Stable Anticancer Gold(III)–Porphyrin Complexes: Effects of Porphyrin Structure

Abstract

In the design of physiologically stable anticancer gold(III) complexes, we have employed strongly chelating porphyrinato ligands to stabilize a gold(III) ion [Chem. Commun. 2003, 1718; Coord. Chem. Rev. 2009, 253, 1682]. In this work, a family of gold(III) tetraarylporphyrins with porphyrinato ligands containing different peripheral substituents on the meso-aryl rings were prepared, and these complexes were used to study the structure-bioactivity relationship. The cytotoxic IC(50) values of [Au(Por)](+) (Por=porphyrinato ligand), which range from 0.033 to >100 microM, correlate with their lipophilicity and cellular uptake. Some of them induce apoptosis and display preferential cytotoxicity toward cancer cells than to normal noncancerous cells. A new gold(III)-porphyrin with saccharide conjugation [Au(4-glucosyl-TPP)]Cl (2a; H(2)(4-glucosyl-TPP)=meso-tetrakis(4-beta-D-glucosylphenyl)porphyrin) exhibits significant cytostatic activity to cancer cells (IC(50)=1.2-9.0 microM) without causing cell death and is much less toxic to lung fibroblast cells (IC(50)>100 microM). The gold(III)-porphyrin complexes induce S-phase cell-cycle arrest of cancer cells as indicated by flow cytometric analysis, suggesting that the anticancer activity may be, in part, due to termination of DNA replication. The gold(III)-porphyrin complexes can bind to DNA in vitro with binding constants in the range of 4.9 x 10(5) to 4.1 x 10(6) dm(3) mol(-1) as determined by absorption titration. Complexes 2a and [Au(TMPyP)]Cl(5) (4a; [H(2)TMPyP](4+)=meso-tetrakis(N-methylpyridinium-4-yl)porphyrin) interact with DNA in a manner similar to the DNA intercalator ethidium bromide as revealed by gel mobility shift assays and viscosity measurements. Both of them also inhibited the topoisomerase I induced relaxation of supercoiled DNA. Complex 4a, a gold(III) derivative of the known G-quadruplex-interactive porphyrin [H(2)TMPyP](4+), can similarly inhibit the amplification of a DNA substrate containing G-quadruplex structures in a polymerase chain reaction stop assay. In contrast to these reported complexes, complex 2a and the parental gold(III)-porphyrin 1a do not display a significant inhibitory effect (<10%) on telomerase. Based on the results of protein expression analysis and computational docking experiments, the anti-apoptotic bcl-2 protein is a potential target for those gold(III)-porphyrin complexes with apoptosis-inducing properties. Complex 2a also displays prominent anti-angiogenic properties in vitro. Taken together, the enhanced stabilization of the gold(III) ion and the ease of structural modification render porphyrins an attractive ligand system in the development of physiologically stable gold(III) complexes with anticancer and anti-angiogenic activities.

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

“…Similar conclusions indicate that both His residues are involved in the metal binding has been reported on Zn-angiotensin I complexes [48]. Doubly gold-attached angiotensin I also shows three species [gold bonded through Arg and His at position 6 (e.g., a 8 , and y 8 ions in Figure 4b), gold bonded through the Arg and His at position 9 (e.g., y 5 ion in Figure 4b), and gold bonded through both His at positions 6 and 9 (e.g., y 5 , y 6 , y 7 , and y 8 ions in Figure 4b)]. Note that bidentate and/or tridentate coordination of gold ion by the Arg and two His residues is also possible structures from these results.…”

“…Since gold(III) ion is isoelectronic with platinum(II) ion and it forms square-planar complexes as in cisplatin, gold(III) compounds are explored for potential anticancer activities. 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].…”

Gold(III) phthalocyanine chloride: Optical and structural characterization of thin films

“…They can be chemically or electrochemically reduced to gold(II) species in M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT solutions, however, isolating them was unsuccessful [7,8]. Au(III) porphyrins have been shown to exhibit cytotoxic properties and anticancer activity [9].…”

Thermodynamics of interaction ofmeso-tetra-(4N-oxyethylpyridyl) porphyrin and its Cu(II)- and Co(II)- containing derivatives with A and B forms of DNA

“…Due to their abilities to accumulate in tumor cells, many porphyrins are used in photodynamic therapy of tumors [1][2][3][4][5]. Recently, new metalloporphyrins with expressed antitumor properties have been synthesized with the aim of creating porphyrin based antitumor drugs [6,7].…”