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Sangre de drago, the sap of Croton lechleri Müll. Arg. tree, has been used for centuries in traditional medicine owing to its diverse biological activities. Extracts derived from different parts of the species contain a multitude of phytochemicals with varied applications. Twigs, however, are among the least studied parts of the plant. This study unveils new biological activities of Croton lechleri twig extracts recovered by applying Soxhlet and advanced green techniques. For all extracts, total phenolic content and antioxidant activity were determined. Subsequently, four were selected, and their cytotoxic effects were assessed on both normal (HaCat) and malignant melanoma (A375) skin cell lines using the MTT assay and trypan blue exclusion assay. All showed dose-dependent cytotoxicity, with the Soxhlet ethanol extract demonstrating the highest selectivity towards A375 cells over HaCat cells. The extracts induced apoptosis and necrosis, as confirmed by Annexin V/PI dual-labeling and flow cytometry, highlighting their ability to trigger programmed cell death in cancer cells. The selective inhibition of cell cycle progression in A375 compared to HaCat observed both for Soxhlet ethanol and pressurized ethanol extracts induces cell cycle arrest at multiple points, primarily in the G1 and G2/M phases, and significantly reduces DNA synthesis as evidenced by the decrease in the S-phase population, confirmed by the EdU assay. Consequently, the Soxhlet extract composition was analyzed using LC-MS, which revealed their richness in polyphenolic compounds, particularly flavonoids from the flavonol subclass., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

The Croton genus (Euphorbiaceae) is recognized as a promising source for identifying bioactive compounds with antiproliferative activity. However, knowledge on the chemical composition and activity of Croton floribundus, Croton echinocarpus, and Croton zehntneri is limited. Thus, this study aimed to investigate the antiproliferative activity of these species on cells derived from tumoral breast, lung, and melanoma cells, and primary fibroblasts derived from human skin. Metabolomic strategies were applied via ultra-performance liquid chromatography coupled with high-resolution mass spectrometry and multivariate statistical analysis to target the main active compound. The C. floribundus leaf extract exhibited the highest activity, with an IC 50 value lower than that of the reference drug - temozolomide - in the most responsive cell line - SK-MEL-147 - and in all the evaluated melanoma cell lines (SK-MEL-147, CHL-1 and WM-1366). Four tetrahydrofurofuran lignans were isolated for the first time from the most promising fraction of the C. floribundus extract. According to the metabolomic and multivariate statistical analyses, the isolated lignan epi-yangambin constituted the main antiproliferative compound against SK-MEL-147; furthermore, it exhibited selective antiproliferative activity for this cell line (IC 50  = 13.09 μg/mL and selectivity index = 3.82; temozolomide, IC 50  = 121.50 μg/mL) due to, at least in part, its ability to inhibit cell cycle progression at G2/M. This is especially relevant considering the high resistance of melanoma cells to available drugs. Thus, epi-yangambin can serve as a prototype for further antiproliferative investigations., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Croton argyrophyllus Kunth., commonly known as "marmeleiro" or "cassetinga," is widely distributed in the Brazilian Northeast region. Its leaves and flowers are used in traditional medicine as tranquilizers to treat flu and headaches., Aim of the Study: This study was conducted to determine the chemical composition and toxicological safety of essential oil from C. argyrophyllus leaves using in vitro and in vivo models., Materials and Methods: The chemical composition of the essential oil was determined using a gas chromatograph coupled to a mass spectrometer. Cytotoxicity was tested in the HeLa, HT-29, and MCF-7 cell lines derived from human cells (Homo sapiens) and Vero cell lines derived from monkeys (Cercopithecus aethiops) using the MTT method. Acute toxicity, genotoxicity. Mutagenicity tests were performed in Swiss mice (Mus musculus), which were administered essential oil orally in a single dose of 2000 mg/kg by gavage., Results: The main components of the essential oil were p-mentha-2-en-1-ol, α-terpineol, β-caryophyllene, and β-elemene. The essential oil exhibited more than 90% cytotoxicity in all cell lines tested. No deaths or behavioral, hematological, or biochemical changes were observed in mice, revealing no acute toxicity. In genotoxic and mutagenic analyses, there was no increase in micronuclei in polychromatic erythrocytes or in the damage and index in the comet assay., Conclusions: The essential oil was cytotoxic towards the tested cell lines but did not exert toxic effects or promote DNA damage when administered orally at a single dose of 2000 mg/kg in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Croton sublyratus (Euphorbiaceae) is a traditional medicinal plant used by the Thai populace to treat helminthic infections and dermatologic conditions. In present study, eight new labdane-type diterpenoids, crotonoids A-H (1-8) and one known analogue (9) were isolated from the aerial parts of C. sublyratus. Compounds 6 and 7 belong to the rare class of 14,15-dinor-labdane diterpenoids. Compound 8 exhibited a rare 14,15,17-trinor-labdane skeleton. The structures of all these diterpenoids were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction analysis. Compound 9 exhibited moderate anti-inflammatory activity via the inhibition of NO production in lipopolysaccharide-induced RAW 264.7 cells., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Introduction: Croton crassifolius Geisel. (CCG) is a traditional Chinese medicine widely used in South China. It has various pharmacological effects and is often used in treating rheumatoid arthritis and gastric and duodenal ulcers. However, the chemical characteristics and its effective constituents are still scarcely studied., Objective: To determine the phytochemical profile of the CCG extract and to investigate the chemical characteristics of terpenoids extracted from rat plasma following oral administration of CCG extract based on UPLC-Q/TOF-MS. Moreover, six terpenoids in CCG were quantified, and in vivo pharmacokinetic behavior after oral CCG extract was further explored., Results: In total, 56 terpenoids were tentatively identified in the CCG extract and 16 terpenoids were detected in rat plasma after oral CCG extract. In addition, the contents of six terpenoids in CCG were clarified. The plasma quantification method of six terpenoids was further established, validated, and confirmed to have good sensitivity and specificity. The six analytes exhibited excellent linearity in respective concentration ranges (r ≥ 0.998). The intra-day and inter-day precisions relative standard deviation (RSD, %) were less than 11.27%, and the accuracies ranged from -7.06% to 9.91%. Stability, extraction recovery, and matrix effect in plasma were within the required limits (RSD < 15%)., Conclusion: A total of 56 terpenoids were identified in CCG and 16 prototype components in plasma after oral CCG. The validated quantitative method was successfully applied to the simultaneous determination of six major terpenoids in plasma. The pharmacokinetic parameters are clarified, which can guide the clinical application of CCG., (© 2024 John Wiley & Sons Ltd.)

