Search Results (128)

Chondroitin sulfate is a glycosaminoglycan polysaccharide, playing key roles in a plethora of physiopathological processes typical of higher animals. The position of sulfate groups within CS disaccharide subunits composing the polysaccharide chain is able to encode specific functional information. In order to expand such a “sulfation code”, access to non-natural CS variants and mimics thereof can be pursued. In this context, an interesting topic concerns phosphorylated analogs of CS polysaccharides, as the replacement of sulfate groups with phosphates can lead to unreported activities of phosphorylated CS. In light of this, the phosphorylation reaction of a microbial-sourced, unsulfated chondroitin polysaccharide with phosphoric acid is reported in the present study, testing different microwave irradiation conditions and comparing them with conventional heating procedures. The obtained products were subjected to a detailed characterization, in terms of chemical structure and hydrodynamic properties, by 1D- and 2D-NMR spectroscopy and HP-SEC-TDA analysis, respectively. The characterization study showed how different reaction conditions can not only influence the regioselectivity and degree of phosphorylation but also trigger the formation of phosphate diester functionalities acting as cross-linkers between polysaccharide chains. The results from the screening presented in this work could be interesting for any research devoted to the regioselective phosphorylation of a polysaccharide. 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

Τriterpenic acids represent a prominent class of bioactive compounds, with a wide range of biological properties, including anti-inflammatory, antiviral, and anticancer effects. Among them, 24Z-isomasticadienonic acid (IMNA), a major constituent of Chios Mastic Gum, has attracted little attention compared with other well-studied triterpenes such as oleanolic or betulinic acid, largely because its isolation in sufficient purity and quantity was only recently achieved. In this study, a series of IMNA analogs was synthesized through targeted modifications at the A-ring. These included the introduction of heteroatoms at position 2, the incorporation of heterocyclic rings such as an oxazole and a thiazole, and rearrangements of the ring structure. The new compounds were evaluated for their antiproliferative activity against a diverse panel of cancer cell lines (Capan-1, HCT-116, LN-229, NCI-H460, DND-41, HL-60, K-562, Z-138). Among the synthesized analogs, compounds 3, 7 and 9 demonstrated selective anticancer activity toward the Capan-1 cell line, whereas compounds 6 and 10 exhibited broad-spectrum cytotoxic effects across multiple cancer cell lines. Overall, these findings highlight IMNA as a promising scaffold for anticancer drug design and demonstrate the value of A-ring modifications in improving activity and selectivity. Full article

The hydroxamic acid moiety is part of many bioactive molecules, including several clinical drugs, which can be constructed through, generally, the parent carboxylic acid and a source of hydroxylamine by a variety of methods. Hydroxamic acids compose a remarkable group of N-hydroxy amides with high capacity to chelate certain transition metal ions such as Fe(III), considered siderophores in Nature, and Ni(II), for instance. During a synthetic program towards the derivatization of natural resinic acids, it was decided to prepare some corresponding hydroxamic acid derivatives with potential biological activity for further studies. There are few reports on hydroxamate-derived terpenoids. It was predicted that adding a hydroxamic acid moiety to the carbon skeleton could enhance the antiproliferative activities or other pharmacological properties, as it occurs in other terpenoid compounds. In this communication, we describe the several issues that we faced in this generally straightforward conversion. Generally, the carboxylic group needs to be activated towards coupling with hydroxylamine. We screened several methods and realized that the desired conversion is difficult in this kind of substrate. After extensive testing, we propose a new protocol via a phosphate intermediate for better results than standard procedures. A basic computational study on the mechanism of this transformation was also carried out to support our experimental results. Full article

This work reports progress in the semi-synthetic modification of cassane-type diterpenes isolated from Coulteria platyloba, a plant of ethnopharmacological relevance. The approach involves a sequence of transformations, including oxidative aromatization, ring opening, and Knoevenagel condensation, to generate key intermediates for further diversification. Preliminary studies demonstrated the feasibility of organocatalytic reactions under trienamine activation, including a successful Diels–Alder cycloaddition. The initial steps were achieved with good yields and high purity, underscoring the potential of this strategy to access novel molecular scaffolds through efficient and sustainable methods aligned with the principles of Diversity-Oriented Synthesis (DOS). Full article

