Search Results (139)

A total of 24 novel steroidal derivatives were synthesized, including 1,3,4-thia(selena)diazolines and structurally unique spirothiadiazolines, obtained through intramolecular cyclization under standard acetylation conditions. This strategy was further extended to the construction of a novel dimeric compound bearing a thiadiazoline linker. Seleno- and thiosemicarbazone precursors were derived from various functionalized steroidal monomers and dimers via straightforward synthetic protocols. Key intermediates included aldehyde 7 and ketones 16, 19, and 24. Rotameric equilibria were observed in certain thiosemicarbazones, attributed to partial double-bond character in the N–CS bond. Cyclization yielded heterocyclic systems as epimeric mixtures, and in some cases, inseparable mixtures of isomers were obtained due to low diastereoselectivity. Full structural elucidation of epimeric pairs was achieved using 2D NMR and IR spectroscopy, with compounds 2, 3, 5, 11, 17, 27, 28a, and 28b further confirmed by single-crystal X-ray diffraction. Preliminary antiproliferative assays against human cancer cell lines revealed GI₅₀ values below 10 µM for compounds 21, 22, and 27. Full article

Metabolic rewiring is a hallmark of both hepatic regeneration and malignant transformation, complicating the identification of cancer-specific traits. This study aimed to distinguish the metabolic profiles of proliferating hepatocytes and hepatocellular carcinoma (HCC) cells through integrated analyses of mRNA and protein expression, along with functional characterization. We compared non-malignant Upcyte^® hepatocytes (HepaFH3) cultured under proliferative and confluent conditions with primary human hepatocytes, primary human hepatoma cells, and hepatoma cell lines. Proliferating HepaFH3 cells exhibited features of metabolic reprogramming, including elevated glycolysis, increased HIF1A expression, and ketone body accumulation, while maintaining low c-MYC expression and reduced BDH1 levels, distinguishing them from malignant models. In contrast, HCC cells showed upregulation of HK2, c-MYC, and BDH1, reflecting a shift toward aggressive glycolytic and ketolytic metabolism. Functional assays supported the transcript and protein expression data, demonstrating increased glucose uptake, elevated lactate secretion, and reduced glycogen storage in both proliferating and malignant cells. These findings reveal that cancer-like metabolic changes also occur during hepatic regeneration, limiting the diagnostic utility of individual metabolic markers. HepaFH3 cells thus provide a physiologically relevant in vitro model to study regeneration-associated metabolic adaptation and may offer insights that contribute to distinguishing regenerative from malignant processes. Our findings highlight the potential of integrated metabolic profiling in differentiating proliferation from tumorigenesis. Full article

Rheum tataricum L.fil., known for its high tolerance to drought, salinity, and nutritional deficiency, is the least studied species of wild rhubarb. Extract of roots and rhizomes of R. tataricum has been traditionally used for the treatment of different diseases such as liver, kidney, womb, and bladder diseases and also relapsing fever. An ethanol extract of the roots of R. tataricum was prepared and further successively fractionated by extraction with tert-butyl methyl ether (TBME) and ethyl acetate (EtOAc). The obtained extract fractions were subjected to a series of chromatographic separations on silica gel for the isolation of its individual compounds. A total of 12 individual compounds, 2-O-β-D-glucopyranoside of R-(4-hydroxyphenyl)-2-butanol (rhododendrin) 1, gallic acid 2, 2-O-β-D-glucopyranoside of S-4-(4-hydroxyphenyl)-2-butanol (epi-rhododendrin) 3, their aglycones (-)-(2R)-rhododendrol 4 and (+)-(2S)-rhododendrol 5, gallotannin β-glucogallin 6, chlorogenic acids (3,5-di-O-caffeoylquinic acid 7 and 5-O-caffeoyl-3-O-(p-coumaroyl) quinic acid 8), 4-(4-hydroxyphenyl)-2-butanon (raspberry ketone) 9 and three stilbenes (rhaponticin 10, desoxyrhaponticin 11 and resveratroloside 12), were isolated and characterized. The structure of desoxyrhaponticin 11 was confirmed by X-ray diffraction analyses. The results of in vitro biological assays (the MTT test) showed that ethanol extract Rheum tataricum was non-toxic against the normal epithelial VERO cells. The isolated compounds 1, 4, 11 and 12 exhibited cytotoxicity against a cervical cancer cell line (CaSki), breast adenocarcinoma (MCF7) and glioblastoma cell line (SNB-19) at low micromolar concentrations. Polyhydroxystilbenes 11 and 12 showed the best potency against adenocarcinoma cells (GI₅₀ = 7–8 μM). The inhibition activity towards cancer cells was comparable to those of the standard drug doxorubicin. The available from R. tataricum secondary metabolites may serve as new leads for the discovery of anticancer drugs. Full article

