Search Results (298)

The multidirectional bioactivity of betulin (BN), its widespread occurrence in plants, relatively low toxicity, and acceptable safety profile make it an attractive scaffold for scientific research and potential therapeutic applications. Due to the presence of reactive functional groups (C-3-OH and C-28-OH), BN is an interesting source of new semisynthetic bioactive compounds obtained via structural modifications of the parent backbone. In our study, we designed new BN–amino acid (BNAA) molecular hybrids, aiming to exploit synergistically the properties of both components. We prepared and evaluated a total of 18 new compounds for antitumor activity against the two human cancer cell lines (HCT 116 and MCF-7) and one non-cancerous cell line (NHDF) using a standard Cell Counting Kit-8 (CCK-8) assay. The potential signaling pathways of the obtained BN derivatives were identified based on the measurement of p21 and Bax mRNA expression levels using the RT-qPCR method. We successfully synthesized a series of new BN hybrids by conjugation of the C-3 and C-28 hydroxyl groups via a succinyl (-CO-CH₂-CH₂-CO-, Suc) linker with selected amino acid methyl esters. The structures of all obtained BNAA molecular hybrids were confirmed by spectroscopic analysis (¹H and ¹³C NMR) and high-resolution mass spectrometry (HR-MS). Analysis of the biological activity of the obtained BN derivatives indicated that both the attached amino acids and the substituents at C3 carbon alter BN activity. The obtained BN–amino acid hybrids represent a useful platform for further optimization, especially derivatives (3a, 3e, 3f, and 7d), which showed the most relevant biological profiles in this study. Full article

Weeds are a major cause of crop production losses worldwide, and environmentally friendly chemical control based on natural or semisynthetic compounds has attracted increasing attention. In this study, flavokawains, a class of natural chalcones, and their analogues were converted into dihydrochalcones (1–27) via Pd-catalyzed hydrogenation. The herbicidal activities of these compounds were evaluated against Chinese amaranth (Amaranthus tricolor) and barnyard grass (Echinochloa crus-galli). Several compounds significantly inhibited seed germination and seedling growth in both species. Herbicidal activity was strongly influenced by the type and position of aromatic substituents, with electron-withdrawing groups and meta substitution providing higher activity. The meta-chloro derivative (15) exhibited the highest activity, markedly inhibiting seed germination as well as shoot and root growth. Further investigation of its mode of action revealed that this compound interfered with seed imbibition, inhibited α-amylase activity, and affected membrane integrity and malondialdehyde (MDA) levels in A. tricolor in a concentration-dependent manner. These findings provide valuable insights for the development of natural product-derived herbicides. Full article

The antioxidant activity of natural and semi-synthetic depsides and benzofurans—including R-(+)-usnic acid (1), dibenzoyl usnic acid (2), atranorin (3), 2,4-bis(benzoyloxy)atranorin (4), 4-O-methyl atranorin (5), decarboxythamnolic acid (6), thamnolic acid (7), and perlatolic acid (8)—was evaluated in this study. Natural compounds were isolated from selected lichen species, whilst semi-synthetic derivatives were prepared to investigate the influence of esterification and methylation on electronic properties and radical-scavenging capacity. Structural elucidation was performed using NMR spectroscopy and mass spectrometry (MS). Electronic and thermodynamic descriptors, including the bond dissociation energy (BDE) of the most reactive O–H group, HOMO and LUMO_r energies, the HOMO–HOMO-1 energy gap (ΔH(H-1)), polarisability, and logP, were calculated and correlated with experimentally determined antioxidant capacity using the TEAC assay. Multivariate partial least squares (PLS-1) analysis identified ΔH(H-1) and LUMO_r as the primary determinants of antioxidant activity, with BDE and ΔHf providing complementary contributions. Perlatolic acid (8) exhibited the highest radical-scavenging capacity (TEAC = 2.7), whereas R-(+)-usnic acid (1) and dibenzoyl usnic acid (2) were the least active compounds (TEAC ≈ 0.1). Antioxidant activity was found not to correlate with the number of hydroxyl groups, but rather to be governed by electronic redistribution, conjugation effects, and substituent modulation. Exclusion of the outlier decarboxythamnolic acid (6) improved model performance, explaining 79.8% of the variance in TEAC values (R²Y), with strong predictive ability (Q² = 0.724) using a single latent variable. Overall, these findings provide a robust basis for the prediction and rational design of new antioxidant compounds, highlighting the relevance of lichen-derived metabolites as structurally stable scaffolds with potential applications in pharmaceutical and nutraceutical development. Full article

