A pH-Sensitive Fluorescent Chemosensor Turn-On Based in a Salen Iron (III) Complex: Synthesis, Photophysical Properties, and Live-Cell Imaging Application.

pH regulation is essential to allow normal cell function, and their imbalance is associated with different pathologic situations, including cancer. In this study, we present the synthesis of 2-(((2-aminoethyl)imino)methyl)phenol (HL1) and the iron (III) complex (Fe(L1)2Br, (C1)), confirmed by X-ray diffraction analysis. The absorption and emission properties of complex C1 were assessed in the presence and absence of different physiologically relevant analytes, finding a fluorescent turn-on when OH- was added. So, we determined the limit of detection (LOD = 3.97 × 10-9 M), stoichiometry (1:1), and association constant (Kas = 5.86 × 103 M-1). Using DFT calculations, we proposed a spontaneous decomposition mechanism for C1. After characterization, complex C1 was evaluated as an intracellular pH chemosensor on the human primary gastric adenocarcinoma (AGS) and non-tumoral gastric epithelia (GES-1) cell lines, finding fluorescent signal activation in the latter when compared to AGS cells due to the lower intracellular pH of AGS cells caused by the increased metabolic rate. However, when complex C1 was used on metastatic cancer cell lines (MKN-45 and MKN-74), a fluorescent turn-on was observed in both cell lines because the intracellular lactate amount increased. Our results could provide insights about the application of complex C1 as a metabolic probe to be used in cancer cell imaging.

Metal-Organic Compounds as Anticancer Agents: Versatile Building Blocks for Selective Action on G-quadruplexes.

BACKGROUND: Since the 1980s, cancer research has focused primarily on developing new therapeutic agents targeting DNA alterations rather than understanding cancer as an integrated system composed of several modules. In this sense, G-quadruplex (G4) nucleic acids are a promising target for drug development for cancer therapy since they exist in the chromosomal telomeric sequences and the promoter regions of numerous genes. The G4 structures within telomeric DNA can inhibit telomerase activity and prevent the proliferation and immortalization of cancer cells. Furthermore, such G4 systems within the promoter regions of oncogenes can inhibit the transcription and expression of the oncogene. OBJECTIVE: The rational design of small molecules such as organic ligands and their metal- organic derivative compounds can stabilize G4 structures through different binding modes on several G4 DNA topologies. Metal-based compounds have demonstrated their competitiveness compared to organic molecules to distinguish G4 over the DNA duplex owing to their convenient coordination features, positive charge, and electron density promoted by organic ligand. RESULTS: This article is a comprehensive review of metal compounds G4-binders and their structural features that confer them the ability to recognize G-quartets and stabilize several DNA G4s. CONCLUSION: This stabilization can be achieved through extended square aromatic surfaces, increased hydrophobicity, different auxiliary ligands, axially coordinated ligands, and the nature of the metal center.

Regulation of DAPK1 by Natural Products: An Important Target in Treatment of Stroke.

Stroke is a sudden neurological disorder that occurs due to impaired blood flow to an area of the brain. Stroke can be caused by the blockage or rupture of a blood vessel in the brain, called ischemic stroke and hemorrhagic stroke, respectively. Stroke is more common in men than women. Atrial fibrillation, hypertension, kidney disease, high cholesterol and lipids, genetic predisposition, inactivity, poor nutrition, diabetes mellitus, family history and smoking are factors that increase the risk of stroke. Restoring blood flow by repositioning blocked arteries using thrombolytic agents or endovascular therapy are the most effective treatments for stroke. However, restoring circulation after thrombolysis can cause fatal edema or intracranial hemorrhage, and worsen brain damage in a process known as ischemia-reperfusion injury. Therefore, there is a pressing need to find and develop more effective treatments for stroke. In the past, the first choice of treatment was based on natural compounds. Natural compounds are able to reduce the symptoms and reduce various diseases including stroke that attract the attention of the pharmaceutical industry. Nowadays, as a result of the numerous studies carried out in the field of herbal medicine, many useful and valuable effects of plants have been identified. The death-associated protein kinase (DAPK) family is one of the vital families of serine/threonine kinases involved in the regulation of some biological functions in human cells. DAPK1 is the most studied kinase within the DAPKs family as it is involved in neuronal and recovery processes. Dysregulation of DAPK1 in the brain is involved in the developing neurological diseases such as stroke. Natural products can function in a variety of ways, including reducing cerebral edema, reducing brain endothelial cell death, and inhibiting TNFα and interleukin-1ß (IL-1ß) through regulating the DAPK1 signal against stroke. Due to the role of DAPK1 in neurological disorders, the aim of this article was to investigate the role of DAPK1 in stroke and its modulation by natural compounds.

