Facile, Single-Step Synthesis of a Series of D-Ring Ethisterones Substituted with 1,4-1,2,3-Triazoles: Preliminary Evaluation of Cytotoxic Activities.

A series of new D-ring ethisterones substituted with 1,4-1,2,3-triazoles were obtained in a facile manner via click chemistry reactions. The new compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, IR and unequivocally by single crystal X-ray diffraction studies for compound 1. The cytotoxic activity of these derivatives was tested against a series of human cancer cell lines including human glioblastoma (U-251), human prostatic adenocarcinoma (PC-3), human colorectal adenocarcinoma (HCT-15), human mammary adenocarcinoma (MCF-7), human chronic myelogenous leukemia (K562), and human lung adenocarcinoma (SKLU-1). Derivatives (3, X=Cl) and (5, X=I) showed promising cytotoxicity activities for leukemia adenocarcinoma (K562) and lung adenocarcinoma (SKLU). CI50% of K562: 11.72±0.9 µM (3) and 24.50±1.0 µM (5). CI50% of SKLU: 14.9±0.8 µM (3) and 46.0±2.8 µM (5). In addition, DNA docking simulations showed that all compounds interact with DNA through crosslink instrastrand p-alkyl-like interactions.

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer's Disease: Experimental and Computational Insights.

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

Transition Metal Complexes with Tridentate Schiff Bases (O N O and O N N) Derived from Salicylaldehyde: An Analysis of Their Potential Anticancer Activity.

Although it is known that the first case of cancer was recorded in ancient Egypt around 1600 BC, it was not until 1917 during the First World War and the development of mustard gas that chemotherapy against cancer became relevant; however, its properties were not recognised until 1946 to later be used in patients. In this sense, the use of metallopharmaceuticals in cancer therapy was extensively explored until the 1960s with the discovery of cisplatin and its anticancer activity. From that date to the present, the search for more effective, more selective metallodrugs with fewer side effects has been an area of continuous exploration. Efforts have led to considering a wide variety of metals from the periodic table, mainly from the d-block, as well as a wide variety of organic ligands, preferably with proven biological activity. In this sense, various research groups have found an ideal binder in Schiff bases, since their raw materials are easily accessible, their synthesis conditions are friendly and their denticity can be manipulated. Therefore, in this review, we have explored the anticancer and antitumor activity reported in the literature for coordination complexes of d-block metals coordinated with tridentate Schiff bases (O N O and O N N) derived from salicylaldehyde. For this work, we have used the main scientific databases CCDC® and SciFinder®.

Relevance of Fluorinated Ligands to the Design of Metallodrugs for Their Potential Use in Cancer Treatment.

Fluorination of pharmaceutical agents has afforded crucial modifications to their pharmacological profiles, leading to important advances in medicinal chemistry. On the other hand, metallodrugs are considered to be valuable candidates in the treatment of several diseases, albeit with the caveat that they may exhibit pharmacological disadvantages, such as poor water solubility, low bioavailability and short circulating time. To surmount these limitations, two approaches have been developed: one based on the design of novel metallodrug-delivering carriers and the other based on optimizing the structure of the ligands bound to the metal center. In this context, fluorination of the ligands may bring beneficial changes (physicochemical and biological) that can help to elude the aforementioned drawbacks. Thus, in this review, we discuss the use of fluorinated ligands in the design of metallodrugs that may exhibit potential anticancer activity.

In Vitro Evaluation of the Potential Pharmacological Activity and Molecular Targets of New Benzimidazole-Based Schiff Base Metal Complexes.

Metal-based drugs, including lanthanide complexes, have been extremely effective in clinical treatments against various diseases and have raised major interest in recent decades. Hence, in this work, a series of lanthanum (III) and cerium (III) complexes, including Schiff base ligands derived from (1H-benzimidazol-2-yl)aniline, salicylaldehyde, and 2,4-dihydroxybenzaldehyde were synthesized and characterized using different spectroscopic methods. Besides their cytotoxic activities, they were examined in human U-937 cells, primate kidney non-cancerous COS-7, and six other, different human tumor cell lines: U251, PC-3, K562, HCT-15, MCF-7, and SK-LU-1. In addition, the synthesized compounds were screened for in vitro antiparasitic activity against Leishmania braziliensis, Plasmodium falciparum, and Trypanosoma cruzi. Additionally, antibacterial activities were examined against two Gram-positive strains (S. aureus ATCC® 25923, L. monocytogenes ATCC® 19115) and two Gram-negative strains (E. coli ATCC® 25922, P. aeruginosa ATCC® 27583) using the microdilution method. The lanthanide complexes generally exhibited increased biological activity compared with the free Schiff base ligands. Interactions between the tested compounds and model membranes were examined using differential scanning calorimetry (DSC), and interactions with calf thymus DNA (CT-DNA) were investigated by ultraviolet (UV) absorption. Molecular docking studies were performed using leishmanin (1LML), cruzain (4PI3), P. falciparum alpha-tubulin (GenBank sequence CAA34101 [453 aa]), and S.aureus penicillin-binding protein 2a (PBP2A; 5M18) as the protein receptors. The results lead to the conclusion that the synthesized compounds exhibited a notable effect on model membranes imitating mammalian and bacterial membranes and rolled along DNA strands through groove interactions. Interactions between the compounds and studied receptors depended primarily on ligand structures in the molecular docking study.

