Daniel Chavarria

Abstract The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell's adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.

Abstract The crucial role of human monoamine oxidases (hMAOs), particularly the B isoform, in the pathogenesis of neurodegenerative diseases has been extensively studied. Alongside numerous other factors, the clinical use of hMAO-B inhibitors to alleviate symptoms of Parkinson's disease is well-established. In order to develop novel hMAO-B inhibitors as potential candidates for the treatment of these conditions, we have designed and synthesized two libraries of compounds based on the 2-aroylbenzofuran-3-ol and the 2-aroylbenzofuran scaffolds. The hMAO inhibitory activity and selectivity of these compounds was thoroughly investigated. In general, the 2aroylbenzofuran-3-ols were unable to inhibit hMAO isoforms. In contrast, 2-aroylbenzofuran derivatives acted as potent and selective hMAO-B inhibitors, showing IC50 values within the nanomolar range and as low as 8.2 nM. The best compounds exhibited broad safety ranges in human gingival fibroblasts (hGFs) and SH-SY5Y neuroblastoma cells. A preliminary evaluation of the compounds' neuroprotective effects was conducted through the co-exposure of the cells to the neurotoxic agent 6-hydroxydopamine (6-OHDA) and the synthesized compounds, whose activity was comparable to that of (R)-(-)-deprenyl, the reference hMAO-B inhibitors. The characterization of the compounds was enriched with the in silico prediction of the drug-likeness of the most active compounds among the 2-aroyl benzofurans using the free web tool SwissADME. All compounds were predicted to have high gastrointestinal absorption and to permeate the blood-brain barrier and molecular modelling studies provided insights into the molecular mechanisms responsible for the high hMAO-B inhibitory potency and selectivity of 2-aroylbenzofurans.

Abstract Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive neuronal dysfunction and loss and represent a significant global health challenge. Oxidative stress, neuroinflammation, and neurotransmitter dysregulation, particularly affecting acetylcholine (ACh) and monoamines, are key hallmarks of these conditions. The current therapeutic strategies targeting cholinergic and monoaminergic systems have some limitations, highlighting the need for novel approaches. Metallodrugs, especially ruthenium and platinum complexes, are gaining attention for their therapeutic use. Among metal complexes, gold(I) and silver(I) N-heterocyclic carbene (NHC) complexes exhibit several biological activities, but their application in NDDs, particularly as monoamine oxidase (MAO) inhibitors, remains largely unexplored. To advance the understanding of this field, we designed, synthesized, and evaluated the biological activity of a new series of Au(I) and Ag(I) complexes stabilized by NHC ligands and bearing a carboxylate salt of tert-butyloxycarbonyl (Boc)-N-protected proline as an anionic ligand. Through in silico and in vitro studies, we assessed their potential as acetylcholinesterase (AChE) and MAO inhibitors, as well as their antioxidant and anti-inflammatory properties, aiming to contribute to the development of potential novel therapeutic agents for NDD management.

Abstract New psychoactive substances (NPS) are designed to evade legal regulation while mimicking the effects of classic illicit drugs such as 3,4-methylenedioxymethamphetamine (MDMA). This category includes phenethylamine derivatives, such as the psychedelic 2C and NBOMe drugs. Given the lack of data regarding the toxicological profile of these substances, the goal of this study was to evaluate the neurotoxicity of 2C-I and 25I-NBOMe and explore their neurotoxic pathways. Lower EC50 values, in both NR uptake and MTT reduction assays in differentiated SH-SY5Y cells and primary rat cortical cultures, revealed that 25I-NBOMe is significantly more cytotoxic than 2C-I, likely due to its higher lipophilicity. Both drugs triggered severe mitochondrial dysfunction, characterized by decreased intracellular ATP levels and mitochondrial membrane depolarization, although no significant changes in intracellular ROS/RNS levels were observed. Additionally, 25I-NBOMe increased the intracellular Ca2* levels. Apoptosis was an observed mechanism of cell death for both drugs, as demonstrated by a significant increase in the number of cells undergoing early apoptosis (AnV+/PI-) and late apoptosis/necrosis (AnV+/PI+). However, only 2C-I induced autophagy and strongly triggered caspase-3 activation. This suggests that 2C-I induces caspase-3-dependent apoptosis, whereas 25I-NBOMe may also induce apoptosis through a caspase-3-independent pathway, possibly involving increased intracellular Ca2* levels and direct mitochondrial damage. These findings underscore the complex interplay between mitochondrial dysfunction, calcium dysregulation, and cell death pathways, highlighting the central role of mitochondria in the cytotoxicity of 2C-I and 25INBOMe.

Abstract Ethnopharmacological relevance: Plants contain various bioactive molecules that may promote human health by preventing the onset and progression of different illnesses, including cancer, diabetes, neurodegenerative conditions, and cardiovascular issues. Salvia species have been employed since ancient times in traditional medicine and for culinary use. Aim of the study: Herein, four extracts from leaves of Salvia officinalis L., cultivated in Calabria (Italy) were obtained and quali-and quantitatively characterized, finding a high presence of bioactive compounds. The extracts were investigated for their biological activities, showing interesting antioxidant, anti-inflammatory and anticancer properties. In addition, all the extracts were tested for their potential regulation of some enzymes involved in neurological and neurodegenerative diseases, as MAO-A and B, AChE and BChE. Finally, the safety of the extracts was also investigated. Materials and methods: The extracts were obtained using conventional maceration and ultrasound-assisted extractions. The chemical characterization was achieved by the means of Ultra-High Performance Liquid Chromatography. The biological evaluation was performed by in vitro, direct enzymatic, fluorescence and cell-based assays. Results: The chromatographic analysis indicated a high presence of bioactive compounds, which confer high ability in ROS scavenging, NO production inhibition and impacting breast cancer cells viability. In addition, all the extracts targeted some enzymes involved in neurological and neurodegenerative diseases, as MAO-A and B, AChE and BChE. Moreover, the extracts were found safe and with a low hepatotoxic toxicity. Conclusions: The present study demonstrated that the extracts from Salvia officinalis L. leaf, traditionally used for many puproses, possess various biological activities, regulating the oxidative stress and inflammation, reducing the growth of breast cancer cells and blocking some key enzymes involved in neurological diseases. The combined low toxicity and biological features reported in this work suggest a high potential of the studied extracts for the management of some pathological conditions and/or for the achievement of nutraceutical products.