Antioxidant properties of flavonoid metal complexes and their potential inclusion in the development of novel strategies for the treatment against neurodegenerative diseases.

The increased oxidative stress in the acceleration of the aging process and development of the neuronal disorder are the common feature detected in neurodegenerative illness, such as Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Searching for new treatment against these diseases, the inclusion of exogenous antioxidant agents has shown good results. Flavonoids are polyphenols compounds present in plants, fruits and vegetables that exhibit potent antioxidant and biological properties, which are related to their chemical structure that to confer an excellent radical scavenging ability. The design of metal-flavonoid complexes allows to obtain compounds with improved biological and physicochemical properties, generating important increase of the flavonoid antioxidant properties. This evidence we motive to propose that antioxidant properties of the metal flavonoids compounds can play an important role in the design of potential novel therapeutic strategies. This review presents the structure-activity relationship on the antioxidant properties of three series of metal-flavonoid complexes: M-(quercetin), M-(morin), and M-(rutin). In general, we observed that the coordination sites, the metal ion type used, and the molar ratio metal:flavonoid present in the complexes, are important factors for to increase the antioxidant activity. On these evidences we motive to propose that the development of metal-flavonoid compounds is a potentially viable approach for combating neurodegenerative diseases.

Multifunctional Therapeutic Potential of Phytocomplexes and Natural Extracts for Antimicrobial Properties.

Natural products have been known for their antimicrobial factors since time immemorial. Infectious diseases are a worldwide burden that have been deteriorating because of the improvement of species impervious to various anti-infection agents. Hence, the distinguishing proof of antimicrobial specialists with high-power dynamic against MDR microorganisms is central to conquer this issue. Successful treatment of infection involves the improvement of new drugs or some common source of novel medications. Numerous naturally occurring antimicrobial agents can be of plant origin, animal origin, microbial origin, etc. Many plant and animal products have antimicrobial activities due to various active principles, secondary metabolites, or phytochemicals like alkaloids, tannins, terpenoids, essential oils, flavonoids, lectins, phagocytic cells, and many other organic constituents. Phytocomplexes' antimicrobial movement frequently results from a few particles acting in cooperative energy, and the clinical impacts might be because of the direct effects against microorganisms. The restorative plants that may furnish novel medication lead the antimicrobial movement. The purpose of this study is to investigate the antimicrobial properties of the phytocomplexes and natural extracts of the plants that are ordinarily being utilized as conventional medications and then recommended the chance of utilizing them in drugs for the treatment of multiple drug-resistant disease.

Crystal structures and Hirshfeld surface analysis of [κ2-P,N-{(C6H5)2(C5H5N)P}Re(CO)3Br]·2CHCl3 and the product of its reaction with piperidine, [P-{(C6H5)2(C5H5N)P}(C5H11N)Re(CO)3Br].

The coordination of the ligands with respect to the central atom in the complex bromido-tricarbon-yl[diphen-yl(pyridin-2-yl)phosphane-κ2 N,P]rhenium(I) chloro-form disolvate, [ReBr(C17H14NP)(CO)3]·2CHCl3 or [κ2-P,N-{(C6H5)2(C5H5N)P}Re(CO)3Br]·2CHCl3, (I·2CHCl3), is best described as a distorted octa-hedron with three carbonyls in a facial conformation, a bromide atom, and a biting P,N-di-phenyl-pyridyl-phosphine ligand. Hirshfeld surface analysis shows that C-Cl⋯H inter-actions contribute 26%, the distance of these inter-actions are between 2.895 and 3.213 Å. The reaction between I and piperidine (C5H11N) at 313 K in di-chloro-methane leads to the partial decoord-ination of the pyridyl-phosphine ligand, whose pyridyl group is replaced by a piperidine mol-ecule, and the complex bromido-tricarbon-yl[diphen-yl(pyridin-2-yl)phosphane-κP](piperidine-κN)rhenium(I), [ReBr(C5H11N)(C17H14NP)(CO)3] or [P-{(C6H5)2(C5H5N)P}(C5H11N)Re(CO)3Br] (II). The mol-ecule has an intra-molecular N-H⋯N hydrogen bond between the non-coordinated pyridyl nitro-gen atom and the amine hydrogen atom from piperidine with D⋯A = 2.992 (9) Å. Thermogravimetry shows that I·2CHCl3 losses 28% of its mass in a narrow range between 318 and 333 K, which is completely consistent with two solvating chloro-form mol-ecules very weakly bonded to I. The remaining I is stable at least to 573 K. In contrast, II seems to lose solvent and piperidine (12% of mass) between 427 and 463 K, while the additional 33% loss from this last temperature to 573 K corresponds to the release of 2-pyridyl-phosphine. The contribution to the scattering from highly disordered solvent mol-ecules in II was removed with the SQUEEZE routine [Spek (2015 ▸). Acta Cryst. C71, 9-18] in PLATON. The stated crystal data for M r, µ etc. do not take this solvent into account.

