Endolysin CHAP domain-carbosilane metallodendrimer complexes with triple action on Gram-negative bacteria: Membrane destabilization, reactive oxygen species production and peptidoglycan degradation.

Bacterial resistance to antibiotics is a significant challenge that is associated with increased morbidity and mortality. Gram-negative bacteria are particularly problematic due to an outer membrane (OM). Current alternatives to antibiotics include antimicrobial peptides or proteins and multifunctional systems such as dendrimers. Antimicrobial proteins such as lysins can degrade the bacterial cell wall, whereas dendrimers can permeabilize the OM, enhancing the activity of endolysins against gram-negative bacteria. In this study, we present a three-stage action of endolysin combined with two different carbosilane (CBS) silver metallodendrimers, in which the periphery is modified with N-heterocyclic carbene (NHC) ligands coordinating a silver atom. The different NHC ligands contained hydrophobic methyl or N-donor pyridyl moieties. The effects of these endolysin/dendrimer combinations are based on OM permeabilization, peptidoglycan degradation, and reactive oxygen species production. The results showed that CBS possess a permeabilization effect (first action), significantly reduced bacterial growth at higher concentrations alone and in the presence of endolysin, increased ROS production (second action), and led to bacterial cell damage (third action). The complex formed between the CHAP domain of endolysin and a CBS silver metallodendrimer, with a triple mechanism of action, may represent an excellent alternative to other antimicrobials with only one resistance mechanism.

Cytotoxicity Evaluation of Unmodified Paddlewheel Dirhodium(II,II)-Acetate/-Formamidinate Complexes and Their Axially Modified Low-Valent Metallodendrimers.

Two diphenyl formamidine ligands, four dirhodium(II,II) complexes, and three axially modified low-valent dirhodium(II,II) metallodendrimers were synthesized and evaluated as anticancer agents against the A2780, A2780cis, and OVCAR-3 human ovarian cancer cell lines. The dirhodium(II,II) complexes show moderate cytotoxic activity in the tested tumor cell lines, with acetate and methyl-substituted formamidinate compounds displaying increased cytotoxicity that is relative to cisplatin in the A2780cis cisplatin resistant cell line. Additionally, methyl- and fluoro-substituted formamidinate complexes showed comparable and increased cytotoxic activity in the OVCAR-3 cell line when compared to cisplatin. The low-valent metallodendrimers show some activity, but a general decrease in cytotoxicity was observed when compared to the precursor complexes in all but one case, which is where the more active acetate-derived metallodendrimer showed a lower IC50 value in the OVCAR-3 cell line in comparison with the dirhodium(II,II) tetraacetate.

Elaborated study of Cu(II) carbosilane metallodendrimers bearing substituted iminopyridine moieties as antitumor agents.

Iminopyridine-decorated carbosilane metallodendrimers have recently emerged as a promising strategy in the treatment of cancer diseases. Their unique features such as the nanometric size, the multivalent nature and the structural perfection offer an extraordinary platform to explore structure-to-property relationships. Herein, we showcase the outstanding impact on the antitumor activity of a parameter not explored before: the iminopyridine substituents in meta position. New Cu(II) carbosilane metallodendrimers, bearing methyl or methoxy substituents in the pyridine ring, were synthesized and thoroughly characterized. Electron Paramagnetic Resonance (EPR) was exploited to unveil the properties of the metallodendrimers. This study confirmed the presence of different coordination modes of the Cu(II) ion (Cu-N2O2, Cu-N4 and Cu-O4), whose ratios were determined by the structural features of the dendritic molecules. These metallodendrimers exhibited IC50 values in the low micromolar range (<6 µM) in tumor cell lines such as HeLa and MCF-7. The subsequent in vitro assays on both healthy (PBMC) and tumor (U937) myeloid cells revealed two key facts which improved the cytotoxicity and selectivity of the metallodrug: First, maximizing the Cu-N2O2 coordination mode; second, adequately selecting the pair ring-substituent/metal-counterion. The most promising candidates, G1(-CH3)Cl (8) and G1(-OCH3)NO3(17), exhibited a substantial increase in the antitumor activity in U937 tumor cells, compared to the non-substituted counterparts, probably through two different ROS-production pathways.

