Dinuclear Gold(III) Complexes as Potential Anticancer Agents: Structure, Reactivity and Biological Profile of a Series of Gold(III) Oxo-Bridged Derivatives~!2009-12-08~!2010-01-15~!2010-03-25~!

Abstract

Six homologous gold(III) dinuclear oxo-bridged complexes, of the type [(bipy nR )Au(µ-O) 2 Au(bipy nR )][PF 6 ] 2 , bearing variously substituted 2,2'-bipyridine ligands (bipy nR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl-and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipy nR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best "drug candidate". In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation.

Original Multivalent Gold(III) and Dual Gold(III)–Copper(II) Conjugated Phosphorus Dendrimers as Potent Antitumoral and Antimicrobial Agents

“…Several informative reviews highlighted the use of metallodrugs in the oncology domain (unexhaustive list). 8,9,10,11,12,13 To date, very few examples have described the preparation of dendrimer conjugated-metallodrugs. In early studies, Malik et al conjugated G3.5 PAMAM-CO 2 H dendrimers with cisplatin giving PAMAMplatinate complexes (mono-, bi-and crosslinked-dentates).…”

Gold-based drug encapsulation within a ferritin nanocage: X-ray structure and biological evaluation as a potential anticancer agent of the Auoxo3-loaded protein

“…We have recently described the structure of cisplatin encapsulated apoFt (Aft) nanocage [20], whose cytotoxicity is well documented [14][15]; our structure has provided hints to explain the reasons why Ft can be efficiently used for the transport of drugs to malignant cells. Here, we have used Auoxo3, a potential gold(III) based drug, member of a class of gold 50 compounds of medicinal interest (Auoxos), already well characterized both in its cytotoxicity [23][24][25] and binding to proteins [26][27][28], to prepare gold-based drug-encapsulated AFt. Here, we have used Auoxo3, a potential gold(III) based drug, member of a class of gold 50 compounds of medicinal interest (Auoxos), already well characterized both in its cytotoxicity [23][24][25] and binding to proteins [26][27][28], to prepare gold-based drug-encapsulated AFt.…”

“…Here, we have used Auoxo3, a potential gold(III) based drug, member of a class of gold 50 compounds of medicinal interest (Auoxos), already well characterized both in its cytotoxicity [23][24][25] and binding to proteins [26][27][28], to prepare gold-based drug-encapsulated AFt. Previous data indicated that probable biomolecular targets for Auoxos are histone deacetylase (HDAC), protein kinase C (PKc) 65 or thioredoxin reductase [23,29]. Previous data indicated that probable biomolecular targets for Auoxos are histone deacetylase (HDAC), protein kinase C (PKc) 65 or thioredoxin reductase [23,29].…”

“…Although the use of AFt in the transport of metallodrugs 14,15,20 and in the fabrication of gold nanoparticles 21,22 is well documented, to our knowledge gold-based drugs have never been encapsulated within an AFt nanocage. Here, we have used Auoxo3, a potential gold(III) based drug, a member of a class of gold compounds of medicinal interest (Auoxos), already well characterized both in its cytotoxicity [23][24][25] and binding to proteins, [26][27][28] to prepare gold-based drug-encapsulated AFt.…”

Time-resolved NMR-spectroscopic studies of conformational dynamics in DNA G-quadruplexes

“…417 The different strategies that have been proposed to target G4s with small molecules show the diversity of possible effects that result from interfering with G4-regulation. (PDB: 2HRI) 420 and Braco19 286,421 (PDB: 3CE5) 422 ; a cMYC G4 with Phen-DC3 423,424 (PDB: 2MGN) 425 ; a telomeric hybrid-1 G4 with Telomestatin 409 (PDB: 2MB3) 426 and a telomeric hybrid-2 G4 with an Au(III)-ligand (PDB: 5MVB, AuOxo6) 416,[427][428][429] .…”