Oxoisoaporphines and Aporphines: Versatile Molecules with Anticancer Effects.

Cancer is a disease that involves impaired genome stability with a high mortality index globally. Since its discovery, many have searched for effective treatment, assessing different molecules for their anticancer activity. One of the most studied sources for anticancer therapy is natural compounds and their derivates, like alkaloids, which are organic molecules containing nitrogen atoms in their structure. Among them, oxoisoaporphine and sampangine compounds are receiving increased attention due to their potential anticancer effects. Boldine has also been tested as an anticancer molecule. Boldine is the primary alkaloid extract from boldo, an endemic tree in Chile. These compounds and their derivatives have unique structural properties that potentially have an anticancer mechanism. Different studies showed that this molecule can target cancer cells through several mechanisms, including reactive oxygen species generation, DNA binding, and telomerase enzyme inhibition. In this review, we summarize the state-of-art research related to oxoisoaporphine, sampangine, and boldine, with emphasis on their structural characteristics and the relationship between structure, activity, methods of extraction or synthesis, and anticancer mechanism. With an effective cancer therapy still lacking, these three compounds are good candidates for new anticancer research.

The Effect of Pyrazolyl Substituents on the Photophysical and Photochemical Properties of Pyrazine Derivatives.

The reaction of 2,5-dibromopyrazine with N-Lithium pyrazolate in a 1:2 ratio leads to a mixture of 2-bromo-5-(1H-pyrazol-1-yl)pyrazine (I) and 2,5-di(1H-pyrazol-1-yl)pyrazine (II). The structures of I and II are highly planar. Two absorption bands can be observed for the compounds in the UV-Vis region, having ε in the order of 104  m-1  cm-1 . TD-DFT computed results support the nature of the lower energy absorptions as πpyrazine →π*pyrazine transitions, including an additional intraligand charge transfer transition for I (πpyrazol →π*pyrazine ). Upon excitation at 280 or 320 nm, the emission of both compounds is almost not affected by solvent polarity or oxygen presence, showing two bands for I and one for II in the 350-450 nm region. Emission of II follows a mono-exponential decay, while I decays following a bi-exponential law, hypothesized from πpyrazine →π*pyrazine and πpyrazol →π*pyrazine transitions. Photodegradation of I and II follows a first-order kinetic with constants of 1.18 × 10-2  min-1 and 0.13 × 10-2  min-1 , respectively. Results suggest that photodegradation of I starts with the loose of bromide followed by intermolecular pyrazolyl subtraction and ring opening. This path is not available for II, which is reflected in its enhanced photostability.

The binuclear dual emitter [Br(CO)3Re(PN)(NP)Re(CO)3Br] (PN): 3-chloro-6-(4-diphenylphosphinyl)butoxypyridazine, a new bridging P,N-bidentate ligand resulting from the ring opening of tetrahydrofuran.

