Search Results (106)

Highly degraded sterols belonging to the incisterol group have been identified in a large set of microorganisms. The leading product in the family is demethylincisterol A3 (DM-A3), isolated from various fungi and endowed with marked antitumor properties. Since the initial discovery of incisterol from a marine sponge in the 1990s, more than 30 incisterol-type natural products have been identified, essentially from fungi. An overview of these products, their bio-origin, chemical synthesis, and associated pharmacological properties is presented. The series includes diverse incisterol and demethylincisterol derivatives, chaxines, volemolide, different analogues (salimyxins, phellinignincisterols, daedatrin D, inonotoide F, aplykurodinone-1, dendrodoristerol), and a glycoside derivative (xyloneside), all bearing a tetracyclic incisterol framework. An analysis of the anticancer mechanism of the action of DM-A3 underlined the three main components of its activity associated with the (i) inhibition of β-catenin and the Wnt signaling pathway, (ii) inhibition of tyrosine phosphatase SHP2 (IC₅₀ = 6.75 µM) implicated in cancer cell survival and differentiation, and (iii) blockade of α7nAchR activation coupled with inhibition of acetylcholinesterase (IC₅₀ = 11.16 µM). A comprehensive picture of the DM-A3 mechanism of action is discussed, highlighting the uniqueness of the compound as a dual SHP2/AchE inhibitor able to attenuate an inflammatory response through the cholinergic anti-inflammatory pathway. The review shed light on this little-known category of incisterol-type natural products, with the objective of promoting further research into this neglected group of anticancer agents. Full article

Background/Objectives: Animal and fungal sterols and stanols exhibit remarkable structural diversity, driven by variations in the number and position of C=C bonds within the steroidal tetracyclic core and side chain, along with diverse branching patterns of the latter. Similarly to phytosterols, these metabolites produce highly complex tandem mass spectra, whose interpretation has so far been limited. To address this gap, the fragmentation behavior of selected animal/fungal sterols and stanols was studied in this paper. Methods: Higher-Collisional-energy Dissociation–High-resolution tandem mass spectrometry (HCD-HRMS/MS) of protonated/dehydrated species generated via atmospheric pressure chemical ionization (APCI) was performed on structurally diverse compounds, including lathosterol, desmosterol, zymosterol, lanosterol, ergosterol, chalinasterol, and the stanols coprostanol and cholestanol. Results: Structurally diagnostic product ions originating from the side chains were unveiled, shedding light on the intramolecular migration of positive charge from the initial ionization site at C3 to alternative stable sites across the molecular structure, which is a typical mechanism also noted in cholesterol and phytosterols. In addition, characteristic fragmentation patterns related to the steroidal backbone were found and discussed for Δ⁷, Δ^5,7 and Δ⁸-sterols, and a novel elucidation of the fragmentation behavior of 4,4-dimethyl-Δ⁸-sterols, based on lanosterol as a model compound, was achieved. The relative intensities of diagnostic product ions allowed a correlation with specific structural motifs, and “cholesterol-like” and “stigmasterol-like” fragmentations pathways were recognized. These findings were integrated with prior data on cholesterol and plant sterol fragmentation acquired under identical analytical conditions. Moreover, as a proof of its relevance for novel sterol identification, MS/MS-related information was successfully applied to the identification of a positional isomer (Δ⁷) of zymosterol in baker’s yeast extract, along with typical fungal major sterols. Conclusions: The comprehensive archive of sterol/stanol fragmentations obtained by APCI-HCD-MS/MS might prove very useful for the future characterization of novel sterol/stanol species in complex matrices. Full article

