Overuse and misuse of antibacterial drugs has resulted in bacteria resistance and in an increase in mortality rates due to bacterial infections. Therefore, there is an imperative necessity of new ...antibacterial drugs. Bio‐organometallic derivatives of antibacterial agents offer an opportunity to discover new active antibacterial drugs. These compounds are well‐characterized products and, in several examples, their antibacterial activities have been studied. Both inhibition of the antibacterial activity and strong increase in the antibiotic activity of the parent drug have been found. The synthesis of the main classes of bio‐organometallic derivatives of these drugs, as well as examples of the use of structure–activity relation (SAR) studies to increase the activity and to understand the mode of action of bio‐organometallic antimicrobial peptides (BOAMPs) and platensimicyn bio‐organometallic mimics is presented in this article.
New opportunities: Misuse of antibacterial drugs has resulted in a significant increase in mortality rates due to bacterial infections and in a pressing necessity of new antibacterial drugs (see figure). Bio‐organometallic compounds offer an opportunity to discover new active antibacterial drugs.
Enantiopure bimetallic systems containing three different elements of chirality, namely a main‐group‐based chiral center (sulfur), a transition‐metal chiral center (rhodium or iridium), and a planar ...chiral element (ferrocene or ruthenocene), have been prepared by a sequence of diastereoselective reactions. The chirality of the chiral sulfur center attached to C‐5 of a 1,2,3‐triazolylidene mesoionic carbene (MIC) ligand coordinated to a metal (Ir, Rh) was transferred through the formation of bimetallic complexes having a chiral‐at‐metal center and a planar chiral metallocene by C−H activation of the sandwich moiety (M=Fe, Ru). The sense of the planar chirality formed in this sequence of reactions depended on the nature of the ligands at the metal center of the starting complex. The configurations of these species were assigned on the basis of a combination of X‐ray diffraction and CD measurements. An electrochemical study of these bimetallic complexes in coordinating solvents showed an equilibrium between the cationic complexes and the neutral species. The effect of the half‐sandwich moiety on the oxidation potentials of the system is remarkable, producing notable cathodic displacements. DFT calculations support these findings.
Chirality transferred: Enantiopure bimetallic systems having three different elements of chirality, namely a main‐group‐based chiral center (sulfur), a transition‐metal chiral center (rhodium or iridium), and a planar chiral element (ferrocene or ruthenocene), have been prepared by a sequence of diastereoselective reactions that includes a C−H insertion step (see scheme).
The reaction between bis(1,2,3‐triazol‐1‐yl)methane derivatives and nBuLi and various aldehydes, yielded novel neutral ligand precursors incorporating alcohol functional groups. The resulting ...compounds exhibited distinct characteristics depending on the steric hindrance of the aldehyde employed. In instances where aromatic aldehydes were utilized, functionalization occurred at the methine group bridging both triazole rings. Conversely, the use of pivalic aldehyde prompted functionalization at the C5 position of the triazole ring. These compounds were subsequently employed as ligand precursors in the synthesis of organometallic aluminum and zinc complexes, yielding dinuclear complexes with high efficiency. The structural elucidation of all compounds was accomplished through spectroscopic methods and validated by X‐ray crystallography. Preliminary catalytic investigations into the coupling reaction of cyclohexene oxide and CO2 revealed that aluminum and zinc complexes catalyzed the selective formation of polyether and polycarbonate materials, respectively.
The synthesis of new alcohol neutral ligand precursors based on bis(1,2,3‐triazol‐1‐yl)methane moieties is reported. A substrate‐dependent functionalization is observed allowing access to a variety of ligand precursors. The coordination chemistry of some of them against aluminum and zinc have also been investigated.
The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now.
Evidence that sporadic ...(nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease.
Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings.
Gold mesoionic carbenes having a chiral sulfoxide group attached to the C4 position of the five membered ring have been prepared and tested as catalysts in the cycloisomerization of enynes. These new ...catalysts are very efficient, with the sulfoxide moiety playing a key role in their activity and the N1-substituent in control of the regioselectivity of these processes.
Mesoionic carbenes (MICs) derived from triazolium salts that contain chiral sulfoxide or sulfoximine functional groups were used to construct enantiopure chiral‐at‐metal IrIII and RhIII half‐sandwich ...complexes through the synthetic sequence of MIC complexation/C−H aromatic activation. The process was efficient and diastereoselective for the formation of enantiopure five‐membered metallacycles. The use of the enantiomers of the chiral sulfur groups allowed us to prepare complexes that had opposite configurations at the metal center. Complete retention of the configuration at the metal center was observed during the formation of cationic IrIII complexes and upon insertion of alkynes into the IrIII−C bond, as demonstrated by a combined circular dichroism/X‐ray study. These results point to a vicinal‐assisted SN1‐like mechanism.
Translation
La síntesis de complejos “half‐sandwich”, conteniendo centros metálicos de IrIII y RhIII enantiomericamente puros, se ha efectuado desde carbenos mesoiónicos (MICs) derivados de sales de triazolio enantiomericamente puras sustituidas por sulfóxidos o sulfoximinas. La preparación de estos complejos se ha efectuado usando una secuencia en la que el MIC se ha complejado al metal y, posteriormente, se ha realizado una activación de un enlace C−H aromático. El proceso de formación de metalaciclos de cinco eslabones enantiomericamente puros es eficiente y completamente diastereoselectivo. Cuando se usan los enantiómeros de los grupos de azufre quirales unidos al MIC se pueden preparar complejos con configuraciones opuestas en el centro metálico. Tanto la formación de complejos de IrIII catiónicos como la inserción de alquinos en el enlace IrIII−C, ocurren con retención completa de la configuración. Esto se demuestra usando una combinación de Dicroísmo Circular y estudios de rayos‐X. Los resultados obtenidos sugieren una asistencia vecinal del grupo de azufre quiral en estos procesos similares a la SN1.