According to the World Health Organization, cancer is still the leading cause of death for humans worldwide. Although over 100 chemotherapeutic agents are currently available for the treatment of cancer patients, the overall long term clinical benefit is disappointing due to the lack of effectiveness or severe side effects from these drugs. The use of complementary and alternative medicinal products from plants has continued to increase in past decades, due to fewer side effects of bioactive compounds from medicinal plants of which pentacyclic triterpenoids have been identified as one class of secondary metabolites that could play an important role in the treatment and management of a number of non-communicable diseases. The main aim of this study is to extract, isolate, identify, and elucidate pentacyclic triterpenoid (ursolic acid, UA (1), and oleanolic acid, OA (2)) from Mimusops caffra. Semi-synthesis of UA was carried out to obtain some triterpenoid derivatives (3-O-acetyl ursolic acid, AUA (3), ursolic-28-methylate, UM (4), and 3-acetylursolic-methylate, AUM (5)), and we evaluated these compounds as anti-cancer therapeutic agents. Isolation of ursolic acid (UA) (1) from M. caffra is always accompanied by its isomer oleanolic acid (OA) (2) due to their similar retention factors (Rf) values. Acetylation and deacetylation techniques were used to isolate compounds 1 and 2. In vitro cytotoxicity activities of UA, AUA UM, and AUM were evaluated against various cancer cell lines, such as human breast adenocarcinoma cancer cell lines (MDA), human liver cancer cell lines (HepG2), human prostate cancer cell lines (PC3) and non-cancerous human fibroblast cell lines (KMST-6) using MTT assays. The UM exhibited remarkable cytotoxic activities against cancer cells, while little or no activities were observed on non-cancerous cell lines, which indicates that the addition of methyl at C-28 of UA is essential to enhance its activity as a therapeutic agent for cancer. The AUA showed moderate or no cytotoxicity against the different cancer cell lines, which is less than that of the UA parent compound. Moreover, these results suggest that ursolic acid and UA derivatives are potential therapeutic drugs for human breast, liver, and prostate cancers. Full article

Sinomenine has long been known as an anti-inflammatory drug, while poor efficiency and large-dose treatment had limited its further application. Five novel sinomenine 1-Br-4-cinnamic acid esters derivatives 2a–2e were designed and synthesized to improve its analgesic and anti-inflammatory activity. All synthesized sinomenine derivatives were structurally confirmed by NMR and ESI-MS. Molecular docking results showed that compounds 2a–2e had stable binding to the GBP5 protein. The compounds 2a–2e showed stable binding to the GBP5 protein by molecular docking Pre-preparing the druggability of compounds 2a–2e by ADEMT 3.0 showed that each derivative had similar druggability to sinomenine. The analgesic activity of compounds 2a–2e was preliminarily determined by hot plate and acetic acid writhing experiments, while anti-neuroinflammatory effects were evaluated by a xylene-induced mouse ear edema model. The results of the hot plate method showed that the synthesized sinomenine derivatives 2a–2e had some analgesic effects. The results of the acetic acid writhing test showed that the analgesic effects of 2a, 2c, 2e were better than that of sinomenine, and the other derivatives were equivalent to sinomenine. Compound 2b showed excellent anti-inflammatory properties in mouse ear edema. Full article

Current treatments against leukemia present several limitations, prompting the search for new therapeutic agents, particularly those derived from natural products. In this context, structural modifications were performed on the triterpene 3α,24-dihydroxylup-20(29)-en-28-oic acid (T1), isolated from Phoradendron wattii. Among the five derivatives obtained, 3α,24-dihydroxy-30-oxolup-20(29)-en-28-oic acid (T1c) exhibited the highest activity, with an IC₅₀ value of 12.90 ± 0.1 µM against THP-1 cells. T1c significantly reduced cell viability in both acute lymphoblastic leukemia (CCRF-CEM, REH, JURKAT, and MOLT-4) and acute myeloid leukemia (THP-1) cell lines, inducing apoptosis after 48 h of treatment, while showing minimal cytotoxicity toward normal mononuclear cells (MNCs). In silico molecular docking studies were conducted against three key protein targets: BCL-2 (B-cell lymphoma 2), EGFR (epidermal growth factor receptor, tyrosine kinase domain), and FLT3 (FMS-like tyrosine kinase 3). The lowest binding energies (kcal/mol) observed were as follows: T1–BCL-2: −10.12, EGFR: −12.75, FLT3: −14.05; T1c–BCL-2: −10.23, EGFR: −14.50, FLT3: −14.07; T2–BCL-2: −11.59, EGFR: −15.00, FLT3: −14.03. These findings highlight T1c as a promising candidate in the search for anti-leukemic drugs which deserves further study. Full article