Antimicrobial resistance is a global health issue, in which microorganisms develop resistance to antimicrobial drugs, making infections more difficult to treat. This threatens the effectiveness of standard medical treatments and necessitates the urgent development of new strategies to combat resistant microbes. Studies have increasingly explored natural sources of new antimicrobial agents that harness the rich diversity of compounds found in plant species. This pursuit holds promise for the discovery of novel treatments for combating antimicrobial resistance. In this context, the chemical composition, antibacterial, and antibiofilm activities of the essential oil from Croton urticifolius Lam. leaves (CuEO) were evaluated. CuEO was extracted via hydrodistillation, and its chemical constituents were identified via gas chromatography-mass spectrometry (GC/MS). The antibacterial activity of CuEO was evaluated in a 96-well plate via the microdilution method, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined. The effect of CuEO on biofilm formation was assessed by quantifying the biomass using crystal violet staining and viable cell counting. In addition, alterations in the cellular morphology of biofilms treated with CuEO were examined using scanning electron microscopy (SEM) and laser confocal microscopy. GC/MS analysis identified 26 compounds, with elemicine (39.72%); eucalyptol (19.03%), E-caryophyllene (5.36%), and methyleugenol (4.12%) as the major compounds. In terms of antibacterial activity, CuEO showed bacteriostatic effects against Staphylococcus aureus ATCC 700698, S. aureus ATCC 25923, Staphylococcus epidermidis ATCC 12228, and Escherichia coli ATCC 11303, and bactericidal activity against S. aureus ATCC 700698. In addition, CuEO significantly inhibited bacterial biofilm formation. Microscopic analysis showed that CuEO damaged the bacterial membrane by leaching out the cytoplasmic content. Therefore, the results of this study show that the essential oil of C. urticifolius may be a promising natural alternative for preventing infections caused by bacterial biofilms. This study is the first to report the antibiofilm activity of C. urticifolius essential oil., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Croton laui (Euphorbiaceae) is a traditional medicinal plant used by the Li ethnic group in China to treat headaches, stomachaches, and diphtheria. To understand the pharmacological basis of its medicinal use, an extensive investigation of the ethanolic extract of the bark of C. laui was performed. After repeated chromatography, twenty-four undescribed labdane-type diterpenoids, lauinoids A-X (1-24), and five known analogs (25-29) were isolated. Their structures and absolute configurations were established using a combination of spectroscopic analyses, electronic circular dichroism, nuclear magnetic resonance calculations, and single-crystal X-ray diffraction. Among them, compounds 1-3 exhibited an 11(12 → 13)-abeo-16-nor-labdane skeleton, which originated putatively from 9 through a plausible pathway that involves a semipinacol rearrangement process. Compounds 11 and 12 belong to the rare class of 14,15-dinor-labdane diterpenoids. Compounds 18 and 28 exhibited substantial inhibitory effects by suppressing lipopolysaccharide-induced NO production in RAW 264.7 macrophages, with IC 50 values of 3.37 ± 0.23 and 5.82 ± 0.28 μM, respectively. This study has greatly expanded the chemical diversity of labdane diterpenoids from C. laui and will guide future research on this ethnomedicinal plant., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Melanoma is a cancer type with high lethality, metastatic capacity, and limited therapeutic options. Different essential oils have been reported with antitumoral potential. Thus, the essential oil (EO) of the leaves of C. floribundus was obtained by hydrodistillation and analyzed by GC-MS. The majority of substances annotated were β-selinene, E-Caryophyllene, and Premnaspirodiene. The cytotoxic activity of EO was evaluated on three melanoma cell lines SKMEL-147, WM-1366, and CHL-1, which are representative of metastatic melanoma with different mutation profiles. The IC 50 values found for EO were lower than temozolomide (reference drug) in all melanoma cell lines. In addition, the selectivity of EO was upward when compared to the reference drug. Interestingly, the WM-1366 cell line was the most responsive, and these findings are very promising considering that it has shown high resistance to the plethora of compounds. Thus, the C. floribundus EO is a promising source to drive further studies for the development of new treatments for metastatic melanoma, which is urgently relevant given the resistance of this pathology to current treatments., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Crotonyanes A ( 1 ) and B ( 2 ), two new cembranoids were isolated from the leaves and twigs of Croton yanhuii Y. T. Chang. Their structures were elucidated by extensive spectroscopic analyses and quantum chemical calculations. Bioassays verified that compound 1 exhibited an inhibitory effect on nitric oxide (NO) production in RAW 264.7 cells, with an IC 50 value of 30.6 ± 4.3 µM.