Obesity, a heterogeneous metabolic disease, is linked with severe comorbidities, prominently increasing morbidity and mortality. A weight loss between 5% and 10% is already sufficient to induce clinically relevant improvements in human health. Activation of energy expenditure through an impact on the brown and beige adipose tissues has recently become an interesting new target in obesity treatment. Obeticholic acid (OCA) is a semisynthetic derivative of the primary human bile acid, chenodeoxycholic acid. The compound is an agonist of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor (TGR5), activating the cellular pathways such as fibroblast growth factor-19, tissue-specific uncoupling protein 1, or type 2 iodothyronine deiodinase associated with energy expenditure and brown adipose tissue activity. So far, OCA has been approved to treat primary biliary cholangitis. Interestingly, the drug demonstrated therapeutic effects in animal models of obesity. Preliminary results from the human studies show that OCA administration holds potential as a treatment option in obesity, although some adverse effects may occur. Long-term administration of OCA might constitute an attractive therapeutic add-on approach, complementary to the currently approved treatments. The design of OCA derivatives targeting similar mechanisms, yet with a better pharmacological profile, seems to be an exciting pathway in the search of novel anti-obesity drugs. Further clinical trials involving larger cohorts of patients, with and without comorbidities, are warranted to confirm the benefits and safety of OCA administration. Full article

Ophiobolin A is a fungal sesterterpenoid initially characterised as a phytotoxin but progressively investigated for its biomedical significance due to its potent and mechanistically characteristic cellular activities. In this review, Ophiobolin A is discussed within the wider landscape of natural products as a source of bioactive molecular scaffolds, and current knowledge on its structural features, biosynthesis, chemical synthesis, semi-synthetic modification, and in vitro biological applications is summarised. Evidence drawn from chemical, biochemical, and cell biology studies is integrated to describe the distinctive 5-8-5 tricyclic scaffold, the electrophilic dicarbonyl motif, and their roles in covalent modification of cellular components. Collectively, the reviewed evidence underscores that Ophiobolin A and its derivatives trigger both apoptotic and non-apoptotic cell death pathways. These include paraptosis-like death, which is a regulated form of cell death not associated with apoptosis that is defined by major cytoplasmic vacoulisation. This commonly occurs in apoptosis-resistant cancer models via disruption of membrane lipid homeostasis, calmodulin-dependent signalling, mitochondrial function, and proteostasis. Structure–activity relationship studies show that modulation of electrophilicity, oxidation state, and peripheral functionality enables tuning of potency, selectivity, and traceability while retaining key phenotypes. In addition to anticancer effects, antimicrobial and anti-inflammatory activities are also briefly summarised. Taken together, the literature supports Ophiobolin A as a useful molecular probe for considering cell death mechanisms and as a chemically complex yet suitable starting point for derivative development, while reinforcing the need for improved selectivity, delivery strategies, and in vivo validation to further translational potential. Full article

Studies of natural products and their semisynthetic derivatives are a valuable source of therapeutic agents. The aim of this work was to obtain new 30-phosphoramidate derivatives of betulin and determine their biological potential. The synthetic approach utilized the Staudinger reaction (the introduction of a phosphoramidate group), the Steglich reaction (the introduction of an alkynyl group), and the Jones reaction (the introduction of a carboxyl group). The structures of the target compounds were determined using spectroscopic methods (¹H NMR, ¹³C NMR, ³¹P NMR, and HRMS). The new derivatives were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, and HCT116 cancer cells and against normal MCF-10A cells using the MTT and SRB methods. Apoptosis studies were performed for the most active compounds (6B and 7A), potential molecular targets (AutoDock software) were identified, and lipophilicity parameters (RP-TLC method, SwissADME website) were determined. The greatest effect on apoptosis and caspase 3/7 activation was observed for the diester derivative 7A. Compound 7A showed a high lipophilicity parameter in the study group. Full article

