy * ) 2 ] [32 -35] and [Pt(2ppy * )(2ppy)X] (X = Cl, Br, I, SCN, ONO 2 , NO 2 ), [19] while those of 15 [36] while trans(N,N)-[Pt(2ppy * )(2ppy)Cl] and trans(S,N)-[Pt(2ppy * )(DMSO-d 6 )Cl] exhibit high cytotoxicity. [6,22,37,38] Experimental Materials 2-Phenylpyridine (2ppy, 98% purity) was purchased from Aldrich, while Pt (99.9%) and Au (99.99%) were from the Polish State Mint.…”

“…The 195 Pt NMR spectra were described for cis-[Pt(2ppy * ) 2 ] [32 -35] and [Pt(2ppy * )(2ppy)X] (X = Cl, Br, I, SCN, ONO 2 , NO 2 ), [19] while those of 15 [36] while trans(N,N)-[Pt(2ppy * )(2ppy)Cl] and trans(S,N)-[Pt(2ppy * )(DMSO-d 6 )Cl] exhibit high cytotoxicity. [6,22,37,38] Experimental Materials 2-Phenylpyridine (2ppy, 98% purity) was purchased from Aldrich, while Pt (99.9%) and Au (99.99%) were from the Polish State Mint. K 2 PtCl 4 was prepared by dissolving Pt in aqua regia, precipitation with KCl to K 2 PtCl 6 and its reduction with hydrazine; NaAuCl 4 was prepared by dissolving Au in aqua regia, neutralization with NaOH and evaporation to dryness.…”

“…The NMR spectra were measured at 298 K in DMSO-d 6 or CDCl 3 by a Varian VNMRS-500 MHz NMR spectrometer, equipped with an inverse 1 H{ 31 P/ 15 N} 5-mm Z-SPEC Nalorac probe with an actively shielded z-gradient coil.…”

“…[2] Among them, an important group are the chloride species; a few of them were investigated by single crystal X-ray diffraction: [Au(2ppy * )Cl 2 ] -IJAQEP, [3] (CH 3 CH 2 CH 2 CH 2 ) 4 N[Pt(2ppy * )Cl 2 ] -ZUDGAG, [4] trans(N,N)-[Pt(2 ppy * )(2ppy)Cl] -YUBJEK, YUBJEK01. [5,6] Some other X-ray structures were reported for the related Au(III) and Pt(II) cyclometallated compounds with various auxiliary ligands, e.g. [Au(2ppy * [3] trans(S,N)-[Au(2ppy * )(SCN)(NCS)] -ILETOI; [7] trans(C,N)-[Au(2ppy * )(CH 2 COCH 3 )Cl] -BIGRAL and trans(C,N)-[Au(2ppy * ) (CH 2 COCH 3 )(ONO 2 )] -BIGREP; [8] [9] [Pt(2ppy * )(NH 2 CH 2 CH 2 NH 2 )]Cl -ZUDGIO; [4] trans(C,N)-[Pt(2ppy * ) (DMSO)(CH 3 )] -BEZPEC; [10] trans(C,N)-[Pt(2ppy * )(DMSO)(C 6 H 5 )] -TICSII and trans(C,N)-[Pt(2ppy * )(DMSO) (3,5-dimethylphenyl)] -TICSEE; [11] trans(N,N)-[Pt(2ppy * )(8-oxyquinolinate)] -WESQUH; [12] cis-[Pt(2ppy * ) 2 ] -CULWUB; [13] K[Pt(2ppy * )(CN) 2 ]· 2(CH 3 COC H 3 ).…”