The semi-synthesis of the (5R,7R,11bR)-9-(di(1H-indol-3-yl)methyl)-4,4,7,11b-tetramethyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodecahydrophenanthro[3,2-b]furan-5-yl acetate was performed via a pseudo-multicomponent reaction involving a double Friedel–Crafts alkylation between the natural product-derived aldehyde 6β-acetoxyvouacapane and the corresponding indole. The transformation was carried out under solvent-free mechanochemical conditions using mortar and pestle grinding, with ZnCl₂ as the catalyst. Structural elucidation of the target compound was accomplished using 1D and 2D NMR spectroscopy (¹H, ¹³C, COSY, HSQC, and HMBC), FT-IR, and high-resolution mass spectrometry (HRMS). Full article

Glycogen synthase kinase-3 beta (GSK-3β) plays a crucial role in multiple cellular processes and is implicated in different types of cancers and neurological disorders, including Alzheimer’s disease. Despite extensive efforts to develop novel GSK-3β inhibitors, the discovery of potent and selective lead compounds remains a challenge. In this study, we evaluated the GSK-3β inhibitory potential of semisynthetic flavonoid derivatives, which exhibited sub-micromolar activity. To gain further insights, we employed molecular docking, molecular dynamics simulations, and pharmacokinetic profile predictions. The docking studies revealed that the most potent inhibitor, compound 10, establishes key interactions with the ATP-binding site. Molecular dynamics simulations further confirmed that compound 10 maintains stable interactions with GSK-3β throughout the simulation. Additionally, pharmacokinetic predictions identified compound 3 as a promising candidate for Alzheimer’s disease therapy due to its ability to cross the blood–brain barrier. These findings suggest that, within the studied flavonoid derivatives, these compounds (particularly 10 and 3) hold potential as lead compounds for GSK-3β inhibition. The combination of strong enzymatic inhibition, stable binding interactions, and favorable pharmacokinetic properties highlights their promise for further development in cancer and neurodegenerative disease research. Full article

A novel series of oleanolic acid (OA, 1) derivatives incorporating phenolic and coumarin moieties were synthesized. This acid was extracted from olive pomace (Olea europaea L.) using an ultrasound-assisted method. The structures of these novel derivatives of OA were characterized through the utilization of ¹H-NMR, ¹³C-NMR and ESI-HRMS analyses. An evaluation of some biological activities of the prepared derivatives was conducted. The evaluation focused principally on the capacity of these structures to inhibit 15-lipoxygenase and α-glucosidase, as well as their anticancer properties when tested against tumour cell lines (HCT-116 and LS-174T) and a non-tumour cell line (HEK-293). In terms of their cytotoxic activity, the majority of the compounds exhibited notable inhibitory effects compared to the starting molecule, OA. Derivatives 4d, 4k and 4m exhibited particularly strong inhibitory effects against the HCT-116 cell line, with IC₅₀ values of 38.5, 39.3, 40.0 µM, respectively. Derivatives 4l, 4e and 5d demonstrated the most effective inhibition against the LS-174T cell line, with IC₅₀ values of 44.0, 44.3, 38.0 µM, respectively. However, compound 2a was the most effective, exhibiting the most potent inhibition of 15-lipoxygenase and α-glucosidase, with IC₅₀ values of 52.4 and 59.5 µM, respectively. Furthermore, molecular docking studies supported in vitro cytotoxic activity, revealing that the most potent compounds exhibited low binding energies and interacted effectively within the EGFR enzyme’s active pocket (PDB: 1M17). These findings highlight the potential of these derivatives as anticancer agents and enzymatic inhibitors, warranting further investigation. Full article

