Synthesis, characterization, and in vivo evaluation of the anticancer activity of a series of 5- and 6-(halomethyl)-2,2'-bipyridine rhenium tricarbonyl complexes.

We report the synthesis, characterization, and in vivo evaluation of the anticancer activity of a series of 5- and 6-(halomethyl)-2,2'-bipyridine rhenium tricarbonyl complexes. The study was promoted in order to understand if the presence and position of a reactive halomethyl substituent on the diimine ligand system of fac-[Re(CO)3]+ species may be a key molecular feature for the design of active and non-toxic anticancer agents. Only compounds potentially able to undergo ligand-based alkylating reactions show significant antiproliferative activity against colorectal and pancreatic cell lines. Of the new species presented in this study, one compound (5-(chloromethyl)-2,2'-bipyridine derivative) shows significant inhibition of pancreatic tumour growth in vivo in zebrafish-Panc-1 xenografts. The complex is noticeably effective at 8 µM concentration, lower than its in vitro IC50 values, being also capable of inhibiting in vivo cancer cells dissemination.

Anticancer and Antibiotic Rhenium Tri- and Dicarbonyl Complexes: Current Research and Future Perspectives.

Organometallic compounds are increasingly recognized as promising anticancer and antibiotic drug candidates. Among the transition metal ions investigated for these purposes, rhenium occupies a special role. Its tri- and dicarbonyl complexes, in particular, attract continuous attention due to their relative ease of preparation, stability and unique photophysical and luminescent properties that allow the combination of diagnostic and therapeutic purposes, thereby permitting, e.g., molecules to be tracked within cells. In this review, we discuss the anticancer and antibiotic properties of rhenium tri- and dicarbonyl complexes described in the last seven years, mainly in terms of their structural variations and in vitro efficacy. Given the abundant literature available, the focus is initially directed on tricarbonyl complexes of rhenium. Dicarbonyl species of the metal ion, which are slowly gaining momentum, are discussed in the second part in terms of future perspective for the possible developments in the field.

Non-destructive molecular FTIR spectromicroscopy for real time assessment of redox metallodrugs.

Recent emergence of FTIR spectromicroscopy (micro-FTIR) as a dynamic spectroscopy for imaging to study biological chemistry has opened new possibilities for investigating in situ drug release, redox chemistry effects on biological molecules, DNA and drug interactions, membrane dynamics, and redox reactions with proteins at the single cell level. Micro-FTIR applied to metallodrugs has been playing an important role since the last decade because of its great potential to achieve more robust and controlled pharmacological effects against several diseases, including cancer. An important aspect in the development of these drugs is to understand their cellular properties, such as uptake, accumulation, activity, and toxicity. In this review, we present the potential application of micro-FTIR and its importance for studying metal-based drugs, highlighting the perspectives of chemistry of living cells. We also emphasise bioimaging, which is of high importance to localize the cellular processes, for a proper understanding of the mechanism of action.

Photochemistry of Rhenium(i) Diimine Tricarbonyl Complexes in Biological Applications.

Luminescent rhenium complexes continue to be the focus of growing scientific interest for catalytic, diagnostic and therapeutic applications, with emphasis on the development of their photophysical and photochemical properties. In this short review, we explore such properties with a focus on the biological applications of the molecules. We discuss the importance of the ligand choice to the contribution and their involvement towards the most significant electronic transitions of the metal species and what strategies are used to exploit the potential of the molecules in medicinal applications. We begin by detailing the photophysics of the molecules; we then describe the three most common photoreactions of rhenium complexes as photosensitizers in H2 production, photocatalysts in CO2 reduction and photochemical ligand substitution. In the last part, we describe their applications as luminescent cellular probes and how photochemical ligand substitution is utilized in the development of photoactive carbon monoxide-releasing molecules as anticancer and antimicrobial agents.

Identification of novel potent and non-toxic anticancer, anti-angiogenic and antimetastatic rhenium complexes against colorectal carcinoma.