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease. Full article

Curcumin is recognized for its diverse biological activities, including the ability to induce apoptosis and ferroptosis. Therefore, it represents a promising candidate for the development of new compounds with neuroprotective and anticancer properties. In order to synthesize mimics with improved pharmacokinetic properties (better solubility and stability than curcumin) here, we present the design and synthesis of novel curcumin analogues named Ethylphosphonate-based curcumin mimics (EPs), which preserve the pharmacophoric features of curcumin. New EP mimics were synthesized by tyrosol- and melatonin-based building blocks using an orthogonal protection approach of the different precursors’ OH functions with good yields and in a few steps. Comparative screenings of the cytotoxic and cytoprotective properties (curcumin was used as a reference compound) were carried out on all new mimics in different cell lines (HeLa, A375, WM266, MDA-MB-231, LX2, and HDF). Assays with inhibitors of ferroptosis (Ferrostatin-1, Fer-1) and apoptosis (Quinoline-Val-Asp-difluorophenoxymethyl ketone, Q-VD), in combination with curcumin, suggested the specific cell death pathway (apoptotic or ferroptotic) of EPs, depending on the aromatic moieties contained in them. Interestingly, EP4 exhibited substantial cytotoxic effects against various human cancer cell lines (HeLa, A375, WM266) while sparing normal cells (HDFs). EP4 displayed a five-times-higher toxicity in triple-negative MDA-MB-231 and LX2 stellate cells than curcumin. The cytotoxicity exerted by EP4 involves only an apoptotic mechanism, contrary to curcumin, which exerts both apoptotic and ferroptotic effects. Additionally, EP4 was also found to be a very potent inhibitor of the ubiquitin-activating enzyme E1, reinforcing the anticancer potential of this compound. Furthermore, EP2 possesses high antioxidant properties, efficiently protects against cell death by ferroptosis, and inhibits the amyloid aggregation involved in AD. Full article

Background/Objectives: Microcolins A–M are cytotoxic marine lipopeptides produced by the cyanobacterium Moorena producens, also known as Lyngbya majuscula. Recent studies have shown that two compounds in the series, microcolins B and H, can form covalent complexes with phosphatidylinositol transfer proteins α and β (PITPα/β) upon the reaction of their α,β-unsaturated ketone group with the thiol group of a key cysteine residue of PITP. These observations prompted us to compare the binding of all microcolins and a few related derivatives (VT01454 and (deoxy)majusculamide D) to PITP to delineate structure–binding relationships. Methods: A molecular docking analysis led to the identification of microcolin E as the potentially best PITPα binder in the series, followed by microcolins B and H and analog VT01454. The computational data agree well with the published experimental results. Results: The binding of microcolin H into a large cavity of PITPα positions its reactive electrophilic α,β-unsaturated ketone close to the thiol of Cys95, enabling the facile formation of a covalent C-S linkage. A similar bonding can occur with the Cys94 of PITPβ. Molecular models of microcolins bound to PITP were compared to identify structural elements chiefly implicated in the recognition process. Conclusions: This computational study provides guidance in the design of microcolin derivatives targeting PITPα/β considered targets for cancer and inflammatory pathologies. Full article