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles.

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

Fluorinated-NHC Transition Metal Complexes: Leading Characters as Potential Anticancer Metallodrugs.

In the last 20 years, N-Heterocyclic Carbene (NHC) ligands have been ubiquitous in biological and medicinal chemistry. Part of their success lies in the tremendous number of topologies that can be synthesized and thus finely tuned that have been described so far. This is particularly true in the case of those derivatives, including fluorine or fluorinated fragments on their NHC moieties, gaining much attention due to their enhanced biological properties and turning them into excellent candidates for the development of novel metallodrugs. Thus, this review summarizes the development that fluorinated-NHC transition metal complexes have had and their impact on cancer treatment.

Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes.

The dianionic aza crown ether-dtc N,N'-bis(dithiocarbamate)-1,10-diaza-18-crown-6 (L2-) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [µ-(κ2-S,-S'-L)M2(PPh3)4]Cl2 (M = Pd (1), Pt (2)), [µ-(κ2-S,-S'-L)M2(PPh3)4](BPh4)2 (M = Pd (3), Pt (4)), and µ-(κ-S,-S'-L)Ni2(PPh3)2Cl2 (5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC50 values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC50 = 2.3 ± 0.2 µM for 2 versus 3.6 ± 0.5 µM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC50 decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 µM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC50 improves by ca. 40% reaching 1.3 ± 0.1 µM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the X-ray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.

Synthesis of Pt(II) complexes of the type [Pt(1,10-phenanthroline)(SArFn)2] (SArFn = SC6H3-3,4-F2; SC6F4-4-H; SC6F5). Preliminary evaluation of their in vitro anticancer activity.

A series of Pt(II) complexes of the type [Pt(1,10-phenanthroline)(SArFn)2] (SArFn = SC6H3-3,4-F2(1); SC6F4-4-H (2); SC6F5(3)) were synthesized from [Pt(1,10-phenanthroline)(Cl)2] and [Pb(SArFn)2] via metathesis reactions. The complexes were fully characterized including the unambiguous determination of their molecular structures by single-crystal X-ray diffraction techniques, showing the metal centers to be into a slightly distorted square-planar environments. The in vitro cytotoxic activity of the complexes was evaluated on six cancerous cell lines, i.e: glial cells of nervous central system (U-251), prostate (PC-3), leukemia (K-562), colon (HCT-15), breast (MCF-7) and lung (SKLU-1); we also included a healthy cell line of COS-7 (African green monkey kidney) for comparative purposes. We found that complex 2 was selective for PC-3. In addition, the IC50 values for the series of complexes were determined using the U-251, HCT-15 and SKLU-1 cancerous cell lines, as well as in the healthy cell line (COS-7), where complex 1 exhibited the best activity, with IC50 values going from 4.56 to 4.78 µM. These studies where further complemented with DNA docking theoretical calculations and DNA affinity experiments.

Synthesis, biological evaluation and model membrane studies on metal complexes containing aromatic N,O-chelate ligands.

Novel lanthanide (Ln) compounds [Ln(L)2]Cl.xH2O (Ln = La3+, Ce3+, Sm3+) containing aromatic N,O-chelate ligands [HL1 = 4-amino-2-(1H-benzimidazol-2-yl)phenol; HL2 = 5-amino-2-(1H-benzimidazol-2-yl)phenol] have been synthesized and structurally characterized by elemental analysis, NMR and IR spectroscopy, molar conductance measurements, and mass spectrometry (MS). The spectroscopic data suggested that the benzimidazolyl-phenol ligands act as N,O-chelate ligands through the iminic nitrogen and phenolic oxygen atoms. Elemental analysis indicated that lanthanide compounds were formed in a 1:2 stoichiometry (metal:ligand). In vitro biological evaluation was carried out using these complexes, exhibiting moderate cytotoxicity against six different human tumor cell lines (U251, human glioblastoma; HCT-15, colorectal carcinoma; MCF-7, breast epithelial adenocarcinoma; PC-3, prostate cancer; K562, myelogenous leukemia; SKLU-1, lung carcinoma) and lower toxicity against a non-cancerous cell line (COS-7, primate kidney). In addition, the antibacterial activity of the compounds was assessed against two gram-positive strains (Staphylococcus aureus ATCC 25923, Listeria monocytogenes ATCC 19115) and two gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27583) using the microdilution method. The results obtained show that the metal complexes exhibit higher biological activity than the free ligands, confirming a synergistic effect. Further benzimidazolyl-phenol derivatives were explored for the detection of bacteria using fluorescence imaging studies. Interestingly, the fluorescent properties of these compounds make them potential candidates to monitor the morphology of bacteria at different compound concentrations. Hence, the interaction of the ligand and complexes with model membranes mimicking those of bacteria was studied by using differential scanning calorimetry (DSC) and molecular dynamics (MD), showing that both compounds decreased the enthalpy of transition in two model membranes as the concentration of the compounds increased. In addition, the main transition temperature was slightly reduced as a result of these interactions.

