👤 Vadde Ramu

The precise design strategies that achieve structural optimization of both metallodrugs and self-reported metallodrug carriers can overcome the major limitations of metallodrug development. Herein, we structurally modified a conventional half-sandwich Ru(arene)(bipyridine) complex into a fluorogenic and esterase-responsive prodrug nanosystem via functionalizing the N,N'-bidentate bipyridine ligand with 10,12-pentacosadiynoic acid derivative, thereby designing an amphiphilic complex with the ability for coassembly. Prior to obtaining the nanoassembly, in an attempt to infer the benefits of functionalizing the ligand, a series of four organoruthenium complexes, including the amphiphilic complex, was prepared and characterized. The nanoassembly is found to release the Ru complex in the presence of porcine liver esterase concomitantly with a 4-fold increase in its fluorescence intensity. Such a stimuli-responsive behavior is exploited for real-time release monitoring of Ru complex and understanding its functionality to induce cell death in HeLa and THP-1 cancer cells. Compared to the free Ru complex, this nanosystem exhibits better cellular uptake and 100-fold higher cytotoxicity in HeLa cancer cells while being less toxic in noncancerous GM5756 cells. N-Acetylcysteine-induced GSH augmentation studies revealed that the nanoassembly exerts antiproliferative activity through oxidative stress. Toxicity analysis in zebrafish embryos confirmed the biocompatibility of the nanoformulations, suggesting a promising future in vivo studies. Show less

In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H₂biqbpy1 and H₂biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1]⁺, two pyridyl rings coordinate to the metal via a Au-C bond (C^∧N^∧N^∧C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2]⁺ all four pyridyl rings of the ligand coordinate to the metal via a Au-N bond (N^∧N^∧N^∧N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [³H]dofetilide equally well from cell membranes expressing the K_v11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H₂biqbpy1 and H₂biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H₂biqbpy2 and TrxR-inhibiting Au⁺ ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au⁺ ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells. Show less