The ferrociphenol family is a group of molecules in which a ferrocenyl moiety is connected to at least one 4-hydroxyphenyl group through a C-C double bond. Among them, ferrocidiphenols in which the double bond is substituted by two gem 4-hydroxyphenyl groups have been largely studied, demonstrating interesting anticancer properties. The fourth available position of the double bond could be substituted by a simple ethyl group (1a) inherited from Tamoxifen, but also by ethyl or methyl acetate, propionate, butanoate, pentanoate (1b-g), hydroxyethyl or hydroxypropyl (1h–i). Ethyl 4-ene-4-ferrocenyl-5,5-bis-(4-hydroxyphenyl)-pentanoate 1e shows an IC₅₀ on the MDA-MB-231 breast cancer cell line very close to that of 1a. These compounds were synthesized in moderate to good yields by McMurry coupling reaction from the corresponding ketones. Ethyl 4-ene-4-ferrocenyl-5,5-bis-(4-hydroxyphenyl)-pentanoate (1e) was fully characterized by ¹H NMR (including COSY), ¹³C NMR (including DEPT135), low resolution mass spectrometry, HRMS, infrared spectroscopy, elemental analysis, and X-ray diffraction (XRD). The data of already published crystal structures of five structurally related ferrocidiphenols are also included for comparison purposes. Full article

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression. This study leverages multiomics coverage of the microenvironment via liquid chromatography and high-resolution, high-mass-accuracy mass spectrometry-based untargeted metabolomics, ¹³C-stable isotope tracing, and RNA sequencing to uncover the metabolic impact of co-localized primary hepatocytes and a colon adenocarcinoma cell line, SW480, using a 2D co-culture model. Metabolic profiling revealed disrupted Warburg metabolism with an 80% decrease in glucose consumption and 94% decrease in lactate production by hepatocyte–SW480 co-cultures relative to SW480 control cultures. Decreased glucose consumption was coupled with alterations in glutamine and ketone body metabolism, suggesting a possible fuel switch upon co-culturing. Further, integrated multiomics analysis indicates that disruptions in metabolic pathways, including nucleoside biosynthesis, amino acids, and TCA cycle, correlate with altered SW480 transcriptional profiles and highlight the importance of redox homeostasis in tumor adaptation. Finally, these findings were replicated in three-dimensional microtissue organoids. Taken together, these studies support a bioinformatic approach to study metabolic crosstalk and discovery of potential therapeutic targets in preclinical models of the tumor microenvironment. Full article

Background/Objectives: New indole/1,2,4-triazole hybrids were synthesized and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization inhibitors. Methods: All final compounds, 6a–j and 7a–j were evaluated at a single concentration of 10 µM against a panel of sixty cancer cell lines. Results: Compounds 7a–j, featuring the NO-releasing oxime moiety, exhibited superior anticancer activity to their precursor ketones 6a–j across all tested cancer cell lines. Compounds 6h, 7h, 7i, and 7j were chosen for five-dose evaluations against a comprehensive array of 60 human tumor cell lines. The data showed that all tested compounds had significant anticancer activity throughout the nine tumor subpanels studied, with selectivity ratios ranging from 0.52 to 2.29 at the GI₅₀ level. Compounds 7h and 7j showed substantial anticancer effectiveness against most cell lines across nine subpanels, with GI₅₀ values ranging from 1.85 to 5.76 µM and 2.45 to 5.23 µM. Compounds 6h, 7h, 7i, and 7j were assessed for their inhibitory effects on tubulin polymerization. Conclusions: The results showed that compound 7i, an oxime-based derivative, was the most effective at blocking tubulin, with an IC₅₀ value of 3.03 ± 0.11 µM. This was compared to the standard drug CA-4, which had an IC₅₀ value of 8.33 ± 0.29 µM. Additionally, cell cycle analysis and apoptosis assays were performed for compound 7i. Molecular computational investigations have been performed to examine the binding mode of the most effective compounds to the target enzyme. Full article