Natural products are a valuable source of structurally diverse bioactive compounds, many of which have contributed significantly to the discovery of new anticancer drugs. Carnosic acid 1, an abietane-type diterpenoid primarily found in rosemary and sage, has emerged as a promising scaffold due to its ability to modulate key cellular pathways involved in cancer development and progression, including the cell cycle, apoptosis, autophagy, inflammation, and oxidative stress. Despite its multifaceted approach to combat cancer and promising results obtained in vitro and in vivo, its moderate potency limits its clinical application. To address this limitation, several chemical modifications have been performed to generate semisynthetic derivatives with improved efficacy. Several semisynthetic derivatives have demonstrated significantly enhanced anticancer activity across diverse cancer models, highlighting the importance of structural optimization of the carnosic acid 1 backbone. This review provides a comprehensive overview of carnosic acid 1 and its semisynthetic derivatives, focusing on their anticancer activities, underlying molecular mechanisms, and structure–activity relationships, with the aim of guiding the future design and development of carnosic acid 1-derived anticancer drugs. Full article

Multidrug resistance (MDR) is a central cause of chemotherapy failure and tumor recurrence and metastasis, and its mechanism involves enhanced drug efflux, target mutation, upregulation of DNA repair and remodeling of the tumor microenvironment. ABC transporter protein (P-gp, MRP, and BCRP)-mediated efflux of drugs is the most intensively researched aspect of the study, but the first three generations of small-molecule reversal agents were stopped in the clinic because of toxicity or pharmacokinetic defects. Natural products are considered as the fourth generation of MDR reversal agents due to their structural diversity, multi-targeting and low toxicity. In this paper, we systematically summarize the inhibitory activities of monoterpenes, sesquiterpenes, diterpenes and triterpenes against ABC transporter proteins in in vitro and in vivo models and focus on the new mechanism of reversing drug resistance by blocking efflux pumps, modulating signaling pathways such as PI3K-AKT, Nrf2, NF-κB and remodeling the tumor microenvironment. For example, Terpenoids possess irreplaceable core advantages over traditional multidrug resistance (MDR) reversers: Compared with the first three generations of synthetic reversers, natural/semisynthetic terpenoids integrate low toxicity (mostly derived from edible medicinal plants, half-maximal inhibitory concentration IC₅₀ > 50 μM), high target specificity (e.g., oleanolic acid specifically inhibits the ATP-binding cassette (ABC) transporter subtype ABCC1 without cross-reactivity with ABCB1), and multi-mechanistic synergistic effects (e.g., β-caryophyllene simultaneously mediates the dual effects of “ABCB1 efflux inhibition + apoptotic pathway activation”). These unique characteristics enable terpenoids to effectively circumvent key limitations of traditional synthetic reversers, such as high toxicity and severe drug–drug interactions. Among them, lupane-type derivative BBA and euphane-type sooneuphanone D (triterpenoids), as well as dihydro-β-agarofuran-type compounds and sesquiterpene lactone Conferone (sesquiterpenoids), have emerged as the core lead compounds with the greatest translational potential in current MDR reverser research, attributed to their potent in vitro and in vivo MDR reversal activity, low toxicity, and excellent druggable modifiability. At the same time, we point out bottlenecks, such as low bioavailability, insufficient in vivo evidence, and unclear structure–activity relationship and put forward a proposal to address these bottlenecks. At the same time, the bottlenecks of low bioavailability, insufficient vivo evidence and unclear structure–activity relationship have been pointed out, and future research directions such as nano-delivery, structural optimization and combination strategies have been proposed to provide theoretical foundations and potential practical pathways for the clinical translation research of terpenoid compounds, whose clinical application still requires further in vivo validation and translational research support. Full article

