Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib

Abstract

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl(1,7-phen-κN7)] (1) and [AuCl(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89μM, while had low toxicity with LC value (the concentration inducing the lethal effect of 50% embryos) of 128μM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.

Mononuclear silver(I) complexes with 1,7-phenanthroline as potent inhibitors of Candida growth

“…The room temperature UVeVis spectra of silver(I) complexes 1e5, recorded in DMF/H 2 O, resemble that of the 1,7-phen. In all complexes, the corresponding absorbance peak at~269.0 nm, respectively, can be attributed to p / p* transitions in phenanthroline [25,30] and they show slight red shift compared to that for the free ligand (l ¼ 267.0 nm).…”

“…Zebrafish has been suggested as suitable animal model for in vivo drug discovery and development [67], and has been successfully utilized for the safety assessment of metal complexes with biomedical application [25,28]. Therefore, the toxicity of the complex 1 was investigated using the 6 hpf zebrafish (Danio rerio) embryos in a 114 h exposure study and compared with the toxicity of the 1,7-phen and AgSD as a clinically used antimicrobial agent.…”

“…In contrast to 1,10-phen, its structural isomer does not possess chelating properties; nevertheless 1,7-phen could behave as bridging ligand between two silver(I) ions by providing an acute 60 bridging angle [24]. However, due to the steric hindrance effect of the N1 nitrogen atom, 1,7-phen can also act as kN7 monodentate ligand exclusively [24,25]. A previous study related to the antifungal properties of 1,7-phen showed that, unlike 1,10-phen, this compound and their copper(II), manganese(II) and zinc(II) complexes displayed only marginal activity against C. albicans [14].…”

Streptomyces sp. BV410 isolate from chamomile rhizosphere soil efficiently produces staurosporine with antifungal and antiangiogenic properties

“…The antiangiogenic activity of the isolated staurosporine was evaluated using transgenic zebrafish Tg ( fli1:EGFP ) embryos with EGFP‐labeled endothelial cells, as was previously described (Pavic et al, ). Briefly, transgenic embryos were generated by natural spawning of wild‐type and Tg( fli1:EGFP ) adults and reared in embryo water at 28°C.…”

Anti-Virulence Potential and In Vivo Toxicity of Persicaria maculosa and Bistorta officinalis Extracts

“…The evaluation of the toxicity of the extracts and pure constituents was performed in the zebrafish (Danio rerio) model according to the general rules of the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Testing of Chemicals [38], following a previously described procedure [39]. Embryos of wild-type zebrafish were raised to the adult stage in a temperature-and light-controlled zebrafish facility at 28 • C and standard 14:10 h light-dark photoperiod.…”