Perillic acid (PA) is a limonene derivative in which the exocyclic methyl is oxidized to a carboxyl group. Although endowed with potential anticancer activity, PA has been much less explored regarding its biological properties than analogous compounds such as perillyl alcohol, perillaldehyde, or limonene itself. PA is usually described in mixture with alcohols and ketones produced in the oxidation of monoterpenes, with relatively few existing reports focusing on the PA molecule. This study provides a comprehensive review of PA, addressing its origin, the processes of obtaining it through organic synthesis and biotransformation, and the pharmacological tests in which it is either the lead compound or reference for in vitro efficacy in experimental models. Although feasible and generally poorly yielded, the synthesis of PA from limonene requires multiple steps and the use of unusual catalysts. The most economical process involves using (−)-β-pinene epoxide as the starting material, ending up with (−)-PA. On the other hand, some bacteria and yeasts are successful in producing, exclusively or at satisfactory purity level, PA from limonene or a few other monoterpenes, through environmentally friendly approaches. The compiled data revealed that, with few exceptions, most reports on PA bioactivity are related to its ability to interfere with the prenylation process of oncogenic proteins, an essential step for the growth and dissemination of cancer cells. The present survey reveals that there is still a vast field to disclose regarding the obtaining and scaling of PA via the fermentative route, as well as extending prospective studies on its properties and possible pharmacological applications, especially in the preclinical oncology field. Full article

Reprogramming energy metabolism is pivotal to tumor development. Ketone bodies (KBs), which are generated during lipid metabolism, are fundamental bioactive molecules that can be modulated to satisfy the escalating metabolic needs of cancer cells. At present, a burgeoning body of research is concentrating on the metabolism of KBs within tumors, investigating their roles as signaling mediators, drivers of post-translational modifications, and regulators of inflammation and oxidative stress. The ketogenic diet (KD) may enhance the sensitivity of various cancers to standard therapies, such as chemotherapy and radiotherapy, by exploiting the reprogrammed metabolism of cancer cells and shifting the metabolic state from glucose reliance to KB utilization, rendering it a promising candidate for adjunct cancer therapy. Nonetheless, numerous questions remain regarding the expression of key metabolic genes across different tumors, the regulation of their activities, and the impact of individual KBs on various tumor types. Further investigation is imperative to resolve the conflicting data concerning KB synthesis and functionality within tumors. This review aims to encapsulate the intricate roles of KBs in cancer metabolism, elucidating a comprehensive grasp of their mechanisms and highlighting emerging clinical applications, thereby setting the stage for future investigations into their therapeutic potential. Full article

Although immune checkpoint blockade (ICB) therapy has attained unprecedented clinical success, the tolerance and immune suppression mechanisms evolved by tumor cells and their tumor microenvironment (TME) hinder its maximum anti-cancer potential. Ferroptosis therapy can partially improve the efficacy of ICB, but it is still subject to immune suppression by myeloid-derived suppressor cells (MDSCs) in the TME. Recent research suggests that an MDSC blockade can unleash the full therapeutic potential of the combined therapy of ferroptosis and ICB in liver cancer treatment. However, whether blocking the intrinsic ferroptosis pathways of MDSCs can relieve imidazole ketone erastin (IKE)-initiated ferroptosis-induced immune suppression and ultimately trigger the optimal therapeutic effect of the combined ferroptosis and ICB therapy is still unknown. Here, we report that TIPE2, a phospholipid transfer protein, regulated the ferroptosis susceptibility in MDSCs through reprogramming lipid peroxidation-related phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species composition. TIPE2-deficient MDSCs resisted IKE-induced ferroptosis by up-regulating SLC7A11 and GPX4, and dissolved ferroptosis-induced immunosuppressive function by down-regulating lipid ROS whilst encouraging T cell proliferation and infiltration into tumor tissues to improve ferroptosis therapy. More importantly, TIPE2-deficient MDSCs achieved the full anti-tumor therapeutic potential of IKE-induced ferroptosis therapy and a PD-L1 blockade. These findings indicate that TIPE2 confers the ferroptosis sensitivity of MDSCs, and combining the targeting of the TIPE2 of MDSCs, ferroptosis therapy, and ICB is a novel therapeutic option for cancer treatment. Full article