Bifunctional colorimetric chemosensing of fluoride and cyanide ions by nickel-POCOP pincer receptors.

Three Ni(ii)-POCOP pincer complexes [NiCl{C6H2-4-OH-2,6-(OPPh2)2}], 1; [NiCl{C6H2-4-OH-2,6-(OPtBu2)2}], 2 and [NiCl{C6H2-4-OH-2,6-(OPiPr2)2}], 3 were studied as bifunctional molecular sensors for inorganic anions and acetate. In CH3CN, fluoride generates a bathochromic shift with a colorimetric change for 1-3 with a simultaneous fluorescence turn on, this optical effect is based on deprotonation of the para-hydroxy group of the POCOP ligand. On the other hand, in a neutral aqueous solution of 80 vol% CH3CN, additions of cyanide produce a distinct change of color by forming very stable complexes with the nickel-based receptors 1-3 with log Ka in the range of 4.38-5.03 M-1 and pronounced selectivity over other common anions such as iodide, phosphate, and acetate. Additionally, bromide shows a modest spectral change and affinity, but lower than those observed for cyanide. On the basis of 1H NMR experiments, UV-vis titrations, ESI-MS experiments, and the crystal structure of the neutral bromo complex of 1, it is proposed that the colorimetric change involves an exchange of chloride by CN- on the Ni(ii) atom. The Ni(ii)-based sensor 1 allows the fluorescent selective detection of fluoride with a limit of 5.66 µmol L-1 and colorimetric sensing of cyanide in aqueous medium in the micromolar concentration range.

A comparative study of the packing of two polymorphs of the nickel(II) pincer complex [2,6-bis(di-tert-butylphosphinoyl)-4-(3,5-dinitrobenzoyloxy)phenyl-κ(3)P,C(1),P']chloridonickel(II).

Pincer complexes can act as catalysts in organic transformations and have potential applications in materials, medicine and biology. They exhibit robust structures and high thermal stability attributed to the tridentate coordination of the pincer ligands and the strong σ metal-carbon bond. Nickel derivatives of these ligands have shown high catalytic activities in cross-coupling reactions and other industrially relevant transformations. This work reports the crystal structures of two polymorphs of the title Ni(II) POCOP pincer complex, [Ni(C29H41N2O8P2)Cl] or [NiCl{C6H2-4-[OCOC6H4-3,5-(NO2)2]-2,6-(OP(t)Bu2)2}]. Both pincer structures exhibit the Ni(II) atom in a distorted square-planar coordination geometry with the POCOP pincer ligand coordinated in a typical tridentate manner via the two P atoms and one arene C atom via a C-Ni σ bond, giving rise to two five-membered chelate rings. The coordination sphere of the Ni(II) centre is completed by a chloride ligand. The asymmetric units of both polymorphs consist of one molecule of the pincer complex. In the first polymorph, the arene rings are nearly coplanar, with a dihedral angle between the mean planes of 27.9 (1)°, while in the second polymorph, this angle is 82.64 (1)°, which shows that the arene rings are almost perpendicular to one another. The supramolecular structure is directed by the presence of weak C-H...O=X (X = C or N) interactions, forming two- and three-dimensional chain arrangements.

trans-Chlorido-(4-fluoro-benzene-thiol-ato-κS)bis-(tri-phenyl-phosphane-κP)palladium(II) methanol hemisolvate.

The title compound, [Pd(SC6H4F-p)Cl(PPh3)2]·0.5CH3OH, features a Pd(II) complex with two tri-phenyl-phosphane (PPh3) ligands arranged in a trans conformation, with one chloride and one 4-fluoro-benzene-thiol-ate ligand completing the coordination sphere, giving rise to a slightly distorted square-planar geometry of the Pd(II) ion. The methanol solvent mol-ecule is disordered about an inversion centre with an occupancy of 0.25 for each molecule. In the crystal, weak C-H⋯Cl hydrogen-bonding inter-actions between the complex mol-ecules generate chain frameworks parallel to [010].

trans-Bis(µ-benzene-thiol-ato-κ(2) S:S)bis[chlorido-(tri-phenyl-phosphane-κP)palladium(II)] chloro-form disolvate.

