Poly-ADP-Ribose Polymerase (PARP-1) is an overexpressed enzyme in several carcinomas; consequently, the design of PARP-1 inhibitors has acquired special attention. Hence, in the present study, three compounds (8–10) were produced through a Michael addition protocol, using phenylmethanethiol, 5-fluoro-2-mercaptobenzyl alcohol, and 4-mercaptophenylacetic acid, respectively, as nucleophiles and perezone as the substrate, expecting them to be convenient candidates that inhibit PARP-1. It is convenient to note that in the first stage of the whole study, the molecular dynamics (MD) simulations and the quantum chemistry studies of four secondary metabolites, i.e., perezone (1), perezone angelate (2), hydroxyperezone (3), and hydroxyperezone monoangelate (4), were performed, to investigate their interactions in the active site of PARP-1. Complementarily, a docking study of a set of eleven sulfur derivatives of perezone (5–15) was projected to explore novel compounds, with remarkable affinity to PARP-1. The molecules 8–10 provided the most adequate results; therefore, they were evaluated in vitro to determine their activity towards PARP-1, with 9 having the best IC₅₀ (0.317 µM) value. Additionally, theoretical calculations were carried out using the density functional theory (DFT) with the hybrid method B3LYP with a set of base functions 6-311++G(d,p), and the reactivity properties were compared between the natural derivatives of perezone and the three synthesized compounds, and the obtained results exhibited that 9 has the best properties to bind with PARP-1. Finally, it is important to mention that 9 displays significant inhibitory activity against MDA-MB-231 and MCF-7 cells, i.e., 145.01 and 83.17 µM, respectively.

Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC₅₀ = 6.44 μM) than perezone (U373 IC₅₀ = 51.20 μM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC₅₀ = 173.66 μM). PARP-1 inhibitory activity (IC₅₀ = 5.25 μM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood–brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent.

Pharmacokinetic considerations need to be taken into account for drugs targeting the central nervous system (CNS). For this reason, in the present chapter, the general pharmacokinetic considerations are described. The CNS comprises the brain and the spinal cord. Both structures are surrounded by a highly selective barrier that protects them, the blood-brain barrier (BBB). However, the permeability of the BBB can be modified in several pathological conditions. To reach the CNS, the free form of the drug must be able to cross the BBB and achieve adequate concentrations, which can be a challenge. Characteristics to consider include the drug’s lipid solubility, active transport mechanisms, such as P-glycoprotein, and protein binding. These factors will influence the absorption, distribution, metabolism, and elimination (ADME) properties of the drug, as well as its ability to cross the BBB. To enhance brain penetration, in addition to systemic methods for administering drugs that target the CNS, the development of delivery systems that enhance the transport of drugs to the brain has emerged as a promising approach for overcoming the challenges of transport across the BBB. Among these methods, the nose-to-brain route has demonstrated effectiveness, then gained considerable interest recently. Finally, in vitro assays to assess the BBB permeability are briefly described. Understanding these factors is essential for optimizing drug delivery, achieving the desired therapeutic effect, and minimizing potential toxicities.

Background: Metabolic memory refers to the long-term adverse effects of short-term disturbances in glucose metabolism. Recent evidence indicates that hyperglycemia-induced metabolic memory contributes to sustained cellular damage even after glycemic control, driven by increased production of reactive oxygen species (ROS), activation of inflammatory pathways, and accumulation of advanced glycation end products (AGEs). Although well characterized in endothelial and smooth muscle cells, this phenomenon may also occur in other cell types, including glial cells. Objective: This study aimed to evaluate the persistence of high-glucose (HG)-induced alterations after returning to normal glucose (NG) conditions in primary mixed glial cell (MGC) cultures. Methods: Primary MGCs were obtained from neonatal Wistar rat pups and cultured under three conditions for 21 days: NG (5.5 mM glucose), HG (25 mM glucose), and HG-NG (14 days in HG followed by 7 days in NG). Cell proliferation, apoptosis, ROS production, lipid peroxidation, mitochondrial activity, TNF-α, IL-6, and AGE formation were assessed. Results: MGCs cultured under HG and HG-NG conditions exhibited reduced proliferation without increased apoptosis. Both HG and HG-NG conditions promoted ROS overproduction accompanied by reduced mitochondrial activity, whereas only HG increased lipid peroxidation. Notably, TNF-α and AGE levels were elevated in both HG and HG-NG conditions, while IL-6 production decreased exclusively in HG-NG. Conclusions: These findings demonstrate the persistence of deleterious effects induced by HG in MGCs, even after restoration to NG conditions.

PARP-1 and COX-2 have played important roles in several carcinomas, representing potential therapeutic targets; natural products have constituted interesting alternatives in cancer research, and complementary computational methods are relevant tools for the proposal of new molecules. Therefore, in this work, a theoretical study of a set of four derivatives of perezone and isoperezone, i.e., α-pipitzol, β-pipitzol, α-isopipitzol, and β-isopipitzol, employing quantum chemistry, bioinformatics, and docking, was performed. Conformational studies were accomplished to obtain minimum energy structures. Subsequently, they were optimized by the B3LYP hybrid method and the 6-311++G(d,p) basis set. With this same level of theory, the geometrical, electronic, and spectroscopic properties and the reactivity parameters were determined; moreover, a molecular docking evaluation was performed to determine their activity towards COX-2 and PARP-1. Additionally, a cytotoxicity activity assay was performed against various cancer cell lines; thus, α-pipitzol and β-pipitzol showed the greatest affinity for COX-2, and the α-isopipitzol exhibited two relevant interactions. Regarding α-pipitzol, it exhibited both affinity and an important interaction with PARP-1. Regarding β-pipitzol, it displayed the lowest inhibitory concentration in A549 (64.49 µM); nevertheless, α-isopipitzol presented the lowest inhibitory concentrations, 83.59 µM and 87.85 µM for U37 and MCF-7 cell lines, respectively.