Self-Assembly of a Dipeptide with a Reduced Amount of Copper into Antifungal and Antibacterial Particles.

With the growing concern over the environmental impact and health risks associated with conventional pesticides, there is a great need for developing safer and more sustainable alternatives. This study demonstrates the self-assembly of antimicrobial and antifungal spherical particles by a dipeptide utilizing a reduced amount of copper salt compared to the commonly employed formulation. The particles can be sprayed on a surface and form an antimicrobial coating.

Titanium complexes affect biofilm formation.

Biofilms are surface or interface-associated communities of bacterial cells, embedded in a self-secreted extracellular matrix (ECM). Cells in biofilms are 100-1000 times more resistant to antibiotic treatment relative to planktonic cells due to various reasons, including the ECM acting as a diffusion barrier to antibiotic molecules, the presence of persister cells that divide slowly and are less susceptible to cell-wall targeting drugs, and the activation of efflux pumps in response to antibiotic stress. In this study we tested the effect of two titanium(iv) complexes that have been previously reported as potent and non-toxic anticancer chemotherapeutic agents on cells in culture and in biofilm forming conditions.

Phenolato Ti(IV) hexacoordinate complexes for anticancer chemotherapy: enhancement of solubility, hydrolytic stability, and cytotoxicity.

A new series of five titanium(IV) complexes based on diaminobis(phenolato)-bis(alkoxo) ligands with different substitutions was synthesized and characterized. All complexes were analyzed by X-ray crystallography, and all structures indicated symmetrical octahedral compounds. All complexes exhibited enhanced solubility in aqueous media compared with the parent methylated derivative phenolaTi (up to 0.

An anticancer Ti(IV) complex increases mitochondrial reactive oxygen species levels in relation with hypoxia and endoplasmic-reticulum stress: A distinct non DNA-related mechanism.

PhenolaTi is a promising Ti(IV) anticancer complex, with high stability and cytotoxicity, without notable toxic side-effects. Its cellular mechanism was proposed to relate to ER stress. Herein, we investigated the downstream effects of this mode of action in two cancer cell lines: ovarian carcinoma A2780 and cervical adenocarcinoma HeLa.

Hydrolytically Stable and Cytotoxic [ONO]Ti(IV)-Type Octahedral Complexes.

A new family of titanium(IV) complexes based on [ONON] diaminobis(phenolato) ligands with Me, Br, Cl, and F ortho substitutions was synthesized and characterized. X-ray structures of three derivatives revealed homoleptic LTi-type compounds that exhibit an octahedral geometry without binding of the dangling amine unit. DFT calculations demonstrated that the preference of an LTi complex is not driven by solvent or ligand substitutions but rather by entropic effects.

Targeting Protein Interaction Hotspots Using Structured and Disordered Chimeric Peptide Inhibitors.

The main challenge in inhibiting protein-protein interactions (PPI) for therapeutic purposes is designing molecules that bind specifically to the interaction hotspots. Adding to the complexity, such hotspots can be within both structured and disordered interaction interfaces. To address this, we present a strategy for inhibiting the structured and disordered hotspots of interactions using chimeric peptides that contain both structured and disordered parts.

Binding of the anticancer Ti(IV) complex phenolaTi to serum proteins: Thermodynamic and kinetic aspects.

Titanium(IV) anticancer complexes are promising candidates for treatment of various cancers, and previous studies have pointed to possible interactions between Ti(IV) anticancer complexes and the serum proteins albumin and transferrin. Herein, we explored the binding of phenolaTi, a leading diaminobis(phenolato)bis(alkoxo) Ti(IV) anticancer complex, to serum proteins, and derived the binding constants and thermodynamic parameters. The results were compared with those obtained for a salan Ti(IV) bis(isopropoxo) complex and titanocene dichloride, studied under similar conditions.

From medium to endoplasmic reticulum: Tracing anticancer phenolato titanium(IV) complex by F NMR detection.

Titanium(IV) complexes of diaminobis(phenolato)-bis(alkoxo) ligands are promising anticancer drugs, showing marked in-vivo efficacy with no toxic side-effects in mice, hence, it is of interest to elucidate their mechanism of action. Herein, we employed a fluoro-substituted derivative, FenolaTi, for mechanistic analysis of the active species and its cellular target by quantitative F NMR detection to reveal its biodistribution and reactivity in extracellular and intracellular matrices. Upon administration to the serum-containing medium, FenolaTi interacted with bovine serum albumin.

Synthesis of asymmetrical diaminobis(alkoxo)-bisphenol compounds and their C-symmetrical mono-ligated titanium(iv) complexes as highly stable highly active antitumor compounds.

