Catalysis-free synthesis of thiazolidine-thiourea ligands for metal coordination (Au and Ag) and preliminary cytotoxic studies.

The reaction of propargylamines with isothiocyanates results in the selective formation of iminothiazolidines, aminothiazolines or mixed thiazolidine-thiourea compounds under mild conditions. It has been observed that secondary propargylamines lead to the selective formation of cyclic 2-amino-2-thiazoline derivatives, while primary propargylamines form iminothiazoline species. In addition, these cyclic thiazoline derivatives can further react with an excess of isothiocyanate to give rise to thiazolidine-thiourea compounds. These species can also be achieved by reaction of propargylamines with isothiocynates in a molar ratio of 1 : 2. Coordination studies of these heterocyclic species towards silver and gold with different stoichiometries have been carried out and complexes of the type [ML(PPh3)]OTf, [ML2]OTf (M = Ag, Au) or [Au(C6F5)L] have been synthesised. Preliminary studies of the cytotoxic activity in lung cancer cells have also been performed in both ligands and complexes, showing that although the ligands do not exhibit anticancer activity, their coordination to metals, especially silver, greatly enhances the cytotoxic activity.

Heterocycles in Breast Cancer Treatment: The Use of Pyrazole Derivatives.

Among the aromatic heterocycle rings, pyrazole -a five-membered ring with two adjacent nitrogen atoms in its structure has been postulated as a potent candidate in the pharmacological context. This moiety is an interesting therapeutic target covering a broad spectrum of biological activities due to its presence in many natural substances. Hence, the potential of the pyrazole derivatives as antitumor agents has been explored in many investigations, showing promising results in some cases. In this sense, breast cancer, which is already the leading cause of cancer mortality in women in some countries, has been the topic selected for this review, which covers a range of different research from the earliest studies published in 2003 to the most recent ones in 2021.

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties.

In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group (T2) or 3,5-di-CF3 substituted phenyl ring (T1) have been prepared and their coordination to Au and Ag has been studied. A different behavior is observed for gold complexes, a linear geometry with coordination only to the phosphorus atom or an equilibrium between the linear and three-coordinated species is present, whereas for silver complexes the coordination of the ligand as P^S chelate is found. The thiourea ligands and their complexes were explored against different cancer cell lines (HeLa, A549, and Jurkat). The thiourea ligands do not exhibit relevant cytotoxicity in the tested cell lines and the coordination of a metal triggers excellent cytotoxic values in all cases. In general, data showed that gold complexes are more cytotoxic than the silver compounds with T1, in particular the complexes [AuT1(PPh3)]OTf, the bis(thiourea) [Au(T1)2]OTf and the gold-thiolate species [Au(SR)T1]. In contrast, with T2 better results are obtained with silver species [AgT1(PPh3)]OTf and the [Ag(T1)2]OTf. The role played by the ancillary ligand bound to the metal is important since it strongly affects the cytotoxic activity, being the bis(thiourea) complex the most active species. This study demonstrates that metal complexes derived from thiourea can be biologically active and these compounds are promising leads for further development as potential anticancer agents.

Novel ureido-dihydropyridine scaffolds as theranostic agents.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

Bioactive and luminescent indole and isatin based gold(i) derivatives.

A series of luminescent monometallic [AuL(PPh3)] (1-3) and bimetallic [Au2(µ-dppe)L2] (4, 6, 8) and [Au2(µ-dppp)L2] (5, 7, 9) complexes, where L is either 4-cyano-indole, isatin, or 5,7-dimethyl-isatin, and dppe and dppp are 1,2-bis(diphenylphosphino)ethane and 1,3-bis(diphenylphosphino)propane, respectively, have been synthesised. X-ray diffraction confirmed the tendency to establish aurophillic interations for those complexes containing dppe. Luminescence studies and theoretical calculations revealed a different origin for both families, i.e. indole and isatin species. Thus, indole derivatives presented a ligand-to-ligand-charge-transfer transition (LLCT) from the indole to the PPh3 fragment, whereas for the isatin derivatives an intraligand-charge-transfer transition (ILCT) within the isatin fragment is proposed. In both cases, the gold centre was slightly implicated as a ligand-to-metal-charge transfer transition (LMCT) (from the indole/isatin to Au(i)). Cell antiproliferative assays in lung cancer cells (A549), leukemia Jurkat-pLVTHM and Jurkat-shBak cells (cisplatin sensitive and resistant, respectively) showed excellent cytotoxic values (10.11-0.28 µM), showing the leukemia cells to be the most sensitive and the bimetallic species to be the most active agents. Preliminary studies associated the cytotoxicity with a combination of different factors, the metallic fragment being mainly responsible. Remarkably, these complexes are able to inhibit the cellular growth of cisplatin resistant Jurkat-shBak cells highlighting their promising future as an alternative anticancer agent.