Enantioenriched metallacycles: Enantiopure chiral‐at‐metal IrIII and RhIII half‐sandwich complexes are produced from mesoionic carbenes (MICs) that contain chiral sulfoxide or sulfoximine functional groups. The synthetic sequence of MIC complexation/C−H aromatic activation efficiently affords enantiopure five‐membered metallacycles. The configuration at the metal center remains unaltered during the formation of the cationic IrIII complexes and the insertion of alkynes, as demonstrated by a combined circular dichroism/X‐ray study.
The cause of Alzheimer's disease (AD) is unknown. This gap in knowledge has created a stumbling block in the search for a genuinely effective treatment or cure for this dementia. This article ...summarises the arguments for a causal role for either amyloid deposition or cerebrovascular pathology as the primary trigger in the development of non-genetic AD. A bare-bones survey of the published research reveals no compelling evidence that amyloid deposition is neurotoxic in human beings or that it results in neurodegenerative changes involving synaptic, metabolic, or neuronal loss in human or transgenic-mouse brains. By contrast, the data supporting AD as a primary vascular disorder are more convincing. Findings suggesting a vascular cause of AD come from epidemiological, neuroimaging, pathological, pharmacotherapeutic, and clinical studies. The consensus of these studies indicates that chronic brain hypoperfusion is linked to AD risk factors, AD preclinical detection and pharmacotherapeutic action of AD symptoms.
Procedures for the preparation of transition metal complexes having intact bicyclic cepham or penam systems as ligands have been developed. Starting from readily available 4-azido-2-azetidinones, a ...synthetic approach has been tuned using a copper-catalyzed azide–alkyne cycloaddition between 3-azido-2-azetinones and alkynes, followed by methylation and transmetalation to Au(I) and Ir(III) complexes from the mesoionic carbene Ag(I) complexes. This methodology was applied to 6-azido penam and 7-azido cepham derivatives to build 6-(1,2,3-triazolyl)penam and 7-(1,2,3-triazolyl)cepham proligands, which upon methylation and metalation with Au(I) and Ir(III) complexes yielded products derived from the coordination of the metal to the penam C6 and cepham C7 positions, preserving intact the bicyclic structure of the penicillin and cephalosporin scaffolds. The crystal structure of complex 28b, which has an Ir atom directly bonded to the intact penicillin bicycle, was determined by X-ray diffraction. This is the first structural report of a penicillin-transition-metal complex having the bicyclic system of these antibiotics intact. The selectivity of the coordination processes was interpreted using DFT calculations.
Considerable information is currently available from neuroimaging, pathological, and population-based prospective studies showing that vascular risk factors are independently associated with an ...increased risk of Alzheimer's disease (AD). Many of these studies indicate that vascular risk factors can predict the clinical development of cognitive dysfunction and AD onset. This review examines the role of cerebral hemodynamics and vasoactive molecules that contribute to the regulation of cerebral perfusion and how three common vascular risk factors to AD, namely, hypertension, diabetes type 2, and atherosclerosis, can alter cerebral blood flow (CBF) regulation and generate perfusion pressure deficits. It is proposed that these vascular risk factors (and presumably other vascular risk factors) initiate chronic brain hypoperfusion that ultimately impair signaling from neurons, astrocytes, and endothelial cells to vascular smooth muscle controlling vessel diameter. Impaired signaling involving vascular pathways in the elderly can attenuate vessel tone and deregulate CBF. Noxious cerebral hemodynamic responses to vascular risk factors and chronic brain hypoperfusion are partly explained by Poiseuille's Law which states that miniscule changes in vessel diameter can have a dramatic effect on vessel resistance and on the rate of blood flow. Using Poiseuille's model, even minor narrowing of arteriolar diameter can lead to major reductions in CBF and in suboptimal delivery of high energy nutrients to the brain, with lethal consequences to brain cells that participate in cognitive function. Regional brain cell loss sets the stage for age-related cognitive impairment and AD onset. Keeping cerebral hemodynamic homeostasis by careful management of vascular risk factors could be a decisive therapeutic target in the prevention of AD.
A defining feature of vertebrate immunity is the acquisition of immunological memory, which confers enhanced protection against pathogens by mechanisms that are incompletely understood. Here, we ...compared responses by virus-specific naive T cells (TN) and central memory T cells (TCM) to viral antigen challenge in lymph nodes (LNs). In steady-state LNs, both T cell subsets localized in the deep T cell area and interacted similarly with antigen-presenting dendritic cells. However, upon entry of lymph-borne virus, only TCM relocalized rapidly and efficiently toward the outermost LN regions in the medullary, interfollicular, and subcapsular areas where viral infection was initially confined. This rapid peripheralization was coordinated by a cascade of cytokines and chemokines, particularly ligands for TCM-expressed CXCR3. Consequently, in vivo recall responses to viral infection by CXCR3-deficient TCM were markedly compromised, indicating that early antigen detection afforded by intranodal chemokine guidance of TCM is essential for efficient antiviral memory.
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► CXCR3+ TCM and CXCR3− TN differentially respond to viral infections in lymph nodes ► CXCL10 and CXCL9 are induced by IFN-I and IFNγ from macrophages and TCM, respectively ► CXCL9 and CXCL10 guide CXCR3+ TCM toward viral antigens in the lymph node periphery ► CXCR3 guidance is essential for efficient antiviral recall responses by TCM
Chemokines ensure that memory T cells in the lymph node gain rapid access to viral antigens by guiding them to sites of viral entry. This facilitated exposure is important for the development of immunological memory.
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