Asymmetrical 2,2'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))bis(methylene))diphenol substituted compounds and their C-symmetrical diaminobis(phenolato)-bis(alkoxo) titanium(iv) complexes were synthesized, with one symmetrical analogue. X-ray crystallography corroborated tight ligand binding. Different substitutions on the two aromatic rings enabled fine-tuning of the complex properties, giving enhanced solubility, high anticancer activity (IC < 4 μM), and significant hydrolytic stability.

Targeting an Interaction Between Two Disordered Domains by Using a Designed Peptide.

Invited for the cover of this issue is the group of Assaf Friedler at the Hebrew University of Jerusalem. The image depicts the protein-protein interactions reported in this work. Read the full text of the article at 10.

Effective Oral Administration of an Antitumorigenic Nanoformulated Titanium Complex.

Orally administered anticancer drugs facilitate treatment, but the acidic conditions in the stomach often challenge their availability. PhenolaTi is a Ti -based nontoxic anticancer drug with marked in-vivo efficacy. We report that nanoformulation protects phenolaTi from decomposition in stomach-like conditions.

Titanium Tackles the Endoplasmic Reticulum: A First Genomic Study on a Titanium Anticancer Metallodrug.

PhenolaTi is an advanced non-toxic anticancer chemotherapy; this inert bis(phenolato)bis(alkoxo) Ti(IV) complex demonstrates the intriguing combination of high and wide efficacy with no detected toxicity in animals. Here we unravel the cellular pathways involved in its mechanism of action by a first genome study on Ti(IV)-treated cells, using an attuned RNA sequencing-based available technology. First, phenolaTi induced apoptosis and cell-cycle arrest at the G2/M phase in MCF7 cells.

Targeting an Interaction Between Two Disordered Domains by Using a Designed Peptide.

Intrinsically disordered regions in proteins (IDRs) mediate many disease-related protein-protein interactions. However, the unfolded character and continuous conformational changes of IDRs make them difficult to target for therapeutic purposes. Here, we show that a designed peptide based on the disordered p53 linker domain can be used to target a partner IDR from the anti-apoptotic iASPP protein, promoting apoptosis of cancer cells.

Electrochemical Triggered Dissolution of Hydroxyapatite/Doxorubicin Nanocarriers.

The controlled release of drugs by an external stimulus is of pivotal interest and importance as a means of increasing administration efficacy. Accordingly, many responsive systems have been developed based on primarily pH, temperature, and light changes. Here, a novel electrochemical triggered release of a doxorubicin (Dox)-loaded hydroxyapatite (HAp) nanoparticle (NP) system is presented.

Racemic enantiopure inert Ti(iv) complex of a single diaminotetrakis(phenolato) ligand in anticancer activity toward human drug-sensitive and -resistant cancer cell lines.

A tetrakis(phenolato) Ti(iv) complex was synthesized in racemic and optically pure form, exhibiting high hydrolytic stability, and similar cytotoxicity for all stereochemical forms on HT-29 and A2780 cancer cells. Higher activity of the racemate on drug-resistant A2780cp and A2780adr lines implies a beneficial activity of both enantiomers rendering enantiomeric resolution unnecessary.

Cytotoxic homoleptic Ti(iv) compounds of ONO-type ligands: synthesis, structures and anti-cancer activity.

Eight Ti(iv) compounds 1-8, of the type [Ti(Ln)2] where Ln is a variously substituted dianionic tridentate acylhydrazone, were synthesized by reacting the appropriate hydrazide with 2-hydroxybenzaldehyde or 2'-hydroxyacetophenone and titanium(iv) tetra(isopropoxide) in a 2 : 2 : 1 molar ratio. The solid-state structures of 1-6 and 7·CH2Cl2 were deduced from the single crystal X-ray diffraction data, which indicated that each L2- ligand is fully deprotonated and coordinated to the Ti(iv) cation via the enolic oxygen, the imino nitrogen and the phenolic oxygen atoms (ONO donor set) in an enol tautomeric form, the metal assuming the distorted octahedral geometry. The structures of pro-ligands H2L3 and H2L5 are also reported.

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs.

Due to the toxicity of platinum compounds used in the clinic as anticancer chemotherapies, titanium serves as a safe and attractive alternative. Lately, we introduced a new family of Ti complexes based on readily available phenolato ligands, demonstrating incredibly high hydrolytic stability, with the lead compound phenolaTi demonstrating wide cytotoxic activity toward the NCI-60 panel of human cancer cell lines, with an average GI value of 4.7±2 μm.

combinations of inert phenolato Ti(iv) complexes with clinically employed anticancer chemotherapy: synergy with oxaliplatin on colon cells.