Although chlorpromazine is primarily used in psychiatry, it has been shown since its introduction to influence the course of neoplastic diseases. According to the strategy of drug repurposing, chlorpromazine has been successfully tested for its potential antitumor effects on multiple cancer cell lines. This effect is consistent with the overlap of molecular pathways observed for years between schizophrenia and cancer. The main objective of this work was to evaluate the lipophilicity of 17 previously synthesized tetracyclic chlorpromazine analogues exhibiting diverse anticancer and antimicrobial activity using thin-layer chromatography and computational methods. For a compound to become an effective drug, it must have a favorable ADMET profile, which determines its pharmacokinetic properties as a drug candidate. Lipophilicity is one of the key parameters widely employed in designing new bioactive compounds as potential therapeutic agents. In this article, chromatographic plates precoated with silica gel 60 RP-18F₂₅₄ and a mixture of acetone and TRIS buffer were used as the mobile phase. The chromatographic parameter of lipophilicity (R_M0) of the investigated compounds determined by means of the Soczewinski–Wachtmeister formula was useful to obtain the values of the experimental lipophilicity parameter expressed as logP_TLC. The results of logP_TLC were compared with theoretical values of logP obtained using different algorithms (iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, and ClogP). Furthermore, the online platforms, such as SwissADME and pkCSM, allowed the determination of the remaining ADME parameters of the quinoline derivatives of chlorpromazine. The study of lipophilicity and ADME factors enabled confirmation that the tested compounds demonstrated favorable properties. Therefore, they can be considered as promising starting structures for further studies. Full article

Cucurbitacin B (CuB), a tetracyclic triterpenoid compound isolated from Cucurbitaceae plants, exhibits inhibitory effects on various tumor cells (e.g., liver, gastric, and colorectal cancer cells). Since the 1970s–1980s, cucurbitacin tablets containing CuB have been used as an adjuvant therapy for chronic hepatitis and primary liver cancer. CuB exerts anticancer effects through multiple mechanisms: inducing apoptosis, cell cycle arrest (G2/M or S phase), autophagy, and cytoskeleton disruption; inhibiting migration, invasion, and angiogenesis (via VEGF/FAK/MMP-9 and Wnt/β-catenin pathways); regulating metabolic reprogramming and immune responses; inducing pyroptosis, ferroptosis, and epigenetic changes; and reversing tumor drug resistance. These effects are associated with signaling pathways like JAK/STAT, PI3K/Akt/mTOR, and FOXM1-KIF20A. To improve its application potential, strategies such as structural modification (e.g., NO donor conjugation), combination therapy (with gemcitabine or cisplatin), and nanomaterial-based delivery (e.g., liposomes and exosome-mimicking nanoparticles) have been developed to enhance efficacy, reduce toxicity, and improve bioavailability. CuB shows broad-spectrum anticancer activity, but further research is needed to clarify the mechanisms underlying its cell-specific sensitivity and interactions with the immune system. This review systematically summarizes the physicochemical properties, anticancer mechanisms, and strategies for applying CuB and suggests future research directions, providing references for scientific research and clinical translation. Full article

Madangamine alkaloids have attracted considerable interest in the scientific community due to their complex polycyclic structures and potent biological activities. The six members identified to date have exhibited diverse and significant cytotoxic activities against various cancer cell lines. Despite their structural complexity, seven total syntheses—covering five of the six members—have been reported to date. These syntheses, involving 28 to 36 steps and global yields ranging from 0.006% to 0.029%, highlight the formidable challenge these compounds present. This review summarizes the key synthetic strategies developed to access critical fragments, including the construction of the ABC diazatricyclic core and the ACE ring systems. Approaches to assembling the ABCD and ABCE tetracyclic frameworks are also discussed. Finally, we highlight the completed total syntheses of madangamines A–E, with a focus on pivotal transformations and strategic innovations that have enabled progress in this field. Full article