Green silver nanoparticles (G-Ag NPs) have contributed to the development of ecological technologies with low environmental impact and safer for human health, as well as demonstrating potential for the control of vectors and intermediate hosts. However, knowledge about its toxicity in the early stages of gastropod development remains scarce. Therefore, the current study aimed to investigate the toxicity of G-Ag NPs synthesized from Croton urucurana leaf extracts in snail species Biomphalaria glabrata, which is an intermediate host for Schistosoma mansoni parasite. G-Ag NPs were synthesized using two types of plant extracts (aqueous and hydroethanolic) and characterized using multiple techniques. Bioassays focused on investigating G-Ag NPs and plant extracts were carried out with embryos and newly hatched snails, for 144 h and 96 h, respectively; toxicity was analyzed based on mortality, hatching, development inhibition, and morphological changes. Results have shown that both G-Ag NPs were more toxic to embryos and newly hatched snails than the investigated plant extracts. G-Ag NPs deriving from aqueous extract have higher molluscicidal activity than those deriving from hydroethanolic extract. Both G-Ag NPs induced mortality, hatching delay, development inhibition, and morphological changes (i.e., hydropic embryos), indicating their molluscicidal activities. Moreover, embryos were more sensitive to G-Ag NPs than newly hatched snails. Thus, the toxicity of G-Ag NPs to freshwater snails depends on the type of extracts and the snail's developmental stages. These findings can contribute to the development of green nanobiotechnologies applicable to control snails of medical importance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Thirty-two diterpenoids including 18 ent-kauranes (1-6, and 12-23), nine 8,9-seco-ent-kauranes (7-8, and 24-30), four ent-abietanes (9-10, and 31-32), and one crotofolane (11) were isolated from the twigs and leaves of Croton kongensis. The structures of previously unreported crokokaugenoids A-H (1-8), crokoabiegenoids A-B (9-10), and crokocrotogenoid A (11) were determined by spectroscopic data analyses, TDDFT-ECD and GIAO NMR calculations, and X-ray crystallographic studies. All compounds were evaluated for their cytotoxic activity against five human tumor cell lines, and the structure-activity relationships were discussed. Biological tests exhibited that compound 1 possessed strong anti-proliferation activity, arrested cell cycle at G2/M phase, and induced cell apoptosis of MDA-MB-231. The mechanism investigation showed that compound 1 can inhibit tumor proliferation and migration by targeting mitochondria to increase intracellular reactive oxygen species (ROS) and regulating STAT3 and FAK signal pathways. Collectively, these findings supported the great potential of compound 1 as a hopeful anticancer agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Eighteen compounds including eleven previously undescribed diterpenes were isolated from the leaves of Croton mangelong. The structures were determined by HRESIMS, IR, NMR, X-ray diffraction and ECD spectroscopic analysis. All isolates were assayed for their anti-hyperglycemic activities in insulin resistance (IR) 3T3-L1 adipocytes, and compound 4 was tested for its anti-diabetic activity in vivo. Results suggested compound 4 could effectively reduce blood glucose level in diabetic SD rats in a dose of 30 mg/kg., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Two new heptapeptides, [1-7-NαC]-crocaorbs A1 (1) and A2 (2), were isolated from the latex of Croton campanulatus. Their structures were determined using NMR spectroscopic techniques, ESI-HRMS data, Marfey's method, and further refined using molecular dynamics with simulated annealing (MD/SA). Molecular dynamics calculations of peptides 1 and 2 demonstrated greater stability in simulations using a biological solvent compared to those using DMSO. Compound 1, the most abundant peptide in latex, was assessed for NO production, antiplasmodial and cytotoxicity activities. The peptide significantly increased nitric oxide (NO) production at concentrations of 40, 20 or 10 μM (17.932 ± 1.1, 18.270 ± 0.9, 18.499 ± 0.7, respectively). Its antiplasmodial activity exhibited limited efficacy, with only 5% inhibition of Plasmodium falciparum 3D7 growth at a concentration of 50 μM. Also, it exhibited no cytotoxic effects in the J774A.1 murine macrophages cell line. This study represents the first report of a phytochemical investigation of the species C. campanulatus, which showed orbitides with distinctive sequences in contrast to other peptides described for the genus Croton and contributes to the study of structural diversity within this particular class of compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer., Aim of the Study: At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root., Materials and Methods: Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets., Results: Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50  = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax., Conclusions: Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Methodology: The chemical constituents of LCT were identified and quantified using high-performance liquid chromatography with a diode array detector. A characteristic fingerprint was then established and combined with multivariate statistical analysis of 16 common peaks and eight diterpenoids to identify the quality markers., Introduction: The leaves of Croton tiglium (LCT) have long been used in folk and ethnic medicine in China. Owing to the various regions, the chemical composition and content of LCT may differ, and hence, the quality of medicinal materials may be different. However, quality standards have not yet been established, although some studies have been conducted on their composition., Objectives: To quantitatively compare the chemical constituents of LCT from different areas and establish a quality evaluation of LCT based on quality markers., Results: Eight quality markers selected based on 16 common peaks and three quality markers selected based on eight diterpenoids can distinguish LCT from three regions. The diterpenoids, including 12-O-acetylphorbol-13-(2-methylbutyrate) (3), 12-O-tiglyl-4-deoxy-4α-phorbol-13-acetate (6), and 12-O-(2-methyl)butyrylphorbol-13-tiglate (8), can be used as potential quality markers for the quality evaluation of LCT., Conclusion: Diterpenoids are highly efficient markers for quality evaluation. This study provides robust identification data and lays the foundation for formulating quality standards for LCT., (© 2024 John Wiley & Sons Ltd.)