Hexahydrocannabinol (HHC), a hydrogenated derivative of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), is a semi-synthetic cannabinoid marketed as an alternative to Δ⁹-THC. Its hydroxylated metabolite, 8-hydroxyhexahydrocannabinol (8-OH-HHC), exists as four stereoisomers: (6aR,8R,9R,10aR), (6aR,8S,9S,10aR), (6aR,8S,9R,10aR), and (6aR,8R,9S,10aR). However, the lack of reference standards has hindered pharmacokinetic and forensic studies. This work reports the first stereoselective synthesis and structural confirmation of all four 8-OH-HHC stereoisomers. Two strategies were employed: hydroboration–oxidation and epoxidation–reduction. Hydroboration of Δ⁸-THC with BH₃·THF followed by oxidation predominantly produced anti-isomers (6aR,8R,9R,10aR) and (6aR,8S,9S,10aR) in moderate yields, along with small amounts of syn-isomer (6aR,8S,9R,10aR), suggesting an atypical mechanistic pathway. In contrast, syn-isomers (6aR,8S,9R,10aR) and (6aR,8R,9S,10aR) were accessed via epoxidation of Δ⁸-THC acetate using mCPBA and subsequent reduction with NaBH₃CN/BF₃·OEt₂, affording the desired products with moderate selectivity. Absolute configurations were confirmed by nuclear Overhauser effect spectroscopy (NOESY). These methods will facilitate future pharmacokinetic and forensic research and support the development of improved detection strategies. Full article

The diterpene sessein, isolated from Salvia sessei, is a metabolite of interest due to its conjugated p-quinone system, δ-lactone ring, and phenolic hydroxyl in C-12. These functionalities make it an ideal starting point for reactivity studies and semi-synthetic derivatization. In this work, we report the obtainment of two derivatives by selective esterification of phenolic hydroxyl in C-12, through acetylation and benzoylation reactions under mild conditions and with high yields. The structures were characterized by UPLC-MS, FTIR, and NMR spectroscopy ¹H, ¹³C, and 2D, which allowed to precisely confirm the modifications made in the derivatives. These results confirm that hydroxyl in C-12 constitutes a privileged site of reactivity within the royleanone family, consolidating sessein as a versatile nucleus for the generation of derivatives. Finally, the preliminary evaluation of the antimicrobial activity showed that sessein shows a broad spectrum of action against Gram-positive, Gram-negative, and Candida albicans strains. The acetylated derivative showed an increase in activity against gram-negative bacteria, while the benzoyl derivative had a loss of effect at the concentrations evaluated. These findings demonstrate that structural modifications influence the properties of the derivatives with respect to the compound sessein. Full article

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Cannabis and its derivatives are increasingly popular. The public perception of “cannabis” is commonly related to abuse potential with no sharp distinction to “marijuana”, “cannabinoids”, “hemp”, and cannabis derivatives. Delta 9-tetrahydrocannabinol (THC)—rich cannabis (“marijuana”), needs to be distinguished from hemp and cannabidiol (CBD)—rich; the former is psychotomimetic, while the latter is not, and it is increasingly used as a “health product”; the phytochemical composition makes the difference. However, this is still inadequately addressed. Without a detailed characterization of the components and effects conclusions cannot be generalized and are only applicable to the product used. Cannabis varieties have a highly variable phytochemical composition; the effects cannot always be attributed solely to the “main cannabinoids.” Growth conditions and processing methods also have a significant influence on the properties of the final product, even when the same cannabis variety is used. Therefore, the few comparative studies between extracts and the corresponding pure cannabinoids often produce conflicting results, as numerous preclinical and clinical examples demonstrate. They also show how little attention is paid to the phytochemical profile, even in scientific publications. Both in scientific research and consumer products, the phytochemical profile beyond the main cannabinoids should be disclosed in detail, especially since new cannabis products containing semi-synthetic CBD derivatives have recently entered the market. Full article