Background: Cucurbitacin E (CuE), a natural tetracyclic triterpenoid compound extracted from the melon stems of Cucurbitaceae plants, has been reported to exhibit anti-inflammatory and anti-cancer properties, along with the ability to enhance cellular immunity. However, its role and molecular mechanism in regulating lipid metabolism and adipogenesis remain unclear. This study aims to investigate the potential anti-adipogenic and anti-obesity effects of CuE in 3T3-L1 adipocytes. Materials and Methods: 3T3-L1 preadipocytes were cultured and induced to differentiate using a standard adipogenic cocktail containing dexamethasone, 3-isobutyl-1-methylxanthine (IBMX), and insulin (DMI). CuE was administered during the differentiation process at various concentrations. Lipid accumulation was assessed using Oil Red O staining, and cell viability was evaluated via the MTT assay. To determine whether CuE induced apoptosis or necrosis, flow cytometry was performed using annexin V/PI staining. Additional molecular analyses, such as Western blotting and RT-PCR, were used to examine the expression of key adipogenic markers. Results: Treatment with CuE significantly reduced lipid droplet formation in DMI-induced 3T3-L1 adipocytes in a dose-dependent manner, as shown by decreased Oil Red O staining. Importantly, CuE did not induce apoptosis or necrosis in 3T3-L1 cells at effective concentrations, indicating its safety toward normal adipocytes. Moreover, CuE treatment downregulated the expression of adipogenic markers such as PPARγ and C/EBPα at both mRNA and protein levels. Discussion: Our findings suggest that CuE exerts a non-cytotoxic inhibitory effect on adipocyte differentiation and lipid accumulation. This anti-adipogenic effect is likely mediated through the suppression of key transcription factors involved in adipogenesis. The absence of cytotoxicity supports the potential application of CuE as a safe bioactive compound for obesity management. Further investigation is warranted to elucidate the upstream signaling pathways and in vivo efficacy of CuE. Conclusions: Cucurbitacin E effectively inhibits adipogenesis in 3T3-L1 adipocytes without inducing cytotoxic effects, making it a promising candidate for the development of functional foods or therapeutic agents aimed at preventing or treating obesity. This study provides new insights into the molecular basis of CuE’s anti-obesity action and highlights its potential as a natural lipogenesis inhibitor. Full article

Five new natural products, including two sorbicillinoids (1–2), one indolinone alkaloid (10), one tetracyclic steroid (11), and one α-pyrone derivative (14), were identified from the endophytic Penicillium sp. NX-S-6, together with thirteen known natural products. The structures of new compounds were unambiguously elucidated by comprehensive spectroscopic analyses (NMR, MS), as well as electronic circular dichroism (ECD) calculation. Notably, quinosorbicillinol (1) was identified as a rare hybrid sorbicillinoid incorporating a quinolone moiety, representing a unique structural scaffold in this natural product class. Biological evaluation revealed that Compounds 1, 4 and 8 potently inhibited the production of nitric oxide and interleukin 6 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mechanistic studies furthermore demonstrated that Compounds 4 and 8 effectively suppressed interleukin-1β secretion in LPS-induced immortalized mouse bone marrow-derived macrophages (iBMDMs) by blocking NLRP3 inflammasome activation. This inhibition was attributed to their ability to disrupt the assembly of the NLRP3-caspase-1 complex, a key event in the pathogenesis of inflammatory disorders. These findings not only expand the structural diversity of endophyte-derived natural products but also highlight their potential as lead compounds for developing anti-inflammatory therapeutics targeting the NLRP3 pathway. Full article

Natural compounds remain a valuable source of anticancer agents due to their structural diversity and multi-targeted mechanisms of action. Roburic acid (RA), a tetracyclic triterpenoid, has been identified as a substance capable of inhibiting key NF-κB and MAPK signaling pathways through direct interaction with TNF-α, as well as preventing the production of inflammatory mediators and cancer progression. In this study, we evaluated the biological activity of RA against a panel of human cancer cell lines—DLD-1, HT-29, and HCT-116 (colorectal), PC-3 (prostate), and BxPC-3 (pancreatic)—as well as two non-malignant lines: WI-38 (fibroblasts) and CCD-841 CoN (colon epithelium). RA exhibited a concentration-dependent inhibitory effect on cancer cell metabolic activity, with colorectal cancer cells showing relatively higher sensitivity, particularly at shorter incubation times. To distinguish between cytotoxic and cytostatic effects, we performed trypan blue exclusion combined with a cell density assessment, clonogenic assay, and BrdU incorporation assay. The results from these complementary assays confirmed that RA acts primarily through an antiproliferative mechanism rather than by inducing cytotoxicity. In addition, NF-κB reporter assays demonstrated that RA attenuates TNF-α-induced transcriptional activation at higher concentrations, supporting its proposed anti-inflammatory properties and potential to modulate pro-tumorigenic signaling. Finally, our in silico studies predicted that RA may interact with proteins such as CAII, CES1, EGFR, and PLA2G2A, implicating it in the modulation of pathways related to proliferation and cell survival. Collectively, these findings suggest that RA may serve as a promising scaffold for the development of future anticancer agents, particularly in the context of colorectal cancer. Full article

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et₃N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI₅₀ < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC₅₀ < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages. Full article