Croton antisyphiliticus Mart. is a plant popularly used in folk medicine by traditional communities from Brazilian savannah to treat general inflammation. According to ethnopharmacological data, this specie can be considered a source of biologically active molecules for the development of new drugs. Thereby, this study reports the results of the dereplication approach of C. antisyphiliticus roots extracts and the in vivo evaluation of its potential antinociceptive and anti-inflammatory in albino Swiss mice. Based on HPLC coupled to Q-Exactive Orbitrap Mass Spectrometer and using GNPS, a total of thirteen polyphenolic compounds were noticed, including four compounds that have been reported for the first time in the genus Croton . Ethanolic and aqueous roots extracts demonstrated a dose-dependent inhibition for the number of writes, reduced pain induced by formalin and hyperalgesia induced by carrageenan. These extracts also reduced paw edema, cell migration, and myeloperoxidase activity, with effects similar to indomethacin and dexamethasone drugs.

A new clerodane diterpenoid, crotolanin A ( 1 ), along with three known clerodane diterpenoids, crotoeurin B ( 2 ), teucvidin ( 3 ) and teucvin ( 4 ), was isolated from the ethanol extract of the leaves and twigs of Croton lachnocarpus Benth. Their structures were identified by extensive NMR spectroscopic and HRESIMS analyses. The dopaminergic neuroprotective activity of compounds 1 - 4 was tested by using transgenic Caenorhabditis elegans pathological model. Compound 2 alleviated dopaminergic neuron degeneration of worms induced by 6-hydroxydopamine (6-OHDA) that represented a potential therapy for Parkinson's disease (PD).

Croton heliotropiifolius Kunth, popularly known as "velame," is a shrub that resides in northeastern Brazil. The essential oil of C. heliotropiifolius contains high concentrations of volatile compounds in the leaves and is widely used in folk medicine for many purposes as an antiseptic, analgesic, sedative, and anti-inflammatory agent. Due to the apparent limited amount of information, the aim of this study was to determine the cytotoxic potential of essential oil extracted from leaves of C. heliotropiifolius , utilizing different human cancer cell lines (HL-60, leukemia; HCT-116, colon; MDA-MB435, melanoma; SF295, glioblastoma) and comparison to murine fibroblast L929 cell line. The chemical characterization of the essential oil revealed the presence of large amounts of monoterpenes and sesquiterpenes, the majority of which were aristolene (22.43%), germacrene D (11.38%), ɣ-terpinene (10.85%), and limonene (10.21%). The essential oil exerted significant cytotoxicity on all cancer cells, with low activity on murine L929 fibroblasts, independent of disruption of cell membranes evidenced by absence of hemolytic activity. The cytotoxicity identified was associated with oxidative stress, which culminated in mitochondrial respiration dysfunction and direct or indirect DNA damage (strand breaks and oxidative damage), triggering cell death via apoptosis. Our findings suggest that extracts of essential oil of C. Heliotropiifolius may be considered as agents to be used therapeutically in treatment of certain cancers.

Ethnopharmacological Relevance: Croton blanchetianus Baill., popularly known as "marmeleiro preto", is an endemic plant from Brazil, being found mainly in the Northeast region. In traditional medicine, the use of medicines based on the leaves of this plant has been reported for the treatment of inflammatory processes, pain, urethral pain, gastrointestinal disorders, rheumatism and headache., Aim of the Study: The present work describes the chemical characterization, as well as toxicological evaluation and antinociceptive activity of an essential oil of C. blanchetianus leaves (EOCb)., Materials and Methods: The chemical constituents of the oil were identified by gas chromatography coupled to mass spectrometry (GC-MS). In vitro hemolytic activity was tested using mouse blood. Acute toxicity in mice was assessed by the oral or intraperitoneal administration of a single dose of 2000 mg/kg b.w. EOCb (1000 and 2000 mg/kg) was also evaluated for genotoxicity and antigenotoxicity in vivo using the micronucleus test. The antinociceptive activity of EOCb (25, 50 and 100 mg/kg) was evaluated through the abdominal writhing, formalin and tail flick tests., Results: The chemical characterization indicated as major components α-pinene (21.23%), β-phelandrene (13.92%), terpinolene (13.01%) and germacrene D (10.89%). EOCb did not cause hemolysis and was also neither toxic nor genotoxic, while protected the animals' bone marrow cells from damage caused by cyclophosphamide in oral treatment. However, all animals died after 15 min of intraperitoneal treatment. There was a reduction in the number of abdominal contortions (69.43-89.41%) as well as in licks in the first (38.77-84.47%) and second (59.75-90.74%) phases of the formalin test. In the latter case, the effects were reduced by naloxone and glibenclamide, indicating action via the opioid system and blockage of K+ channels. The latency time in the tail flick test also increased significantly., Conclusion: In conclusion, ingestion of EOCb proved to be safe when administered orally; however, it was lethal intraperitoneally. Additionally, EOCb protected mouse blood cell DNA against the action of cyclophosphamide and showed an antinociceptive effect via the opioid system and dependent on K+ channels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Croton cajucara Benth showed several pharmacological properties such as: antiinflammatory, antinociceptive hypoglycemic, lipid-lowering, antiulcer, antiestrogenic, antitumor, antigenotoxic, antimutagenic, and cardiovascular. The 19- nor -clerodane diterpene transdehydrocrotonin ( t -DCTN or DCTN) is the major bioactive constituent extracted from the bark of this Croton . Patents for Croton cajucara Benth in the period 2015 to 2022 comprises 14 published documents. Among them 4 patents are colloidal systems (SM/SNEDDS) loading t -DCTN for pharmacological applications. Patent registrations highlighted the huge promising biotechnological potential of Croton cajucara Benth especially in the phytotherapy field, and the correlation with its bioactive constituents of which t -DCTN showed the foremost results, so this herbal could become an alternative in the treatment of COVID-19. However, investigation of more recently published patents for clerodane diterpenes with similar chemical structure of t -DCTN, who previously showed antiviral property must be carried out and should be searched on several patent data bases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chromatographic separation of the leaves of Croton krabas resulted in the isolation of one new clerodane, crotoeurin D (1), along with two known compounds, 6S-crotoeurin C (2) and blumenol A (3). Their structures were determined based on extensive nuclear magnetic resonance spectroscopic data analysis and mass spectrometry. The absolute configuration of the new clerodane was assigned by nuclear overhauser effect spectroscopy correlations and electronic circular dichroism calculations. Compound 1 exhibited significant acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, the binding modes of 1 revealed that its structure formed strong hydrogen bonds and hydrophobic interactions with the active sites of both enzymes., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