Combination therapy targeting both tumor growth and vascularization is considered to be a cornerstone for colorectal carcinomas (CRC) treatment. However, the major obstacles of most clinical anticancer drugs are their weak selective activity towards cancer cells and inherent inner organs toxicity, accompanied with fast drug resistance development. In our effort to discover novel selective and non-toxic agents effective against CRC, we designed, synthesized and characterized a series of rhenium(I) tricarbonyl-based complexes with increased lipophilicity. Two of these novel compounds were discovered to possess remarkable anticancer, anti-angiogenic and antimetastatic activity in vivo (zebrafish-human HCT-116 xenograft model), being effective at very low doses (1-3 µM). At doses as high as 250 µM the complexes did not provoke toxicity issues encountered in clinical anticancer drugs (cardio-, hepato-, and myelotoxicity). In vivo assays showed that the two compounds exceed the anti-tumor and anti-angiogenic activity of clinical drugs cisplatin and sunitinib malate, and display a large therapeutic window.

Cytotoxicity of Mn-based photoCORMs of ethynyl-α-diimine ligands against different cancer cell lines: The key role of CO-depleted metal fragments.

A series of tricarbonyl manganese complexes bearing 4-ethynyl-2,2'-bipyridine and 5-ethynyl-1,10-phenanthroline α-diimine ligands were synthetized, characterized and conjugated to vitamin B12, previously used as a vector for drug delivery, to take advantage of its water solubility and specificity toward cancer cells. The compounds act as photoactivatable carbon monoxide-releasing molecules rapidly liberating on average ca. 2.3 equivalents of CO upon photo-irradiation. Complexes and conjugates were tested for their anticancer effects, both in the dark and following photo-activation, against breast cancer MCF-7, lung carcinoma A549 and colon adenocarcinoma HT29 cell lines as well as immortalized human bronchial epithelial cells 16HBE14o- as the non-carcinogenic control. Our results indicate that the light-induced cytotoxicity these molecules can be attributed to both their released CO and to their CO-depleted metal fragments including liberated ligands.

Photoactivatable Surface-Functionalized Diatom Microalgae for Colorectal Cancer Targeted Delivery and Enhanced Cytotoxicity of Anticancer Complexes.

Systemic toxicity and severe side effects are commonly associated with anticancer chemotherapies. New strategies based on enhanced drug selectivity and targeted delivery to cancer cells while leaving healthy tissue undamaged can reduce the global patient burden. Herein, we report the design, synthesis and characterization of a bio-inspired hybrid multifunctional drug delivery system based on diatom microalgae. The microalgae's surface was chemically functionalized with hybrid vitamin B12-photoactivatable molecules and the materials further loaded with highly active rhenium(I) tricarbonyl anticancer complexes. The constructs showed enhanced adherence to colorectal cancer (CRC) cells and slow release of the chemotherapeutic drugs. The overall toxicity of the hybrid multifunctional drug delivery system was further enhanced by photoactivation of the microalgae surface. Depending on the construct and anticancer drug, a 2-fold increase in the cytotoxic efficacy of the drug was observed upon light irradiation. The use of this targeted drug delivery strategy, together with selective spatial-temporal light activation, may lead to lower effective concentration of anticancer drugs, thereby reducing medication doses, possible side effects and overall burden for the patient.

Slow-targeted release of a ruthenium anticancer agent from vitamin B12 functionalized marine diatom microalgae.

