David Díez

Aberrant glycosylation is a recognized hallmark of cancer, establishing Golgi α-mannosidase II (GMII) as strategic therapeutic target. While the natural alkaloid swainsonine demonstrated potent anticancer activity, its clinical use is hampered by toxicity from off-target inhibition of the lysosomal α-mannosidase (LMan). This review surveys computational methodologies advancing inhibitor development from empirical observations to precision structural optimization. We examine the evolution from Molecular Docking to advanced Quantum Mechanics (QM) and Molecular Dynamics (MD), highlighting their combined role in modeling metalloenzyme flexibility and energetics. Analysis reveals that selectivity relies on exploiting peripheral structural divergences, organelle-specific pH gradients, and distinct substrate conformational itineraries. In this context, electronic structure calculations and pKa predictions prove critical for designing “electrostatic switches”, inhibitors binding neutrally at Golgi pH while incurring lysosomal repulsion. Structurally, targeting the non-conserved “anchor site”, mimicking specific transition-state ring distortions and utilizing conformationally restricted scaffolds represent the most effective strategies. Integrating dynamic sampling with rigorous energetic profiling is therefore crucial for developing the next generation of safe, selective GMII inhibitors.

2-Arylethylamines are present in several natural bioactive compounds, as well as in many nitrogen-containing drugs. Their ability to cross the blood–brain barrier makes this family of compounds of special interest in medicinal chemistry. Asymmetric methodologies towards the synthesis of 2-arylethylamine motifs are of significant interest due to the challenges they present. In this graphical review, we highlight recent advances in the metal-free and metal-catalyzed asymmetric synthesis of 2-arylethylamines, covering the literature published in 2025 (up until late October). We showcase the different methodologies towards the aforementioned motif, including chiral induction, organocatalysis, organophotocatalysis and enzymatic catalysis.

The present report details the 1,3-dipolar cycloaddition between a chiral cyclic nitrone (1) and different carbonyl-type dipolarophiles, thus confirming the regiodivergence observed due to the cyclic nature of the dipolarophile source. An ortho regioselectivity is observed in the resulting isoxazolidines when the dipolarophile is acyclic, whereas the meta adducts are obtained from the cyclic dipolarophiles. This evidence is supported by both electronic calculations and X-ray diffraction.

The phytochemical investigation and evaluation of the antioxidant activity of the leaves, bark, and roots of Cochlospermum angolense Welw ex Oliv—a valued plant that is widely used in traditional Angolan medicine—hold significant importance. Compounds were extracted from the aforementioned plant using acetone and ethanol and identified by HPLC-ESI-MSn. Both extracts demonstrated notable abilities to scavenge 2,2-diphenyl-1-picrylhydrazyl, nitric oxide, and superoxide radicals, as well as to inhibit lipid peroxidation. A HPLC analysis revealed a diverse array of bioactive compounds, including flavonoids, phenols, alkaloids, quinones, and terpenes, which help neutralize free radicals and protect cells against oxidative stress, thereby contributing to the prevention of various diseases. Moreover, the acetone and ethanol extracts proved to be excellent sources of antioxidants. For the first time, the present study identified new compounds never reported in this species, such as (+)-abscisic acid, angustine B, pinobanksin, dihydrogenistein, (−)-8-prenylnaringenin, isoquercetin, samandarine, dihydromyricetin, and eupatoriocromene, in the leaves, bark, and roots, marking a significant advance in the chemical characterization of C. angolense. These findings enhance our understanding of the bioactive phytochemicals and antioxidant properties of C. angolense and open new avenues for future therapeutic and pharmacological research, further supporting its traditional use in Angolan medicine.

The 2-arylethylamine motif is very well-known in medicinal chemistry because of its interesting properties when it comes to interacting with the Central Neural System thanks to its ability to pass the blood–brain barrier. This nitrogen-containing family of compounds is of great interest in synthetic organic chemistry and, when it comes to its asymmetric synthesis, great challenges can be faced in order to obtain the chiral purity required in the drug industry. Thus, we provide a concise transition metal review presenting the recent advances in the synthesis of chiral 2-arylethylamines using transition metals as the main catalysts in the introduction of chirality. Both conventional and photocatalysis methods will be covered, considering the main transition metal used in the studies.