The development of new drugs through studies of candidate molecules is a complex undertaking; however, computational or in silico approaches aimed at optimizing molecules with greater development potential are being utilized for predictions of pharmacokinetic properties such as absorption, distribution, metabolism and excretion (ADME) as well as toxicological parameters. The objective of this study was to examine in silico and in vivo pharmacokinetic and toxicological properties of the chemical constituents present in the essential oil of Croton heliotropiifolius Kunth leaves. The following Pubchem platform as well as Software SwissADME and PreADMET software were employed for in silico studies while micronucleus (MN) testing for in vivo determination of mutagenicity, using Swiss adult male Mus musculus mice. In silico findings demonstrated that all chemical constituents presented (1) high oral absorption (2) medium cellular permeability and (3) high blood brain permeability. As for toxicity, these chemical constituents exhibited low to medium risk of occurrence of cytotoxicity. Regarding in vivo evaluation, peripheral blood samples obtained from animals tested with the oil showed no significant differences in number of MN compared to negative controls. Data indicate that further investigations are necessary to corroborate the findings of this study. Our data suggest that essential oil extracted from Croton heliotropiifolius Kunth leaves may serve as a candidate for new drug development.

Croton grewioides Baill. is an aromatic species with proven bioactive properties. Considering the potential of the species, the aim of this study was to chemically characterize and evaluate the in vitro antibacterial activity of the essential oils of C. grewioides on Xanthomonas campestris pv. campestris. The essential oils of the accessions of C. grewioides were extracted by the hydrodistillation method and analyzed by gas chromatography - mass spectrometry. For determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the essential oils and of the compound eugenol, the microdilution method was used at concentrations that ranged from 125 to 4000 μg.mL -1 . Streptomycin sulfate was used as a positive control (12.5 to 100 μg.mL -1 ). Growth kinetics and the membrane permeability trial were evaluated for the concentrations 2×, 1×, 1/2×, 1/4×, and 1/8× MIC of the essential oil CGR-108. The major compounds identified in the essential oils were eugenol, methyl eugenol, and methyl chavicol. The essential oil of the accession CGR-108 had a lower MIC (> 500 and < 1000 μg.mL -1 ) and MBC equal to <2000 μg.mL -1 . For eugenol, MIC was obtained with contractions >250 and < 500 μg.mL -1 and MBC with >500 μg.mL -1 and < 1000 μg.mL -1 . A loss of cell viability of the bacteria was observed after 30 min of exposure to the essential oil of the accession CGR-108 at the concentrations of 2× and 1× MIC, which was proven by the fluorescence intensity with propidium iodide. The essential oils of Croton grewioides Baill. and the compound eugenol show antibacterial potential on Xanthomonas campestris pv. campestris., Competing Interests: Declaration of Competing Interest The authors declare that does not exist an interest conflict., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To this day, since about 50% of all medicines are derived from natural sources, natural product chemistry, especially the search for biologically active natural components, remains extremely important (Newman and Cragg in J Nat Prod 83:770-803, 2020). In this review, we deal with our continuing research work for promising constituents from plants collected in the Ryukyu Archipelago. The isolation of islands in the archipelago by the sea or by straits gives rise to endemic plant species that are unique to the islands. The structural diversity of the constituents produced by this unique flora is of great scientific interest in various aspects, including chemical structures, biosynthesis, and biological activities. The components from this structural diversity have great potential as new pharmaceutical seeds. In our continuing studies, we have successfully investigated new but extremely unusual diterpenoids: crotofolanes and their rearranged varieties (nor-crotofolane, trinor-crotofolane, neocrotofolane) and a glycoside with a new skeletal diterpenoid (isocrotofolane glucoside) from Croton cascarilloides. This review summarizes our reports on the investigation of crotofolanes as well as those on crotofolanes by other research groups., (© 2023. The Author(s).)

Laeviganoids A-T ( 1 - 20 ), 20 new ent -clerodane-type diterpenoids featuring a 2-furanone ( 1 - 3 ) or a furan ( 4 - 20 ) ring, as well as six analogues ( 21 - 26 ), were isolated from the roots of Croton laevigatus . Their structures were determined by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallographic studies. Compounds 4 - 6 , 16 , 21 - 24 , and 26 could influence the anti-inflammatory protumoral phenotype of macrophages. Among these compounds, 21 and 26 are the most potent, as evidenced by consistently downregulating the classic anti-inflammatory cytokine IL-10 and upregulating the classic pro-inflammatory cytokine TNF-α on the secretion level in RAW 264.7 cells.

A phytochemical investigation on the 90% ethanol extract of the leaves of Croton lachnocarpus Benth. led to three new ent -abietane diterpenoids, 7 β ,15-dihydroxy- ent -abieta-8,11,13-trien-3-one ( 1 ), 2 β ,15-dihydroxy- ent -abieta-8,11,13-triene ( 2 ), and 7 β ,13 α ,15-trihydroxy- ent -abieta-8(14)-en-3-one ( 3 ). Structural elucidation of all the compounds were performed by spectral methods such as 1 D and 2 D ( 1 H - 1 H COSY, HMQC, NOESY and HMBC) NMR spectroscopy, in addition to electronic circular dichroism (ECD) spectra. The isolated compounds were tested in vitro for cytotoxic activity against 6 tumor cell lines. As a result, compound 3 exhibited some cytotoxicities against all the tested tumor cell lines with IC 50 value less than 30 μM.

