New Au (III), Pt (II) and Pd (II) Complexes with Pentapeptide Glycylglycyl-L-Methyonyl-Glycyl-Glycine and Their Interaction with Calf Thymus DNA

Abstract

The three new Au (III), Pt (II) and Pd (II) complexes with pentapeptide glycyl-glycyl-(L)-methyonyl-glycyl-glycine have been synthesized, isolated, and spectroscopically and structurally elucidated in solution and in the solid-state. Solid-state linear-dichroic infrared (IR-LD) spectroscopy of oriented colloids in a nematic liquid crystal host, (1)H- and (13)C-NMR, TGA and DSC, UV-VIS spectroscopy, EPR, ESI- and FAB- mass spectrometry and HPLC tandem mass spectrometry (HPLC-MS/MS) have been used. Quantum chemical calculations and molecular modelling were carried out in order to determine the structures and spectroscopic properties of the ligand, the newly synthesised metal complexes and their interactions with calf thymus DNA. The pentapeptide coordinates in a tetradentate manner with the metal ions via an S-atom on the methyonyl-side chain, two N-amide nitrogens, (after a deprotonation of gly(1) and gly(2) residues) and the primary NH(2) nitrogen of N(termini). The MN(3)S chromophores are distorted to near square planar geometry. Their interaction with calf thymus DNA shows the competitive N7 (G) coordination position, where the pentapeptide residues is coordinated with the metal centers in a tridentate manner through the S-atom and both N-amide centers. This interaction leads to a transfer from a distorted square planar geometry (D(4h) symmetry) to a pseudo tetrahedral (T(d) symmetry) of the metal ions with the obtained dihedral angle values of the MN(3)N7(G) chromophors within 114.67 degrees to 110.92 degrees . The isolated Au (III) complex is stable for about 1.5 months, while the stability of the Au (III) complex/DNA adduct is decreased to 33 days.

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

“…Since there is only one gold binding site in DR (Arg at position 2), as expected, the CID data of the gold iondipeptide DR complex shows that the gold binding site is Arg and not the NH 2 -terminal amino group or Asp. The other two species have the gold anchored at His residue at the sixth position (e.g., VYIH(Au), YIH(Au)P internal ions in Figure 4a) or ninth position (e.g., b 7 and b 8 ions in Figure S1b in Supplementary Material), most likely through the N3 site of the His-imidazole ring (the major metal anchoring site beside sulfur of Cys) [21,26,52,62,63]. Similar conclusions indicate that both His residues are involved in the metal binding has been reported on Zn-angiotensin I complexes [48].…”

“…The bidentate/tridentate complexes have been proposed to be the possible structures in previous studies on Cu-and Zn-angiotensin complexes [34,48]. In addition, many NMR and X-ray studies on simple Au-peptide complexes have proposed multidentate structures involving the amide nitrogen and the N-terminal NH 2 group in addition to the amino acid residues [21][22][23][24][25][26][27]. The angiotensin I solution containing gold ion is digested with trypsin to produce gold ion-VYIHPFHL complex.…”

“…A number of gold(III) complexes with ligands such as bipyridyls, dithiocarbamato, porphyrins, and quinolines, which display in vitro and in vivo potent anticancer activities and reduced systemic toxicity compared with the cisplatin, have been synthesized [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Small peptides such as S-phenylalanine-S-phenylalanine, glycyl-alaline, glycyl-histidine, alanyl-phenylalanine, glycyl-S-serine, glycyl-alanyl-alanine, glycyl-glycyl-histidine, and glycyl-glycyl-methyonyl-glycyl-glycine are another class of ligands of gold(III) ion that have been investigated for development of potential anticancer drugs [18][19][20][21][22][23][24]. Although evidence [10,11,28] suggests that gold-based chemotherapy agents seem to induce antiproliferative activities against tumor cells, the main biological targets and mechanisms responsible for gold-induced cytotoxicity are still largely unknown.…”

“…Collision induced dissociation (CID), a well established tandem mass spectrometry experiment, which produces the information of the sequence and metal ion binding sites of a peptide, of Zn ionand Cu ion-angiotensin peptide complexes [34,41,48] indicate that zinc and copper interaction sites are in the neighborhood of the His and Arg residues, respectively. In addition, there are some MS studies on the gold-protein complexes [14,28,33,[49][50][51][52], disulfide bridge cleavage of gold(I) cationized peptides [53,54], and characterization of synthetic pure gold-peptide complexes [21][22][23][24][25][26][27]. Data from gold-attached glutathione reductase or thioredoxin reductase probed by MALDI-TOF MS speculates that Cys residue is critical to their biological functions [14,50].…”

“…ESI-MS study on the Au(I)-somatostin complex shows that Au(I) incorporation into a disulfide bridge containing peptide is a promising way to effect selective dissociation of disulfide bonds [52]. In another study, ESI-MS is used to confirm the reaction product of a synthetic Au(III)-pentapeptide (GGMGG) complex [21]. The majority of these gold complex studies are all aimed at the binding between gold and sulfur.…”