Podophyllotoxin is a natural compound belonging to the lignan family and is well-known for its great antitumor activity. However, it shows several limitations, such as severe side effects and some pharmacokinetics problems, including low water solubility, which hinders its application as an anticancer agent. Over the past few years, antitumor research has been focused on developing nanotechnology-based medicines or nanomedicines which allow researchers to improve the pharmacokinetic properties of anticancer compounds. Following this trend, podophyllotoxin nanoconjugates have been obtained to overcome its biopharmaceutical drawbacks and to enhance its antitumor properties. The objective of this review is to highlight the advances made over the past few years (2017–2023) regarding the inclusion of podophyllotoxin in different nanosystems. Among the huge variety of nanoconjugates of diverse nature, drug delivery systems bearing podophyllotoxin as cytotoxic payload are organic nanoparticles mainly based on polymer carriers, micelles, and liposomes. Along with the description of their pharmacological properties as antitumorals and the advantages compared to the free drug in terms of biocompatibility, solubility, and selectivity, we also provide insight into the synthetic procedures developed to obtain those podophyllotoxin-nanocarriers. Typical procedures in this regard are self-assembly techniques, nanoprecipitations, or ionic gelation methods among others. This comprehensive perspective aims to enlighten the medicinal chemistry community about the tendencies followed in the design of new podophyllotoxin-based drug delivery systems, their features and applications.

2-Arylethylamines are presented in several natural bioactive compounds, as well as in nitrogen-containing drugs. Their ability to surpass the blood–brain barrier makes this family of compounds of especial interest in medicinal chemistry. Asymmetric methodologies towards the synthesis of 2-arylethylamine motives are of great interest due to the challenges they may present. Thus, a concise metal-free review presenting recent advances in the asymmetric synthesis of 2-arylethylamines is presented, covering last-millennium studies, considering different methodologies towards the aforementioned motif, including chiral induction, organocatalysis, organophotocatalysis and enzymatic catalysis.

Chemomodulation of natural cyclolignans as podophyllotoxin has been a successful approach to obtain semisynthetic bioactive derivates. One example of this approach is the FDA‐approved drug etoposide for solid and hematological tumors. It differs from the antimitotic activity of the natural product in its mechanism of action, this drug being a topoisomerase II inhibitor instead of a tubulin antimitotic. Within the molecular requirements for the activity of these compounds, the trans‐γ‐lactone moiety presented in the parent compound has always been a feature to be explored to chemomodulate its bioactivity. In this study, we have obtained different compounds that comply with the molecular characteristics for antitubulin and antitopoisomerase II activity combined in a single molecule. Furthermore, we explored the influence of the trans‐lactone moiety on the final activity, finding that the cis‐lactone was also interesting in terms of bioactivity. The best values of cytotoxicity and cell cycle inhibition were obtained for a compound lacking the lactone ring, thus mimicking the podophyllic aldehyde functionalization, a selective antimitotic podophyllotoxin derivate. The analogs with cis‐lactone also presented interesting cytotoxic activity. The present study illustrates the potential of the chemomodulation of natural products such as natural cyclolignan podophyllotoxin derivates for the discovery of new antitumor agents.

The concept of bioisostere replacement is of paramount importance in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast area of chemical space of biological importance) in medicinal chemistry is the 2-phenethyl moiety, a key component of diverse drug-like entities. Although the core 2-phenethylamine structure has been recognized by the drug discovery community, little attention has been given to the various ring-based rescaffolding procedures that can be conducted with this unit. In this regard, a review on the use of 2-heteroarylethylamines displaying pharmacological activity is reported. A detailed description of flexible, amine-opened motifs is provided, that describes therapeutic targets and other potent bioactive examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community.