Fusidic acid (FA), a tetracyclic triterpenoid, has been approved to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. However, there are few reports about FA derivatives with high efficacy superior to FA, manifesting the difficulty of discovering the derivatives based on experience-based drug design. In this study, we employed a stepwise method to discover novel FA derivatives. First, molecular dynamics (MD) simulations were performed to identify the molecular mechanism of FA against elongation factor G (EF-G) and drug resistance. Then, we utilized a scaffold decorator to design novel FA derivatives at the 3- and 21-positions of FA. The ligand-based and structure-based screening models, including Chemprop and RTMScore, were employed to identify promising hits from the generated set. Ten generated FA derivatives with high efficacy in the Chemprop and RTMScore models were synthesized for in vitro testing. Compounds 4 and 10 demonstrated a 2-fold increase in potency against MRSA strains compared to FA. This study highlights the significant impact of AI-based methods on the design of novel FA derivatives with drug efficacy, which provides a new approach for drug discovery. Full article

Phlebopus portentosus is an edible and medicinal ectomycorrhizal mushroom with delicious and high nutritional value. However, the mechanism of secondary metabolite biosynthesis in P. portentosus is still unclear. In this study, the genomics, metabolomics, and transcriptomics were integrated to reveal the biosynthesis mechanism of secondary metabolites in P. portentosus under different cultivation conditions. The 31.4 Mb genome of P. portentosus YAF023 with 15 scaffolds was assembled by Illumina and Nanopore sequencing and annotated, and 206 cytochrome P450s, 201 carbohydrate-active enzymes, 186 transcription factors, 18 terpene synthases (TPSs), and 5 polyketide synthases (PKSs) were identified. Multi-omics analysis showed that PpPKS1 is probably involved in the biosynthesis of Ethyl orsellinate; PpPKS2 and PpPKS5 are probably involved in the synthesis of 6-Methylsalicylic acid and Cytochalasin Z5, respectively; PpTRI5 was involved in the tetracyclic sesquiterpene β-type trichodiene compounds; and PpSTCs was involved in the synthesis of β-copaene analogs or derivatives. Co-expression network analysis and binding site prediction of the promoter regions suggested that PpHOX4 and PpHSF1 regulated the gene expression of PpPKS1, and Ppzf-C2H2 32 and PpHSF5 regulated the gene expression of PpSTCs 8, and PpSTCs 3, respectively. This study will provide an important foundation for further development and utilization of secondary metabolites of P. portentosus. Full article

Background: Gibberellins (GAs) are a family of tetracyclic ent-kaurenoid diterpenes found widely in several commonly used plants. Besides agricultural applications, gibberellins play an important role in the synthesis of bioactive compounds, especially those with antiproliferative and antibacterial activity. Methods: A series of gibberellic acid-based 2,4-diaminopyrimidines was designed and synthesized from commercially available gibberellic acid. The antimicrobial activity of the prepared compounds was also explored in B. subtilis, S. aureus, E. coli, and P. aeruginosa bacteria, as well as in C. krusei and C. albicans fungi. Results: The treatment of gibberellic acid with hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate azido alcohol was prepared according to the literature methods. The second key intermediate azidotriol was synthesized by the stereoselective dihydroxylation of the allylic function by the osmium (VIII)-tetroxide/NMO system. Starting from azide intermediates, click reactions were also carried out with 4-monoamino- and 2,4-diaminopyrimidines functionalized with the N-propargyl group. The new chimeric compounds, coupled with gibberellins thus obtained, were characterized by 1D- and 2D-NMR techniques and HRMS measurements. While the 4-monoamino-substituted derivatives exhibited only weak antibacterial activity, they demonstrated significant antifungal effectiveness against C. krusei. In general, 5-chloro-substituted pyrimidine derivatives displayed more consistent biological activities compared to their 5-fluoro counterparts, with the exception of one derivative, which showed acceptable activity against both C. krusei and C. albicans. The two derivatives featuring 5-chloro and 2-((4-(trifluoromethyl)phenyl)amino substituents proved to be highly effective against P. aeruginosa, making them promising candidates for further research. Aiming to elucidate the molecular interactions between the active compounds and their potential targets, molecular docking studies were conducted using AutoDock Vina 1.1.2. involving the most active compounds against P. aeruginosa.Conclusions: The biological effects of 2-monoamino or 2,4-diamino substitution as well as the effect of chloro or fluoro substitution at position 5 of the pyrimidine ring combined with the allo-gibberic acid moiety were determined. Compounds with selective antibacterial activity against P. aeruginosa as well as selective antifungal activity against C. krusei and C. albicans fungi were identified. Full article