Herein we report the synthesis of a new biomaterial designed for targeted delivery of poorly water-soluble inorganic anticancer drugs, with a focus on colorectal cancer. Diatomaceous earth microparticles derived from marine microalgae were coated with vitamin B12 (cyanocobalamin) as a tumor targeting agent and loaded with the well-known anticancer agents cisplatin, 5-fluorouracil (5-FU), and a tris-tetraethyl[2,2'-bipyridine]-4,4'-diamine-ruthenium(ii) complex. The successful functionalization of the biomaterial was demonstrated by different analytical techniques and by synthesizing an organometallic fluorescein analogue of cyanocobalamin detectable by confocal laser scanning microscopy. The drug releasing properties were evaluated for all three species. We found that while cisplatin and 5-FU are rapidly lost from the material, the ruthenium complex showed an unprecedented release profile, being retained in the material up to 5 days in aqueous media but readily released in lipophilic environments as in the cell membrane. The increased adherence of the B12 coated diatoms to colorectal cancer cell line HT-29 and breast cancer cell line MCF-7 was demonstrated in vitro. In both cases, the adherence of the B12 modified diatoms was at least 3 times higher than that of the unmodified ones and was correlated with the increased transcobalamin II (TC(II)) and transcobalamin II receptor (TC(II)-R) expression of the targeted tissue. Our results suggest that this type of B12 modified diatoms could be a promising tool to achieve targeted delivery of water insoluble inorganic complexes to tumor tissues by acting as a micro-shuttle interacting with the sites of interest before delivering the drug in the vicinity of the tumor tissue.

Heptacoordinate CoII Complex: A New Architecture for Photochemical Hydrogen Production.

The first heptacoordinate cobalt catalyst for light-driven hydrogen production in water has been synthesized and characterized. Photochemical experiments using [Ru(bpy)3 ]2+ as photosensitizer gave a turnover number (TON) of 16300 mol H2 (mol cat.)-1 achieved in 2 hours of irradiation with visible (475 nm) light. This promising result provides a path forward in the development of new structures to improve the efficiency of the catalysis.

Organometallic cobalamin anticancer derivatives for targeted prodrug delivery via transcobalamin-mediated uptake.

Herein we report the synthesis of new water-soluble vitamin B12 prodrugs bearing metal complexes at the ß-upper side of the cobalt center. A total of three derivatives with the general design {Co-C[triple bond, length as m-dash]C-bpy-M}, where M represents a cytotoxic metal complex, were prepared and tested for their cytotoxicity against MCF-7 breast cancer cells. The choice of the metal was oriented on the eminent Pt and promising Ru and Re species to demonstrate the general applicability of the approach. The recognition of the derivatives by transcobalamin was demonstrated by competitive displacement assays using rhodamine labeled B12. This compound further served to prepare a dual luminescent probe by orthogonal synthesis with M = ((HCCbpy)Ru(bpy)2)Cl2 and to perform in vitro assays. Cellular imaging experiments allowed us to observe the different compartmentalization of both dyes and thus prove that the species follow the natural cobalamin uptake as well as the self-triggered release of the ß-upper complex.

Synthesis, characterization and cellular location of cytotoxic constitutional organometallic isomers of rhenium delivered on a cyanocobalmin scaffold.

Constitutional isomers of cyanocobalamin adducts based on a fluorescent rhenium tris-carbonyl diimine complex were prepared, characterized and tested against PC-3 cancer cells. The adducts differ only in the relative binding position of the organometallic species which is either bound at the cyano or the 5'-hydroxo group of vitamin B12. When tested for their cytotoxic potency, the species showed IC50 values in the low µM rage. Upon conjugation to the vitamin an energy transfer process causes an extremely low quantum yield of fluorescence emission, making the conjugates unsuitable for fluorescence imaging. However, by exploiting the vibrational signature of the fac-[Re(CO)3](+) core, their cellular distribution was evaluated via FTIR spectromicroscopy.

Post-protein binding metal-mediated coupling of an acridine orange-based fluorophore.

The HEW lysozyme (Lys) and the fac-[Re(CO)(3)(H(2)O)(3)](+) complex (1) are used as a simple model system for the description of a new approach to the labelling polypeptides with fluorescent tags. The strategy takes advantage of the reaction of an acridine orange-based fluorophore (AO) with the non-native metal fragment 1 hybridized on the enzyme. A synthetic methodology for the quantitative metallation of the protein is first described and it is then shown that the exogenous metal complex can be exploited for the coupling of the fluorescent probe. All Lys-derived species were characterized by various spectroscopic techniques. It is shown that the approach does not significantly alter the activity of the final fluorescent metallo-protein conjugate (Lys2). The accumulation of Lys2 on Micrococcus lysodeikticus bacteria was observed via confocal laser scanning microscopy.