Aberrant glycosylation patterns on cancer cells: Therapeutic opportunities for glycodendrimers/metallodendrimers oncology.

Despite exciting discoveries and progresses in drug design against cancer, its cure is still rather elusive and remains one of the humanities major challenges in health care. The safety profiles of common small molecule anti-cancer therapeutics are less than at acceptable levels and limiting deleterious side-effects have to be urgently addressed. This is mainly caused by their incapacity to differentiate healthy cells from cancer cells; hence, the use of high dosage becomes necessary. One possible solution to improve the therapeutic windows of anti-cancer agents undoubtedly resides in modern nanotechnology. This review presents a discussion concerning multivalent carbohydrate-protein interactions as this topic pertains to the fundamental aspects that lead glycoscientists to tackle glyconanoparticles. The second section describes the detailed properties of cancer cells and how their aberrant glycan surfaces differ from those of healthy cells. The third section briefly describes the immune systems, both innate and adaptative, because the numerous displays of cell surface protein receptors necessitate to be addressed from the multivalent angles, a strength full characteristic of nanoparticles. The next chapter presents recent advances in glyconanotechnologies, including glycodendrimers in particular, as they apply to glycobiology and carbohydrate-based cancer vaccines. This was followed by an overview of metallodendrimers and how this rapidly evolving field may contribute to our arsenal of therapeutic tools to fight cancer. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Design, Synthesis and Self-Assembly of Functional Amphiphilic Metallodendrimers.

A new family of alkynylated, amphiphilic dendrimers consisting of amidoamine linkers connected to 5,5'-functionalized 2,2'-bipyridine cores has been developed and evaluated in the formation of metallodendrimers of different generations and in self-assembly protocols. A convergent synthetic strategy was applied to provide dumbbell-shaped amphiphilic dendrimers, where the 2,2'-bipyridine cores could be coordinated to FeII centers to afford corresponding metallodendrimers. The ability of the metallic- and non-metallic dendritic structures to self-assemble into functional supramolecular aggregates were furthermore evaluated in aqueous solution. Spherical aggregates with sizes of a few hundred nanometers were generally produced, where controlled disassembly of the metallodendrimers through decomplexation could be achieved.

In Vitro Anticancer Properties of Copper Metallodendrimers.

Newly synthesized carbosilane copper dendrimers (CCD) with chloride and nitrate surface groups seem to be good candidates to be used as gene and drug carriers in anti-cancer therapy, due to their properties such as size and surface charge. Copper attached to the nanoparticles is an important element of many biological processes and recently their anti-cancer properties have been widely examined. Zeta size and potential, transmission electron microscopy (TEM), circular dichroism (CD), analysis of haemolytic activity, and fluorescence anisotropy techniques were used to characterize copper dendrimers. Additionally, their cytotoxic properties toward normal (PBMC) and cancer (1301; HL-60) cells were examined. All tested dendrimers were more cytotoxic against cancer cells in comparison with normal cells.

Synthesis and antitumour evaluation of mono- and multinuclear [2+1] tricarbonylrhenium(I) complexes.

A series of mono- and multinuclear [2 + 1] Re(I) tricarbonyl complexes were synthesised and evaluated as antiproliferative agents against the epithelial carcinoma (A431), colon carcinoma (DLD-1) and ovarian cancer (A2780) tumour cell lines and a healthy fibroblast (BJ) cell line. The compounds have moderate to good activity against the tumour cell lines, with the trinuclear and tetranuclear complexes showing selective cytotoxicity towards the tumour cell lines. The Re(I) complexes were found to influence programmed cell death mechanisms in vitro. They were able to inhibit the soluble form of the Fas receptor in malignant cells, allowing the Fas domain to receive the apoptotic signal through an extrinsic pathway. The complexes augmented the pro-apoptotic Bax-α concentrations, with the tetranuclear complex more superior at modulating the Bax-α molecular target in all tested cell lines, which influenced its cell growth inhibitory activity. The tetranuclear complex has the best activity against all tumour cell lines.