Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, and of the Inactive Analog Dichloro(N¹,N^1‘-dimethyl-2,2‘-biimidazole)platinum(II)

Abstract

To obtain insight into the structure−activity relationships of new antitumor active platinum compounds the X-ray structure of the antitumor active Pt compound [Pt(bmic)Cl2] (bmic = bis-(N-methylimidazol-2-yl)carbinol) (1) and its interaction with short DNA fragments has been investigated using NMR spectroscopy. For comparison also the structurally related compound [Pt(bmi)Cl2] (bmi = N 1,N 1‘-dimethyl-2,2‘-biimidazole) (2), which is not antitumor active, has been studied. The structure of the compound [Pt(bmic)Cl2] (1) was characterized by single-crystal X-ray structure determination. Compound 1 crystallizes in the monoclinic space group P21/n, with a = 10.055(3) Å, b = 11.802(3) Å, c = 10.620(3) Å, β = 103.78(2)°, V = 1224.0(6) Å3 and Z = 4. Convergence was reached at wR2 = 0.1148 (all data) and R1 = 0.0476 (I > 2 (I)) for 2433 independent reflections and 156 adjustable parameters. The platinum atom is coordinated by two nitrogen and two chlorine atoms, resulting in a square planar PtN2Cl2 coordination sphere. The two best least-squares planes through the two imidazole rings of the bmic ligand show a dihedral angle of 30.6°. The in vitro and in vivo antitumor activity of 1 is significant whereas for compound 2 no antitumor activity could be detected. In P388 mice leukemia an increase of lifespan of 56% was found for complex 1. The antitumor active Pt compound [Pt(bmic)Cl2] binds to G bases in a similar fashion as cisplatin with a clear preference for N7. In reaction with d(GpG) two stereoisomers are formed, due to the unsymmetric bmic complex and the chiral d(GpG) molecule. Stereoisomer A, i.e. the isomer with the OH group of the bmic and the O6 of the G bases oriented on the same side of the Pt−N4 plane, is preferentially formed. Modeling studies suggest that this preference is due to the presence of H bonds from the OH of the bmic moiety toward the O6 of the G bases. The presence of many conformers, present in solution, could also be due to these H bonds. For the inactive complex [Pt(bmi)Cl2] only one GG-N7,N7 chelate is observed. Differences in reactivity toward G bases were also detected for the two platinum complexes. The inactive bmi complex proves to be the most reactive one, whereas the antitumor active bmic compound is less reactive. Thus both structural and kinetic properties may explain the different biological properties of these new platinum compounds.

Synthesis, structure and anti-fungal activity of dimeric Ag(I) complexes containing bis-imidazole ligands

“…1), in which the two imidazole rings are linked via a single tetrahedral carbon atom, can be viewed as primitive models for multi-histidine coordination in biological systems. Such bis(imidazole) ligands have been shown to form stable six-membered chelate rings with a variety of transition metals [6][7][8][9][10][11][12], and the Pt(II) complex [Pt(2-BIM(Me)OH)Cl 2 ] (2-BIM(Me)OH ¼ bis(N-methylimidazol-2-yl)carbinol) [10] has been reported to exhibit notable antitumor activity.…”

Bipyrimidine ruthenium(II) arene complexes: structure, reactivity and cytotoxicity

“…were allowed to equilibrate for 24−48 h at 310 K and were then studied at the same 6 temperature using 1 H NMR spectroscopy. The 1 H NMR spectra of complexes 1−11 and 13 7 initially contained one major set of peaks (halido species) and then a second set of peaks Table S2. scaled displacement vectors are shown in Figure S9.…”

Synthesis and DNA Interaction of Platinum Complex/Peptide Chimera as Potential Drug Candidates

“…Aminopropyl glycine was chosen as flexible and sterically not demanding platinum binding site and the 3,3-bis(1-methylimidazol-2-yl) moiety was used to chelate the platinum moiety. [30,31] N-(3-Aminopropyl)glycine (1) and the 3,3-bis(1-methylimidazol-2-yl) moiety as propionic acid building block 2 were prepared. Both contained the carboxylic acid functionality to allow further peptide coupling with the N-terminal amine (Scheme 1).…”