In this study, liquid chromatography and mass spectrometry were used to screen the active phytochemicals and analyze antioxidant activity of Croton bonplandianum. In addition, cadmium telluride quantum dots were used to analyze the fluorescence quenching capabilities of Croton bonplandianum plants. UPLC-ESI-MS was used to screen polyphenols in the mass range of 100-2000, with both positive and negative ionizations. Based on molecular weight, 7-Spirostanoldihexoside isomer, Rutin, Quercetin hexoside, Kaempferol-3-O-(p-coumaroyl)-glucoside, Kaempferol, Quercetin, and (E) Catechin-(E) Gallocatechin were tentatively identified. In total, 63.34 mg of polyphenols and 20.36 mg of flavonoids were detected. Lipid peroxidation IC 50 values were 212, 38, 56, and 365 g/mL for DPPH, ABTS, and superoxide radicals. Reducing power of the plant material showed the maximum absorbance of 0.56 in 500 μg/mL concentration. Furthermore, the plant extract quenched cadmium telluride quantum dots fluorescence in a dose dependent manner. The results from quenching concluded that Croton bonplandianum with QDs might be used as a drug targeting and delivery nanomaterial., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Using essential oils to control vectors, intermediate hosts, and disease-causing microorganisms is a promising approach. The genus Croton in the family Euphorbiaceae is a large genus, with many species containing large amounts of essential oils, however, essential oil studies are limited in terms of the number of Croton species investigated. In this work, the aerial parts of C. hirtus growing wild in Vietnam were collected and analyzed by gas chromatography/mass spectrometry (GC/MS). A total of 141 compounds were identified in C. hirtus essential oil, in which sesquiterpenoids dominated, comprising 95.4%, including the main components β-caryophyllene (32.8%), germacrene D (11.6%), β-elemene (9.1%), α-humulene (8.5%), and caryophyllene oxide (5.0%). The essential oil of C. hirtus showed very strong biological activities against the larvae of four mosquito species with 24 h LC 50 values in the range of 15.38-78.27 μg/mL, against Physella acuta adults with a 48 h LC 50 value of 10.09 μg/mL, and against ATCC microorganisms with MIC values in the range of 8-16 μg/mL. In order to provide a comparison with previous works, a literature survey on the chemical composition, mosquito larvicidal, molluscicidal, antiparasitic, and antimicrobial activities of essential oils of Croton species was conducted. Seventy-two references (seventy articles and one book) out of a total of two hundred and forty-four references related to the chemical composition and bioactivity of essential oils of Croton species were used for this paper. The essential oils of some Croton species were characterized by their phenylpropanoid compounds. The experimental results of this research and the survey of the literature showed that Croton essential oils have the potential to be used to control mosquito-borne and mollusk-borne diseases, as well as microbial infections. Research on unstudied Croton species is needed to search for species with high essential oil contents and excellent biological activities.

Six new crotofolane diterpenoids ( 1 - 6 ) and 13 known compounds ( 7 - 19 ) were isolated from the MeOH-CH 2 Cl 2 (1:1, v/v) extracts of the leaves and stem bark of Croton kilwae . The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A ( 1 ) was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configuration. The crude extracts and the isolated compounds were investigated for antiviral activity against respiratory syncytial virus (RSV) and human rhinovirus type-2 (HRV-2) in HEp-2 and HeLa cells, respectively, for antibacterial activity against the Gram-positive Bacillus subtilis and the Gram-negative Escherichia coli , and for antimalarial activity against the Plasmodium falciparum Dd2 strain. ent -3β,19-Dihydroxykaur-16-ene ( 7 ) and ayanin ( 16 ) displayed anti-RSV activities with IC 50 values of 10.2 and 6.1 μM, respectively, while exhibiting only modest cytotoxic effects on HEp-2 cells that resulted in selectivity indices of 4.9 and 16.4. Compounds 2 and 5 exhibited modest anti-HRV-2 activity (IC 50 of 44.6 μM for both compounds), while compound 16 inhibited HRV-2 with an IC 50 value of 1.8 μM. Compounds 1 - 3 showed promising antiplasmodial activities (80-100% inhibition) at a 50 μM concentration.

Biscroyunoid A ( 1 ), a 19- nor -clerodane diterpenoid dimer featuring a unique C-16-C-12' linkage and containing an unusual 4,7-dihydro-5 H -spiro[benzofuran-6,1'-cyclohexane] motif, together with its biosynthetic precursor, croyunoid A ( 2 ), were isolated from Croton yunnanensis . Their structures were determined by spectroscopic, computational, and single-crystal X-ray diffraction methods. Compound 1 exerted an antihepatic fibrosis effect in LX-2 cells via inhibition of TGFβ-Smad2/3 signaling.