Synthesis, structural determination and antimicrobial evaluation of two novel CoII and ZnII halogenometallates as efficient catalysts for the acetalization reaction of aldehydes.

BACKGROUND: Complexes of imidazole derivatives with transition metal ions have attracted much attention because of their biological and pharmacological activities, such as antimicrobial, antifungal, antiallergic, antitumoural and antimetastatic properties. In addition, imidazoles occupy an important place owing to their meaningful catalytic activity in several processes, such as in hydroamination, hydrosilylation, Heck reaction and Henry reaction. In this work, we describe the crystallization of two halogenometallate based on 2-methylimidazole. Their IR, thermal analysis, catalytic properties and antibacterial activities have also been investigated. RESULTS: Two new isostructural organic-inorganic hybrid materials, based on 2-methyl-1H-imidazole, 1 and 2, were synthesized and fully structurally characterized. The analysis of their crystal packing reveals non-covalent interactions, including C/N-H···Cl hydrogen bonds and π···π stacking interactions, to be the main factor governing the supramolecular assembly of the crystalline complexes. The thermal decomposition of the complexes is a mono-stage process, confirmed by the three-dimensional representation of the powder diffraction patterns (TDXD). The catalytic structure exhibited promising activity using MeOH as solvent and as the unique source of acetalization. Moreover, the antimicrobial results suggested that metal-complexes exhibit significant antimicrobial activity. CONCLUSION: This study highlights again the structural and the biological diversities within the field of inorganic-organic hybrids.

Highly active group 11 metal complexes with α-hydrazidophosphonate ligands.

α-Hydrazidophosphonates are interesting scaffolds that could combine the biological properties of hydrazones and phosphonyl species, and their coordination properties remain unknown. The coordination chemistry of these ligands towards group 11 metals has been studied. A series of novel gold(i), silver(i) and copper(i) complexes with α-hydrazidophosphonate ligands have been prepared and characterised. The coordination geometries obtained vary from linear to trigonal planar for gold(i) to distorted trigonal planar or tetrahedral for silver(i) and copper(i). Structural characterisation of two silver derivatives shows the ligands in an O^N^O tridentate fashion, with dissimilar bond lengths. These compounds were screened for the in vitro cytotoxic activity against two tumour human cell lines such as HeLa (cervical carcinoma) and A549 (lung carcinoma). The IC50 values reveal an excellent cytotoxic activity of the metal complexes compared with the α-hydrazidophosphonate ligands alone and cisplatin.

The fluxional amine gold(III) complex as an excellent catalyst and precursor of biologically active acyclic carbenes.

A new amine gold(III) complex [Au(C6F5)2(DPA)]ClO4 with the di-(2-picolyl)amine (DPA) ligand has been synthesised. In the solid state the complex has a chiral amine nitrogen because the ligand coordinates to the gold centre through one nitrogen atom from a pyridine and through the NH moiety, whereas in solution it shows a fluxional behaviour with a rapid exchange between the pyridine sites. This complex can be used as an excellent synton to prepare new gold(III) carbene complexes by the reaction with isocyanide CNR. The resulting gold(III) derivatives have unprecedented bidentate C^N acyclic carbene ligands. All the complexes have been spectroscopically and structurally characterized. Taking advantage of the fluxional behaviour of the amine complex, its catalytic properties have been tested in several reactions with the formation of C-C and C-N bonds. The complex showed excellent activity with total conversion, without the presence of a co-catalyst, and with a catalyst loading as low as 0.1%. These complexes also present biological properties, and cytotoxicity studies have been performed in vitro against three tumour human cell lines, Jurkat (T-cell leukaemia), MiaPaca2 (pancreatic carcinoma) and A549 (lung carcinoma). Some of them showed excellent cytotoxic activity compared with the reference cisplatin.

Organocatalytic conjugate addition of formaldehyde N,N-dialkylhydrazones to beta,gamma-unsaturated alpha-keto esters.

(1S,2R)-1-Aminoindan-2-ol-derived thioureas behave as efficient H-bonding organocatalysts for the nucleophilic conjugate addition of formaldehyde hydrazones to beta,gamma-unsaturated alpha-keto esters as enoate surrogates, affording the corresponding adducts in good yields and enantioselectivities.