: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Description Copper induces cell death Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al. investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.

Copper induces cell death by targeting lipoylated TCA cycle proteins

There is great need for stand-alone luminescence-based chemosensors that exemplify selectivity, sensitivity, and applicability and that overcome the challenges that arise from complex, real-world media. Discussed herein are recent developments toward these goals in the field of supramolecular luminescent chemosensors, including macrocycles, polymers, and nanomaterials. Specific focus is placed on the development of new macrocycle hosts since 2010, coupled with considerations of the underlying principles of supramolecular chemistry as well as analytes of interest and common luminophores. State-of-the-art developments in the fields of polymer and nanomaterial sensors are also examined, and some remaining unsolved challenges in the area of chemosensors are discussed.

/pdf/supramolecular-luminescent-sensors-1rs45r4um4.pdf

Supramolecular Luminescent Sensors

Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia–reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO3·−, peroxyl radical, and less efficiently H2O2. By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular tra...

/pdf/superoxide-dismutase-mimics-chemistry-pharmacology-and-1ttn9834vf.pdf

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as pote...

Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

l-Carnosine is an endogenous dipeptide that has high potential for therapeutic purposes, being an antioxidant with metal chelating, anti-aggregating, anti-inflammatory, and neuroprotective properties. Despite its potential therapeutic values, the biomolecular mechanisms involved in neuroprotection are not fully understood. Here, we demonstrate, at chemical and biochemical levels, that insulin-degrading enzyme plays a pivotal role in carnosine neuroprotection.

https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.2c00201

Neuroprotective Effect of Carnosine Is Mediated by Insulin-Degrading Enzyme

Dithiocarbamates (DTCs) are an interesting class of ligands that have been extensively investigated. These compounds have great potential in the field of inorganic and bioinorganic chemistry. In fact, DTCs have been employed as pesticides, fungicides, antibiotics, and antitumor agents. Their applications seem to be tightly related to their ability to form complexes with several metal ions. In this context, DTC derivatives were synthesized and characterized with NMR spectroscopy, electrospray ionization (ESI) mass spectrometry (MS), and UV/Vis spectroscopy. Their copper(II) and zinc(II) complexes were characterized by using ESI-MS and UV/Vis spectroscopy. The in vitro cytotoxic and apoptotic activity of DTC derivatives was assessed in human cancer cell lines, also in the presence of metal ions, such as copper(II) and zinc(II). Moreover, their superoxide dismutase (SOD)-like activity was determined.

Antiproliferative and Antioxidant Activity of Glycoconjugates of Dithiocarbamates and Their Copper(II) and Zinc(II) Complexes

8-Hydroxyquinolines show a wide range of pharmacological activities, and some are marketed as therapeutic agents. Despite the significant number of biologically active hydroxyquinolines proposed, there is a continued interest in the development of new active derivatives to overcome the drawbacks associated with their use. Herein, we report the synthesis and characterization of a set of positional isomers of hydroxyquinoline–mannose conjugates. Since in many cases the complexation ability of 8-hydroxyquinolines seems to be responsible for their pharmacological activities, we investigated the capacity of these systems to complex copper(II) ions. We also examined diverse biological activities (antiproliferative, antimicrobial and antioxidant) of the new derivatives and their copper(II) complex and compared them to those of their parent compounds and an analogous glucose–quinoline conjugate. All compounds show antioxidant activity that depends on the regioisomer. Moreover, specific isomers show significant antibacterial activity against P. aeruginosa and S. aureus. Furthermore only a regioisomer shows a pharmacologically relevant antiproliferative activity against human tumor cells, in the presence of copper(II) ions.

Positional isomers of mannose–quinoline conjugates and their copper complexes: exploring the biological activity

This review focuses on metal complexes of cyclodextrin (CyD) derivatives designed for application as therapeutics or diagnostics We discuss examples of metalloprotein models (hemoglobin, superoxide dismutase and catalase) based on cyclodextrins The hydrophobic microenvironment of CyDs stabilizes the Fe(II) porphyrin system that can reversibly bind O2 or CO in water Superoxide dismutase/catalase mimetics exploit functionalization with CyDs, which increase their solubility and biological activity Furthermore, CyDs have been used as scaffolds to obtain multicenter metal complexes: paramagnetic systems act as high-performance contrast agents for magnetic resonance imaging applications Finally, we review CyD ligands, whose use appears promising in metal chelation therapy, as CyD moiety confers additional properties to the ligands

Metallocyclodextrins in medicinal chemistry.

Over 30 different amyloid proteins and a number of corresponding protein-misfolding diseases have been identified Among these is Alzheimer's disease, the most common neurodegenerative disorder The treatment of these diseases is still a goal to reach and many molecules have been studied in this context Among these, the cyclodextrins have shown interesting potential as agents against protein aggregation (antiaggregants) On the basis of this interest, we investigated the effect on protein aggregation of some oligomers of β-cyclodextrins In particular, it was found that amino oligomers show good inhibition of β-amyloid aggregation in the micromolar concentration range The presence of both a multicavity system and amino groups seems to be essential for preventing protein aggregation

Valentina Oliveri

Papers

Neuroprotective Effect of Carnosine Is Mediated by Insulin-Degrading Enzyme

Antiproliferative and Antioxidant Activity of Glycoconjugates of Dithiocarbamates and Their Copper(II) and Zinc(II) Complexes

Positional isomers of mannose–quinoline conjugates and their copper complexes: exploring the biological activity

Metallocyclodextrins in medicinal chemistry.

Aminocyclodextrin Oligomers as Protective Agents of Protein Aggregation