Lithium diphenylphosphide unexpectedly provokes the ring-opening of tetrahydrofuran (THF) and by reaction with 3,6-dichloropyridazine leads to the formation of the ligand 3-chloro-6-(4-diphenylphosphinyl)butoxypyridazine (P⋯N), which was isolated. The reaction of this ligand with the (Re(CO)3(THF)Br)2 dimer yields the novel complex [Br(CO)3Re(µ-3-chloro-6-(4-diphenylphosphinyl)butoxypyridazine)2Re(CO)3Br] (BrRe(P⋯N)(N⋯P)ReBr), which was crystallized in the form of a chloroform solvate, (C46H40Br2Cl2N4O8P2Re2)·(CHCl3). The monoclinic crystal (P21/n) displays a bimetallic cage structure with a symmetry inversion centre in the middle of the rhenium to rhenium line. The molecule shows two oxidation signals occurring at +1.50 V and +1.76 V which were assigned to the ReI/ReII and ReII/ReIII metal-centered couples, respectively, while signals observed at -1.38 V and -1.68 V were assigned to ligand centered reductions. Experimental and DFT/TDDFT results indicate that the UV-Vis absorption maximum of BrRe(P⋯N)(N⋯P)ReBr occurring near 380 nm displays a metal to ligand charge transfer (MLCT) character, which is consistent with CV results. Upon excitation at this wavelength, a weak emission (Φem < 1 × 10-3) is observed around 580 nm (in dichloromethane) which decays with two distinct lifetimes τ1 and τ2 of 24 and 4.7 ns, respectively. The prevalence of non-radiative deactivation pathways is consistent with efficient internal conversion induced by the high conformational flexibility of the P⋯N ligand's long carbon chain. Measurements in a frozen solvent at 77 K, where vibrational deactivation is hindered, show intense emission associated with the 3MLCT state. These results demonstrate that BrRe(P⋯N)(N⋯P)ReBr preserves the dual emitting nature previously reported for the mononuclear complex RePNBr, with emission associated with and states.

1D magnetic interactions in Cu(II) oxovanadium phosphates (VPO), magnetic susceptibility, DFT, and single-crystal EPR.

We report the crystal face indexing and molecular spatial orientation, magnetic properties, electron paramagnetic resonance (EPR) spectra, and density functional theory (DFT) calculations of two previously reported oxovanadium phosphates functionalized with Cu(II) complexes, namely, [Cu(bipy)(VO2)(PO4)]n (1) and [{Cu(phen)}2(VO2(H2O)2)(H2PO4)2 (PO4)]n (2), where bipy = 2,2'-bipyridine and phen = 1,10-phenanthroline, obtained by a new synthetic route allowing the growth of single crystals appropriate for the EPR measurements. Compounds 1 and 2 crystallize in the triclinic group P1̅ and in the orthorhombic Pccn group, respectively, containing dinuclear copper units connected by two -O-P-O- bridges in 1 and by a single -O-P-O- bridge in 2, further connected through -O-P-O-V-O- bridges. We emphasize in our work the structural aspects related to the chemical paths that determine the magnetic properties. Magnetic susceptibility data indicate bulk antiferromagnetism for both compounds, allowing to calculate J = -43.0 cm(-1) (dCu-Cu = 5.07 Å; J defined as Hex(i,j) = -J Si·Sj), considering dinuclear units for 1, and J = -1.44 cm(-1) (dCu-Cu = 3.47 Å) using the molecular field approximation for 2. The single-crystal EPR study allows evaluation of the g matrices, which provide a better understanding of the electronic structure. The absence of structure of the EPR spectra arising from the dinuclear character of the compounds allows estimation of weak additional exchange couplings |J'| > 0.3 cm(-1) for 1 (dCu-Cu = 5.54 Å) and a smaller value of |J'| ≥ 0.15 cm(-1) for 2 (dCu-Cu = 6.59 Å). DFT calculations allow evaluating two different exchange couplings for each compound, specifically, J = -36.60 cm(-1) (dCu-Cu = 5.07 Å) and J' = 0.20 cm(-1) (dCu-Cu =5.54 Å) for 1 and J = -1.10 cm(-1) (dCu-Cu =3.47 Å) and J' = 0.01 cm(-1) (dCu-Cu = 6.59 Å) for 2, this last value being in the range of the uncertainties of the calculations. Thus, these values are in good agreement with those provided by magnetic and single-crystal EPR measurements.

A new hybrid organic-inorganic chain: [(phen)Cu-µ-(κ2O:O'-VP2O10H3)2-Cu(phen)]n.

The structure of the title compound, poly[(dihydrogenphosphato-κO)(µ(3)-hydrogenphosphato)di-µ-oxido-(1,10-phenanthroline)copper(II)vanadium(V)], [CuV(HPO(4))(H(2)PO(4))O(2)(C(12)H(8)N(2))](n), is defined by [(phen)Cu-µ-(κ(2)O:O'-VP(2)O(10)H(3))(2)-Cu(phen)] units (phen is 1,10-phenanthroline), which are connected to neighbouring units through vanadyl bridges. Neighbouring chains have no covalent bonds between them, although they interdigitate through the phen groups via π-π interactions.