Effects of Geometric Isomerism and Ligand Substitution in Bifunctional Dinuclear Platinum Complexes on Binding Properties and Conformational Changes in DNA

Abstract

The DNA binding profile of a series of dinuclear platinum complexes [{trans-PtCl-(L)2}2H2N(CH2)nNH2]2+ (L = NH3 or py; 1,1/t,t/NH3 and 1,1/t,t/py, respectively) and [{cis-PtCl-(NH3)2H2N(CH2)nNH2]2+ (1,1/c,c/NH3) was examined to compare the effects of geometrical isomerism and the presence of ligands other than NH3 in the coordination sphere. Steric effects, because of the geometry of the leaving groups cis to the diamine bridge or the presence of planar pyridine ligands, result in diminished binding to calf thymus DNA for these isomers. In contrast, the pyridine derivative shows a distinct binding preference for poly(dG-dC).poly(dG-dC) in comparison to both NH3 isomers. Both NH3 complexes induced the B-->Z transition in poly(dG-dC).poly(dG-dC), but the presence of a pyridine ligand stabilized the B conformation. The bifunctional binding of the NH3 isomers results in unwinding of supercoiled pUC19 plasmid DNA equivalent to cis-DDP, while the unwinding of the pyridine derivative is approximately twice that of the mononuclear trans-[PtCl2(py)2]. DNA-DNA interstrand cross-linking is very efficient for all three agents, but sequencing studies indicated that only the 1,1/t,t/NH3 derivative is capable of forming a (Pt,Pt) intrastrand cross-link to the adjacent guanines of a d(GpG) sequence. The effects on DNA caused by bifunctional binding of dinuclear complexes are compared with those from the mononuclear [PtCl2(NH3)2] isomers. The results are discussed with respect to the antitumor activity of the dinuclear series.

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

“…Multinuclear platinum complexes, containing two reactive platinum centers linked by a relatively long chain, were originally designed to form long-distance' DNA cross-links. 1,16 Indeed, the multinuclear complex BBR 3464 is able to form DNA lesions different from those induced by cisplatin and to elicit a cellular response different from that of cisplatin. 2 The results of our study clearly document that BBR 3464 exhibited unusual features that could underlie the completely different pattern of cellular response compared to cisplatin.…”

Câncer e agentes antineoplásicos ciclo-celular específicos e ciclo-celular não específicos que interagem com o DNA: uma introdução

“…Seu espectro de ação é semelhante ao da cisplatina, excetuando-se talvez os sarcomas e os tumores trofoblásticos, para os quais parece ser menos eficaz [6][7][8][9] . Mais recentemente, tem-se desenvolvido complexos diméricos análogos à cisplatina mas, apesar de muito promissores, ainda estão em fase inicial de investigação 39 .…”

Effects of Geometric Isomerism and Anions on the Kinetics and Mechanism of the Stepwise Formation of Long‐Range DNA Interstrand Cross‐Links by Dinuclear Platinum Antitumor Complexes

“…Previous studies using other techniques have shown that 1,1/t,t compounds bind to DNA more readily than 1,1/c,c compounds [5] and the first objective of the current study was to compare the kinetics of the stepwise formation of 1,4-interstrand cross-links by the geometric isomers 1,1/c,c and 1,1/t,t. Therefore, the initial reactions of 1 with duplex I were carried out under similar conditions to those employed in our previous study of 1,1/t,t in the presence of 15 mM phosphate buffer and with the chosen pH approximately 0.2 pH units below the pK a value of the diaquated species.…”

“…[1][2][3][4][5][6] This class includes the trinuclear [{trans-PtCl-(NH 3 ) 2 } 2 (μ-trans-Pt(NH 3 ) 2 {NH 2 (CH 2 ) n NH 2 } 2 )] 4+ (1,0,1/t,t,t, n=6, or BBR3464), which has undergone Phase II clinical trials (summarized in refs [1,[7][8][9]). The overall charge as well as the linker flexibility and hydrogen-bonding capability of these compounds are thought to be related to their improved cytotoxic and antitumor properties relative to cisplatin and its derivatives.…”

“…The extent of formation of interstrand cross-links as well as local conformational distortions on DNA are affected by geometry. [1][2][3][4][5][6] The cis isomer (1,1/c,c) is kinetically more inert in its reactions with DNA and model nucleotides and in double-stranded DNA produces more interstrand cross-links. [1,2,13] Differences between the two geometric isomers are also manifested in their reactions with sulfur nucleophiles.…”