A comprehensive understanding of the compositions and physicochemical properties of coal-based liquids is conducive to the rapid development of multipurpose, high-performance, and high-value functional chemicals. However, because of their complex compositions, coal-based liquids generate two-dimensional gas chromatography (GC × GC) chromatograms that are very complex and very time consuming to analyze. Therefore, the development of a method for accurately and rapidly analyzing chromatograms is crucial for understanding the chemical compositions and structures of coal-based liquids, such as direct coal liquefaction (DCL) oils and coal tar. In this study, DCL oils were distilled and qualitatively analyzed using GC × GC chromatograms. A deep-learning (DL) model was used to identify spectral features in GC × GC chromatograms and predominantly categorize the corresponding DCL oils as aliphatic alkanes, cycloalkanes, mono-, bi-, tri-, and tetracyclic aromatics. Regional labels associated with areas in the GC × GC chromatograms were fed into the mask-region-based convolutional neural network’s (Mask R-CNN’s) algorithm. The Mask R-CNN accurately and rapidly segmented the GC × GC chromatograms into regions representing different compounds, thereby automatically qualitatively classifying the compounds according to their spots in the chromatograms. Results show that the Mask R-CNN model’s accuracy, precision, recall, F1 value, and Intersection over Union (IoU) value were 93.71%, 96.99%, 96.27%, 0.95, and 0.93, respectively. DL is effective for visually comparing GC × GC chromatograms to analyze the compositions of chemical mixtures, accelerating GC × GC chromatogram interpretation and compound characterization and facilitating comparisons of the chemical compositions of multiple coal-based liquids produced in the coal and petroleum industry. Applying DL to analyze chromatograms improves analysis efficiency and provides a new method for analyzing GC × GC chromatograms, which is important for fast and accurate analysis. Full article

A concise, transition metal-free four-step synthetic pathway has been developed for the synthesis of tetracyclic heterosteroidal compounds, 14-aza-12-oxasteroids, starting from readily available 2-naphthol analogues. After conversion of 2-naphthols to 2-naphthylamines by the Bucherer reaction, subsequent selective C-acetylation was achieved via the Sugasawa reaction and reduction of the acetyl group using borohydride, which resulted into the corresponding amino-alcohols. The naphthalene-based amino-alcohols underwent double dehydrations and double intramolecular cyclization with oxo-acids leading to one-pot formation of a C-N bond, a C-O bond and an amide bond in tandem, to generate two additional rings completing the steroidal framework. A series of 14-aza-12-oxasteroids were synthesized using our developed synthetic strategy in moderate yields, and the structure of one of the final products, 12a-Methyl-11-phenyl-11,12a-dihydro-1H-naphtho[2,1-d]pyrrolo[2,1-b][1,3]oxazin-3(2H)-one, was further confirmed by single crystal X-ray crystallography. Full article

Oxazole, a versatile and significant heteroarene, serves as a bridge between synthetic organic chemistry and applications in the medicinal, pharmaceutical, and industrial fields. Polycyclic aromatic compounds with amino groups substituted at the 2-position of an oxazole, such as 2-aminonaphthoxazoles, are expected to be functional probes, but their synthetic methods are extremely limited. Herein, we describe electrochemical reactions of 3-amino-2-naphthol or 3-amino-2-anthracenol and isothiocyanates in DMSO, using a graphite electrode as an anode and a platinum electrode as a cathode in the presence of potassium iodide (KI), which afford N-arylnaphtho- and N-arylanthra[2,3-d]oxazol-2-amines via cyclodesulfurization. This reaction is the first example of synthesis of 2-aminoxazole-based polycyclic compounds using an electrochemical reaction. An examination of the spectroscopic properties of polycyclic oxazoles revealed that the λ_abs value of the tetracyclic oxazoles was redshifted relative to that of the tricyclic oxazoles. Moreover, synthesized naphthalene/anthracene-fused tricyclic and tetracyclic oxazoles exhibited extended π-conjugated skeletons and fluoresced in the 340–430 nm region in chloroform. Full article