Caffeic acid (CA) is a polyphenol belonging to the phenylpropanoid family, commonly found in plants and vegetables. It was first identified by Hlasiwetz in 1867 as a breakdown product of caffetannic acid. CA is biosynthesized from the amino acids tyrosine or phenylalanine through specific enzyme-catalyzed reactions. Extensive research since its discovery has revealed various health benefits associated with CA, including its antioxidant, anti-inflammatory, and anticancer properties. These effects are attributed to its ability to modulate several pathways, such as inhibiting NFkB, STAT3, and ERK1/2, thereby reducing inflammatory responses, and activating the Nrf2/ARE pathway to enhance antioxidant cell defenses. The consumption of CA has been linked to a reduced risk of certain cancers, mitigation of chemotherapy and radiotherapy-induced toxicity, and reversal of resistance to first-line chemotherapeutic agents. This suggests that CA could serve as a useful adjunct in cancer treatment. Studies have shown CA to be generally safe, with few adverse effects (such as back pain and headaches) reported. This review collates the latest information from Google Scholar, PubMed, the Phenol-Explorer database, and ClinicalTrials.gov, incorporating a total of 154 articles, to underscore the potential of CA in cancer prevention and overcoming chemoresistance.

Neurodegenerative disorders are characterized by a progressive process of degeneration and neuronal death, where oxidative stress and neuroinflammation are key factors that contribute to the progression of these diseases. Therefore, two major pathways involved in these pathologies have been proposed as relevant therapeutic targets: The nuclear transcription factor erythroid 2 (Nrf2), which responds to oxidative stress with cytoprotecting activity; and the nuclear factor NF-κB pathway, which is highly related to the neuroinflammatory process by promoting cytokine expression. Caffeic acid phenethyl ester (CAPE) is a phenylpropanoid naturally found in propolis that shows important biological activities, including neuroprotective activity by modulating the Nrf2 and NF-κB pathways, promoting antioxidant enzyme expression and inhibition of proinflammatory cytokine expression. Its simple chemical structure has inspired the synthesis of many derivatives, with aliphatic and/or aromatic moieties, some of which have improved the biological properties. Moreover, new drug delivery systems increase the bioavailability of these compounds in vivo, allowing its transcytosis through the blood-brain barrier, thus protecting brain cells from the increased inflammatory status associated to neurodegenerative and psychiatric disorders. This review summarizes the biosynthesis and chemical synthesis of CAPE derivatives, their miscellaneous activities, and relevant studies (from 2010 to 2023), addressing their neuroprotective activity in vitro and in vivo.

Chemotherapeutic drugs are indispensable in cancer treatment, but their effectiveness is often lessened because of non-selective toxicity to healthy tissues, which triggers inflammatory pathways that are harmful to vital organs. In addition, tumors’ resistance to drugs causes failures in treatment. Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms. In vitro and animal studies have indicated that CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively. This review is a summary of current information about CGA, including its natural sources, biosynthesis, metabolism, toxicology, role in combatting chemoresistance, and protective effects against chemotherapy-induced toxicity. It also emphasizes the potential of CGA as a pharmacological adjuvant in cancer treatment with drugs such as 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin, regorafenib, and radiotherapy. By analyzing more than 140 papers from PubMed, Google Scholar, and SciFinder, we hope to find the therapeutic potential of CGA in improving cancer therapy.

Candida species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans Candida species such as C. glabrata, C. parapsilosis, C. aureus, and C. krusei are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against Candida yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (C1) from barks of Drimys winteri and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (C2, C3, C4, and C5) was elucidated by 1D and 2D NMR spectroscopy resulting in C4 being a novel compound. Antifungal activity assays against C. albicans, C. glabrata, and C. krusei revealed that C4 exhibited an increased activity (IC₅₀ of 75 μg/mL) compared to C1 (IC₅₀ of 125 μg/mL) in all yeast strains. The antifungal activity of C1 and C4 was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that C1 and C4 bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (LAN) to the catalytic pocket. Binding free energy estimates suggested that C4 forms a more stable complex with the enzyme than C1, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of Candida species as inhibitors of 14-alpha demethylase.

Neurodegenerative diseases are characterized by a progressive process of degeneration and neuronal death in the nervous system, with neuroinflammation being one of the main factors contributing to the progression of these diseases. Aristotelia chilensis (Maqui) is a native tree of Chile used in the Mapuche folk medicine for wounds and digestive treatment. It produces edible black berries with the highest antioxidant capacity among berries, and the Mapuche people used it for producing an alcoholic beverage. The leaves of Maqui contain indole alkaloids with different pharmacological properties that suggest neuroprotective effects. Here, the isolation and chemical characterization of a new alkaloid, named 9-hydroxyaristoquinolone, and the evaluation of its anti-inflammatory activity in the microglial cell line HMC-3, treated with LPS, are reported. 9-Hydroxyaristoquinolone protects microglia from LPS-induced morphological changes at concentrations as low as 1 µM, with a reduction in IKBα-P levels and inhibition of the NF-κB pathway, which was assessed by THP-1 NF-κB dual cell reporter and Western blot in HMC-3 cells. In silico studies suggest that 9-hydroxyaristoquinolone does not induce hepatotoxicity or genotoxicity and exhibits BBB permeability.