Breast cancer is the most common and the leading cause of cancer death in women worldwide; treating invasive breast carcinomas is challenging due to the side effects of chemotherapeutics. Compounds isolated from natural sources have been proposed as potential molecules for cancer therapy; for instance, the homoisoflavonoid brazilin has shown pharmacological properties, including anti-tumoral and anti-inflammatory activities. In this study, we isolated brazilin from the heartwood of Haematoxylum brasiletto; then, we performed a semi-synthesis by adding three methyl or acetyl groups to the core structure of brazilin. We confirmed the identity of brazilin and its derivatives by spectroscopic data (¹H NMR and ¹³C NMR) and measured their purity by optical rotation. Then, we analyzed the effects of brazilin and its derivatives in three mammary gland-derived cell lines: the TNBC MDA-MB-231, the ERα(+) MCF7, and the non-tumorigenic MCF10A. We evaluated the cell viability by MTT assays, cell migration by wound-healing assays, and focal adhesion kinase (FAK) activation by Western blot. Regarding biological assays, the MTT assay showed that these compounds showed cytotoxic effects on the MCF7 and MDA-MB-231 breast cancer cells at 20 µM but was not toxic in non-tumorigenic MCF10A mammary epithelial cells. Specifically, the greatest effects found from treatment with the compounds were in the MDA-MB-231 cell line, where the IC50 of brazilin was 49.92 μM, and for MCF7, the brazilin-(OAc)₃ was 49.97 μM. These effects were dose- and time-dependent, as well as being associated with a decrease in the levels of cell migration and FAK activation. Full article

Two natural ent-kaurene diterpenoids, ent-15α-angeloyloxykaur-16-en-3β-ol (7) and ent-15α-angeloyloxykaur-16-en-3β,9-diol (8), were extracted from the aerial parts of Distichoselinum tenuifolium, and six new derivatives were synthesised from compound (7). The antitumour properties of these natural and derivative ent-kaurenes (2, 7, 9–13) were evaluated in three cancer cell lines: HT29 (colon cancer), HepG2 (hepatocellular carcinoma), and B16-F10 (murine melanoma). Among them, the synthesised ent-kaurene (13) containing an exomethylene–cyclopentanone moiety showed the strongest antiproliferative effects in all cell lines tested, with significantly lower IC₅₀ values around 2.5 μM. Compounds 13 and 12, together with their precursor (7), were selected for further comparative cytometric and microscopic analyses. Cell cycle studies revealed that derivatives 12 and 13 exhibited promising cytostatic activity by inducing selective G2/M phase arrest, particularly effective in HT29 and HepG2 cells. Conversely, precursor (7) showed no significant effect on B16-F10 cell cycle distribution. The Annexin V-FITC/PI double staining assay confirmed the robust apoptotic effects of compounds (7), 12 and 13, with compound 13 inducing up to 99% total apoptosis and exhibiting significant apoptotic activity in all cell lines tested. These apoptotic effects were closely linked to mitochondrial dysfunction, as evidenced by a marked loss of mitochondrial membrane potential and reduced Rh123 fluorescence in treated cells, thereby activating the intrinsic apoptotic pathway. These findings highlight the critical role of mitochondrial disruption in the cytotoxic mechanisms of these ent-kaurenes and underscore their potential as promising anticancer agents. Full article

Since ancient times, humans have turned to medicinal plants for treating various ailments and curing specific diseases, as these natural plants serve as the primary source of a range of phytochemicals, including triterpenes. Maslinic acid (MA), also known as (2α,3β)-2,3-dihydroxyolean-12-en-28-oic acid, is a pentacyclic triterpene acid present in numerous plants including olive, known for its high safety profile in humans. Recent experimental data increasingly suggests that MA exhibits diverse biological properties and therapeutic effects on various organ diseases, highlighting its significant potential for clinical applications due to its diverse potential pharmacological activities that promote health and resist various diseases, such as hypoglycemic, neuroprotective, anti-tumor, anti-inflammatory, antioxidant and multiple other biological activities. However, the undesirable pharmacokinetic properties of MA, such as high lipophilicity, pose a limitation to its application and development, impacting its bioavailability. Consequently, extensive research spanning decades has focused on structurally modifying MA to overcome these limitations and enhance its pharmacokinetic and therapeutic characteristics, leading to the identification of several potential lead compounds. In this review, we focus on the progress of research in recent years on MA with interest to its chemical and enzymatic modifications as well as the relationships between the modified structures or derivatives and their biological activities. Full article