Leucine, isoleucine, and valine are collectively known as branched chain amino acids (BCAAs) and are often discussed in the same physiological and pathological situations. The two consecutive initial reactions of BCAA catabolism are catalyzed by the common enzymes referred to as branched chain aminotransferase (BCAT) and branched chain α-keto acid dehydrogenase (BCKDH). BCAT transfers the amino group of BCAAs to 2-ketoglutarate, which results in corresponding branched chain 2-keto acids (BCKAs) and glutamate. BCKDH performs an oxidative decarboxylation of BCKAs, which produces their coenzyme A-conjugates and NADH. BCAT2 in skeletal muscle dominantly catalyzes the transamination of BCAAs. Low BCAT activity in the liver reduces the metabolization of BCAAs, but the abundant presence of BCKDH promotes the metabolism of muscle-derived BCKAs, which leads to the production of glucose and ketone bodies. While mutations in the genes responsible for BCAA catabolism are involved in rare inherited disorders, an aberrant regulation of their enzymatic activities is associated with major metabolic disorders such as diabetes, cardiovascular disease, and cancer. Therefore, an understanding of the regulatory process of metabolic enzymes, as well as the functions of the BCAAs and their metabolites, make a significant contribution to our health. Full article

Gerbera piloselloides, a plant in the Asteraceae family, is a traditional Chinese medicinal herb known for its unique therapeutic properties, including reported anti-tumor and antioxidant effects. Recent studies suggest that the main constitute of G. piloselloides, coumarins, may have potential anti-tumor activity. Recent research suggests that coumarins, the active compounds in G. piloselloides, may hold potential anti-tumor activity. However, the pharmacodynamic constituents remain unidentified. This study aims to isolate and characterize the bioactive compounds of G. piloselloides and to assess its anti-tumor effects. Initially, seven compounds, including coumarins, a ketone, and a furanolide, were isolated and identified from G. piloselloides by semi-preparative high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) analysis. The anti-tumor effects of these compounds were evaluated across four different cancer cell lines. Among them, the compound cyclobrachycoumarin showed a significant inhibitory effect on colorectal cancer (CRC) cell proliferation and was selected for further investigation. Cyclobrachycoumarin was found to induce CRC cell apoptosis and cell cycle arrest in a dose-dependent manner. This treatment also led to increased levels of ROS and cleaved PARP, along with decreased expressions of survivin, cyclin D1, and CDK1. In vivo studies further demonstrated that cyclobrachycoumarin effectively reduced tumor growth in HT-29 xenograft models by promoting apoptosis and cell cycle arrest, with a favorable tolerability profile. In summary, this study suggests that cyclobrachycoumarin may be a promising candidate for safe and effective CRC therapy. Full article

Pulegone is a monoterpene ketone found in a variety of mint species. It has been classified as possibly carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC). In previous studies, pulegone in food was analyzed exclusively via GC-MS, while ¹H NMR methods were limited to essential oils. The aim of this study was to develop an NMR method for the detection and quantification of pulegone in essential oils and foods. A mixture of methanol-d₄/chloroform-d₁ in a 1:1 ratio (v/v) was identified as the most effective solvent for separating pulegone signals. The essential oils were subjected to analysis at this solvent-mixture ratio. The extraction of pulegone was required for food analysis, and the steam distillation method proved to be more effective than the ultrasonic-assisted extraction method. The highest pulegone concentrations were identified in pennyroyal oil and muña oil, whereas lower levels were observed in other matrices, including corn mint oil and select food items. A toxicological assessment showed that the amount consumed did not exert any adverse effects on human health. Full article