Crotofoligandrin ( 1 ), a new endoperoxide crotofolane-type diterpenoid was isolated from the dichloromethane/methanol (1:1) extract of the twigs of Croton oligandrus Pierre Ex Hutch along with thirteen known secondary metabolites including 1-nonacosanol ( 2 ), lupenone ( 3 ), friedelin ( 4 ), β -sitosterol ( 5 ), taraxerol ( 6 ), (-)-hardwickiic acid ( 7 ), apigenin ( 8 ), acetyl aleuritolic acid ( 9 ), betulinic acid ( 10 ), fokihodgin C 3-acetate ( 11 ), D-mannitol ( 12 ), scopoletin ( 13 ) and quercetin ( 14 ). The structures of the isolated compounds were determined based on their spectroscopic data. The crude extract and the isolated compounds were assessed in vitro for their antioxidant, lipoxygenase, butyrylcholinesterase (BChE), urease and glucosidase inhibitory potentials. Compounds 1 - 3, and 10 displayed activities on all the performed bioassays. All the tested samples showed strong to significant antioxidant activity with compound 1 being the most potent (IC 50 39.4 μM)., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Fifteen compounds including nine new diterpenes were isolated from the roots of Croton yunnanensis . By HRESIMS, NMR, ECD data, and X-ray diffraction analysis, the new compounds were characterized as eight neo -clerodane diterpenes (compounds 1 - 8 ) and one 15,16-dinor- ent -pimarane diterpene ( 9 ). All diterpenes were assayed for their hypoglycemic activities. Compounds 1 - 4 , 6 , 7 , and 10 promoted glucose uptake activity in insulin-resistant 3T3-L1 adipocytes. Compounds 1 and 6 showed insulin sensitizing activity, potentiating conspicuously their glucose uptake activity at a concentration of 20 μM when treated synergistically with low-concentration insulin at 1 nM.

Croton kongensis Gagnepain. belongs to the genus Croton, the Euphorbiaceae family, mainly distributed in Hainan and southern Yunnan, China. The aim of present study was to acquire secondary metabolites of the ethanol extract obtained from the leaves and twigs of C. kongensis. Three new abietane-type diterpenoids, crokongenolides A-C (1-3), together with seven known diterpenoids (4-10), were isolated from the leaves and twigs of C. kongensis. The structures of the new compounds were determined by extensive spectroscopic methods (1D and 2D NMR, IR, and HRESIMS), and their absolute configurations were confirmed by single-crystal X-ray diffraction analysis or electronic circular dichroism (ECD) calculations. The absolute configuration of 4 was determined for the first time by single-crystal X-ray diffraction analysis with Cu-Kα irradiation. Some compounds were evaluated for their antimicrobial properties by assessing their inhibitory effects on Staphylococcus aureus, Candida albicans, and Escherichia coli. Compound 10 showed significant antimicrobial activity against S. aureus with MIC value of 1.56 μg/ml., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Three new ent -abietane diterpenoids, 6 β -hydroxy- ent -abieta-7,13-dien-3-one ( 1 ), 2 β ,13 α ,15-trihydroxy- ent -abieta-8(14)-en-3-one ( 2 ), and 2 β ,9 α ,13 β ,15-tetrahydroxy- ent -abieta-7-en-3-one ( 3 ), were isolated from 90% ethanol extract of the leaves of Croton cascarilloide . Their structures were determined by spectral methods such as 1D and 2D ( 1 H - 1 H COSY, HMQC, NOESY, and HMBC) NMR spectroscopy, in addition to electronic circular dichroism (ECD) spectra. The isolated diterpenoids were tested in vitro for antimicrobial activity against 6 pathogenic microorganisms. As a result, compounds 1-3 exhibited antimicrobial activity against the tested Gram positive bacteria with minimum inhibitory concentration values less than 50 μg/ml.

Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from Croton crassifolius, has not been previously reported for its anticancer effects in HCC. This study aims to evaluate the inhibitory effects of MLD in HCC and explore the underlying mechanism. We found that the cell proliferation, DNA synthesis, and colony formation of HepG2 cells and the angiogenesis of HUVECs were all greatly inhibited by MLD. MLD caused mitochondrial damage and decreased the TOM20 expression and mitochondrial membrane potential, inducing ROS overproduction. Moreover, MLD promoted the cytochrome C from mitochondria into cytoplasm, leading to cleavage of caspase-9 and caspase-3 inducing GSDMD-related pyroptosis. In addition, we revealed that MLD activated mitophagy by inhibiting the PI3K/AKT/mTOR pathway. Using the ROS-scavenging reagent NAC, the activation effects of MLD on pyroptosis- and autophagy-related pathways were all inhibited. In the HepG2 xenograft model, MLD effectively inhibited tumor growth without detectable toxicities in normal tissue. In conclusion, MLD could be developed as a candidate drug for HCC treatment by inducing mitophagy and pyroptosis via promoting mitochondrial-related ROS production.

Leaves of Croton argyrophyllus contain essential oil with promising active components for the development of drugs and botanical insecticides. In this study, we evaluated the enzymatic pretreatment process to increase the extraction of essential oil from fresh and dried leaves of C. argyrophyllus. Pretreatment was carried out using a crude multienzymatic extract obtained via solid-state fermentation of forage palm by Aspergillus niger, and the extraction was performed by hydrodistillation. A Doehlert matrix was used to optimize the enzymatic pretreatment variables temperature and enzymatic extract. The effect of pretreatment time was also investigated. At optimum experimental conditions, 41.34°C, 140 min, and 130.73 mL of enzyme in 369.27 mL of water, the essential oil yield from fresh leaves subjected to enzymatic pretreatment increased by 9.35% and that from dry leaves by 6.77%. Based on chromatographic analysis (GC-MS), no compound was degraded in the extraction process. Micromorphological analysis confirmed the rupture of the glandular trichomes, favoring essential oil release. Therefore, enzymatic pretreatment associated with hydrodistillation increased the essential oil yield and is a promising application to obtain essential oil for therapeutic purposes without altering its composition., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

Two new clerodane diterpenoids (1 and 2), a new pyran-2-one derivative (3), along with five known compounds (4‒8), were isolated from Croton crassifolius. Notably, crassifolin X (1) is a novel clerodane diterpenoid, characterized with a peculiar δ-lactone core being formed between C-1 and C-4. Their structures, including absolute configurations, were established on the basis of spectroscopic methods (UV, IR, HRESIMS and NMR), and circular dichroism experiments. In addition, all compounds were evaluated for their anti-neuroinflammatory activities based on the expression of TNF-α and IL-6 levels on LPS-induced BV2 cells, and compounds 1‒3 and 5 showed potential anti-neuroinflammatory activity., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