Advanced anticancer phenolato titanium(iv) complexes were combined with known chemotherapeutic anticancer drugs applied in the clinic and were analyzed on cell lines most sensitive to the Ti(iv) complex and relevant to the clinical application of the known drugs. Combination of the Ti(iv) complex with cisplatin on ovarian cells showed mostly an additive behavior, also on a line resistant to cisplatin. Combination of the Ti(iv) complex with fluorouracil on colon cells gave near additive behavior, and that with oxaliplatin gave a synergistic behavior at a wide range of Ti : Pt ratios, but only when the drugs were administered together.

Synthesis of Pure Enantiomers of Titanium(IV) Complexes with Chiral Diaminobis(phenolato) Ligands and Their Biological Reactivity.

Racemic and enantiomerically pure titanium(IV) complexes with ortho-brominated or para-nitrated chiral diaminobis(phenolato) ligands were prepared with NH and NMe cyclohexyldiamino bridges through ligand to metal chiral induction. The hydrolytic behavior of the complexes was evaluated, identifying the N-methylated complex as the most stable. A representative NH complex hydrolyzed to first give a dimeric structure in solution as deduced by NMR diffusion measurements, followed by formation of clusters with higher nuclearity, as was supported by X-ray characterization of a tetranuclear cluster obtained in trace amounts following 30 days in water solutions.

Fluorescent antitumor titanium(iv) salen complexes for cell imaging.

Two differently substituted fluorescent salen Ti(iv) complexes were developed. One was inactive on human cancer cells, whereas the other showed high cytotoxicity. Based on live cell imaging, both complexes penetrated the cell, but were not detected in the nuclei.

Coordination Complexes of Titanium(IV) for Anticancer Therapy.

Titanium(IV) coordination complexes represent attractive alternatives to platinumbased anticancer drugs. The advantage of the titanium metal lies in its low toxicity, and the hydrolysis of titanium(IV) coordination complexes in biological water-based environment to the safe and inert titanium dioxide is an enormous benefit. On the other hand, the rapid hydrolysis of titanium(IV) complexes in biological environment and their rich aquatic chemistry hampered the exploration and the development of effective compounds.

Insights into molecular mechanism of action of salan titanium(IV) complex with in vitro and in vivo anticancer activity.

Titanium compounds, in particular, Ti(IV) based diaminobis(phenolato) "salan" complexes demonstrate high cytotoxicity towards a wide range of cancer cell lines in vitro, and still, very little is known on their mode of action. A representative salan Ti(IV) complex was tested both in vitro and in vivo on human HT-29 colorectal adenocarcinoma and A2780 ovarian carcinoma cells. Both cell lines were sensitive in vitro with A2780 demonstrating an enhanced rate of uptake and intracellular accumulation and thus an earlier response to the drug.

Selenocysteine containing analogues of Atx1-based peptides protect cells from copper ion toxicity.

Seleno-substituted model peptides of copper metallochaperone proteins were analyzed for the metal affinity and in vitro anti-oxidative reactivity. An acyclic MTCXXC (X is any amino acid) reference peptide previously analyzed as a potent inhibitor of ROS production underwent substitution of the cysteine residues with selenocysteine to give two singly substituted derivatives C3U and C6U and the doubly substituted analogue C3U/C6U. Presumably due to the softer nature of Se vs.

Specific Design of Titanium(IV) Phenolato Chelates Yields Stable and Accessible, Effective and Selective Anticancer Agents.

Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin-resistant cell line. An all-aliphatic control complex was unstable and inactive.

Effective Inhibition of Cellular ROS Production by MXCXXC-Type Peptides: Potential Therapeutic Applications in Copper-Homeostasis Disorders.

Cyclic and acyclic peptides with sequences derived from metallochaperone binding sites, but differing at position 2, were analyzed for their inhibitory reactivity towards cellular ROS (reactive oxygen species) formation and catalytic activity towards oxidation with H2 O2 , in comparison with three commercial drugs clinically employed in chelation therapy for Wilson's disease. Acyclic peptides were more effective inhibitors than the cyclic ones, with one leading peptide with threonine at position 2 systematically showing the highest efficiency in reducing cellular ROS levels and in inhibiting Cu oxidation. This peptide was more effective than all commercial drugs in all aspects analyzed, and showed no toxicity towards human colon HT-29 cancer cells at concentrations 10-100 times higher than the IC50 of the commercial drugs, corroborating its high medicinal potential.