The title compound, [Pd2Cl2(C6H5S)2(C18H15P)2]·2CHCl3, contains a centrosymmetric dinuclear palladium complex with the Pd(II) cation in a slightly distorted square-planar coordination environment. The Pd(II) cations are bridged by the S atoms of two benzene-thiol-ate ligands with different Pd-S distances [2.2970 (11) and 2.3676 (11) Å]. The coordination of the metal atom is completed by a chloride anion [2.3383 (11) Å] and a tri-phenyl-phosphane ligand [2.2787 (11) Å]. Weak C-H⋯Cl inter-actions are present between complex mol-ecules and the CHCl3 solvent mol-ecule. The latter is disordered over two positions in a 0.792 (8):0.208 (8) ratio. The crystal under investigation was found to be twinned by nonmerohedry, with a fraction of 73.4 (1)% for the major twin component.

1,3-Bis[(naphthalen-2-ylsulfan-yl)meth-yl]benzene.

Mol-ecules of the title compound, C(28)H(22)S(2), are located on a crystallographic mirror plane with one half-mol-ecule in the asymmetric unit. The dihedral angle between the phenyl ring and the naphthyl unit is 83.14 (7)°. In the crystal, mol-ecules are inter-connected by C-H⋯S and C-H⋯π inter-actions.

1-Ethenyl-4-[(phenylsulfanyl)methyl]-benzene.

The dihedral angle between the aromatic rings in the title compound, C(15)H(14)S, is 72.38 (7)°. In the crystal, the mol-ecules are connected by C-H⋯π inter-actions.

[2-(Diphenyl-phosphan-yl)benzene-thiol-ato-κP,S](pyridine-2-thiol-ato-κS)(triphenyl-phosphine-κP)palladium(II).

In the title compound, [Pd(C(5)H(4)NS)(C(18)H(14)PS)(C(18)H(15)P)], the Pd(II) atom has a slightly distorted square-planar environment. Two coordination sites are occupied by a P,S-chelating 2-(diphenyl-phosphan-yl)benzene-thiol-ate ligand and the other two by a P atom from a triphenyl-phosphine ligand and an S atom from a pyridine-2-thiol-ate ligand, exhibiting a trans arrangement of the two P-donor atoms. In the crystal structure, weak intra- and inter-molecular C-H⋯π and π-π inter-actions are observed. The pyridyl ring is equally disordered over two positions.

Di-µ(2)-chlorido-bis-[chlorido(η-hexa-methyl-benzene)ruthenium(II)].

Dimeric mol-ecules of the title compound, [Ru(2)Cl(4)(C(12)H(18))(2)], are located on a crystallographic centre of inversion with one mol-ecule in the asymmetric unit. The hexa-methyl-benzene rings are in an η(6)-coordination to the ruthenium centres, which are bridged by two chloride ligands. In addition, the ruthenium centres are bonded to another chloride ligand. The aromatic rings and the Ru(2)Cl(2) four-membered ring enclose a dihedral angle of 55.85 (6)°.

Di-µ(2)-bromido-bis-[bromido(η-1,2,4,5-tetra-methyl-benzene)ruthenium(II)].

The asymmetric unit of the title compound, [Ru(2)Br(4)(C(10)H(14))(2)], contains one half of the centrosymmetric mol-ecule. Each Ru center is coordinated by tetra-methyl-benzene ring in a η(6)-coordination mode, and one terminal and two bridging bromine atoms. The aromatic rings and the Ru(2)Br(2) four-membered ring form a dihedral angle of 55.99 (8)°. In the crystal structure, weak inter-molecular C-H⋯Br inter-actions link mol-ecules into chains propagated in [001].

cis-Bis-[2-(diphenyl-phosphino)benzene-thiolato-κP,S]palladium(II).

The title compound, [Pd(C(18)H(14)PS)(2)], was synthesized by the reaction of (Ph(2)PC(6)H(4)SH) with [PdCl(2)(NCC(6)H(5))(2)] in a 2:1 molar ratio in the presence of a slight excess of NEt(3 )as base in dichloro-methane. The compound crystallizes with the Pd(II) atom on a twofold rotation axis. The palladium center has a slightly distorted square-planar environment, with the two P-S chelating ligands adopting a cis configuration. The present structure is a pseudo-polymorph of [Pd(C(18)H(14)PS)(2)]·CH(2)Cl(2).