In view of the concerning rise in the incidence of cancer, natural products are a valuable source for the development of novel therapies. Among phytochemicals, the pentacyclic triterpenoids betulinic (BA), ursolic (UA), and oleanolic (OA) acids, as well as their 3-oxo-derivatives, have attracted considerable attention because of their significant anticancer potential. However, their clinical use is restricted by poor bioavailability, highlighting the need for obtaining semisynthetic derivatives with optimized pharmacokinetic and pharmacodynamic profiles. This study examined the biological effects of twelve new semisynthetic triterpenic and 3-oxo-triterpenic acid derivatives with methylphosphonate moieties of type C(17)-C(O)OCH₂P(O)(OMe)₂ and C(17)-C(O)OCH₂P(O)(ONa)₂ against the B164A5 murine melanoma cell line. Results have shown that cell viability declined in a dose-dependent fashion, as determined by the MTT assay. In comparison to their parent compounds, derivatives of BoA, OA, OoA, and UoA demonstrated enhanced antiproliferative potential. The Scratch method showed that the anti-migratory effect of all tested compounds was proportional to the dose, while the LDH test indicated no enhanced cytotoxicity relative to the parent compounds. According to the Hoechst 33342 staining, OA derivatives appeared to induce enhanced nuclear condensation signs than the parent compound. Additionally, the HET-CAM assay indicated no evidence of coagulation, hemorrhage, or vascular disintegration. Collectively, these findings suggest that these novel semisynthetic derivatives, particularly OA and OoA derivatives, may be included in future studies on their antimelanoma activity in light of the findings of this preliminary evaluation. Full article

Background/Objectives: Neglected tropical diseases (NTDs) caused by protozoan parasites such as Trypanosoma cruzi, Trypanosoma brucei, Leishmania spp., and Plasmodium falciparum remain a global health challenge due to limited therapies and increasing drug resistance. Natural products provide diverse scaffolds for antiparasitic drug discovery. This study aimed to investigate the multitarget inhibitory potential of alkaloids isolated from Croton linearis Jacq. against validated protozoan enzymes. Methods: Eighteen alkaloids were virtually screened against 17 molecular targets relevant to protozoan parasites. Protein–ligand docking simulations were performed using crystallographic structures of enzymes, including Cyp51, DHFR-TS, PTR1, AD-kinase, and DHODH. Predicted interactions were analyzed to identify hydrogen bonds, hydrophobic contacts, and π–π stacking with key residues in the active sites. Results: Several alkaloids exhibited high binding affinities, in some cases surpassing co-crystallized ligands. Reticuline, norsalutaridine, laudanosine, and jacularine consistently showed the strongest activity, with docking scores ranging from −8.0 to −9.3 kcal/mol across multiple targets. Notably, norsalutaridine displayed the highest predicted affinity for L. infantum Cyp51, while reticuline showed strong binding to T. cruzi DHFR-TS and L. major PTR1. Conclusions: The study highlights the potential of C. linearis alkaloids as multitarget inhibitors against protozoan parasites. These compounds represent promising lead candidates for the development of antiparasitic agents, while emphasizing the value of natural product scaffolds for neglected disease drug discovery. The findings also support the future exploration of semisynthetic derivatives to optimize activity and selectivity. Full article

Andrographis paniculata, a medicinal plant widely found in Asia, contains andrographolide as its main active compound, known for its wide-ranging pharmacological effects, including anti-inflammatory, anti-cancer, anti-obesity, and anti-diabetic properties. Recent investigations have highlighted the anti-infective potential of andrographolide and its derivatives, with demonstrated antiviral, antibacterial, and antimalarial activities. This review summarizes progress in andrographolide’s anti-infective applications, focusing on its structure–activity relationship (SAR) and mechanisms of action. Researchers have used semi-synthetic methods, such as esterification, oxidation, Michael addition, salification, and hybrid design, to enhance andrographolide’s physicochemical properties and biological activity. These derivatives show potent antiviral activity against RNA and DNA viruses, antibacterial activity against Gram-positive and Gram-negative bacteria, antifungal effects, and antiparasitic activity against Plasmodium spp. and Leishmania spp. Nevertheless, poor solubility and limited bioavailability still hinder their clinical translation. Strategies such as nano delivery systems and β-cyclodextrin complexes are discussed to improve bioavailability. Although andrographolide itself has not received regulatory approval as a stand-alone drug, several andrographolide-containing preparations have been clinically used in certain countries. Overall, this review brings together evidence on antiviral, antibacterial, antifungal, and antiparasitic activities, linking them with structure–activity trends and pharmacokinetic insights, thereby providing a consolidated foundation for future development and clinical translation. Full article