An undescribed tigliane diterpenoid, 13-acetyl-12,17-di-O-tiglylphorbol (1), along with thirty-three known components, were isolated from the stems of Croton tiglium L. var. xiaopadou (Euphorbiaceae). Their structures were established based on spectroscopic data and ECD spectra. Their anti-neuroinflammatory effects were evaluated in LPS-induced BV-2 microglia. Thirteen tested compounds showed significant inhibitory activities, especially compounds 10, 16, 18 and 21 exhibited an inhibitory effect with IC 50 values in the range of 12.39 to 17.80 μM, which are comparable with that of the positive control (minocycline, IC 50 13.92 μM)., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Objectives: Croton tiglium Linn. (Euphorbiaceae) is an ancient medicinal plant that has been used for a long time, which is widely distributed in tropical and subtropical regions. And it is widely used for defecation, induced labour, treatment of gastrointestinal diseases, headache, as well as rheumatoid arthritis., Key Findings: Approximately 150 compounds have been isolated and identified from the seeds, stems, leaves and branches of C. tiglium, including fatty acids, terpenoids, alkaloids, the plants proteins and other types of components. Based on a wide range of biological properties, C. tiglium has a wide range of pharmacological effects, such as antitumor, anti-HIV, analgesic, anti-inflammatory and antibacterial effects., Summary: The review aims to provide a critical and comprehensive evaluation of the botany, phytochemistry, pharmacology and toxicity of C. tiglium, with a vision for promoting further pharmaceutical research to explore its complete potential for better clinical application. The tigliane diterpenoids have been the most studied compounds isolated from C. tiglium, which showing a variety of biological activities, but there is insufficient evidence to explain the mechanism of action. In addition, C. tiglium may have potential toxic effects, and it is necessary to reduce the toxic effects to ensure the safety of clinical medication, which may promote the discovery and development of new drugs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

One new clerodane-type diterpenoid, together with one known, was isolated from the leaves and twigs of C. krabas . The structures of these compounds were elucidated as krabasinolide A ( 1 ) and taraxerol ( 2 ) by spectroscopic methods (UV, IR, HRESIMS, 1 D, and 2 D NMR), and the relative stereochemistry was confirmed by X-ray diffraction analysis with graphite monochromated Mo-Kα (λ = 0.71073 Å) radiation at 296(2) K. Extracts and compounds 1 - 2 were evaluated for in vitro antiviral activity.

Objective: Croton tiglium L. seeds were studied against colon cancer induced chemically in rats after incorporating silver nanoparticles (Ag-NPs) but the body has no the ability to discrete silver or silver ions. Therefore, the present study was designed to reveal the biological activities of different C. tiglium L. seeds extracts incorporated with zinc oxide nanoparticles (ZnO-NPs)., Results: It was found that C. tiglium L. seeds provided with high contents of total protein (27.43 g/100g), carbohydrate (18.29 g/100 g) and lipid (46.31 g/100 g). The chromatographic techniques revealed that concentrations of the predominant compounds increased in all studied extracts (ethanolic, aqueous and petroleum ether) after incorporating ZnO-NPs. The in vitro biological activities showed that the aqueous extract possessed the highest antioxidant and scavenging activities. It exhibited the highest inhibitory effect on α-amylase (41.89%) and acetyl cholinesterase (AChE) (23.00%) in addition to its higher anti-arthritic activity. All the biological activities increased after incorporating ZnO-NPs. It showed the highest cytotoxic activity that increased after incorporating ZnO-NPs against human colon carcinoma (CACO-2) cells. Therefore, this extract was selected for undergoing further studies on CACO-2 cells. The aqueous extract incorporated with ZnO-NPs arrested growth of CACO-2 cells at G2/M and increased percentage of total apoptotic cells and necrosis. The median lethal dose (LD50) showed that the extracts incorporated with ZnO-NPs were safer than the native extracts., Conclusion: The study showed that the aqueous extract was the most active extract that consequently exhibited promising biological activities after incorporating ZnO-NPs.

Crotonianoids A-C ( 1 - 3 ), three unusual tigliane diterpenoids, were isolated from the seeds of Croton tiglium . Compound 1 is a 13,14:13,15- diseco -tigliane featuring a unique spiro[bicyclo[5.3.0]decane-2,5'-2'(3' H ,4' H )-furanone] core; 2 is a 13,15- seco -tigliane incorporating a rare peroxide bridge between C-13 and C-15; and 3 is the first example of a phorbol ester with a 10 R -configuration. Their structures were determined by spectroscopic, computational, and X-ray diffraction methods. Compounds 1 and 2 markedly inhibited the growth and survival of prostate cancer cell C4-2B at micromolar concentrations and induced cell apoptosis. Mechanistic study revealed that 1 and 2 could suppress androgen receptor (AR) signaling pathway by promoting the degradation of AR protein.

Croton macrostachyus is an important plant in traditional African medicine, widely utilized to treat a variety of diseases. In Kenya, HIV-infected patients use leaf and root decoctions of the plant as a cure for cough, back pain, bleeding, skin diseases, warts, pneumonia, and wounds. This study aimed to evaluate the anti-HIV activities and cytotoxic effects of extracts and chemical constituents isolated from C. macrostachyus. In our previous study we demonstrated that the hexane, CH 2 Cl 2 , ethyl acetate and methanol soluble fractions of a 1:1 v/v/ CH 2 Cl 2 /MeOH crude extracts of the leaves and stem bark of C. macrostachyus exhibited potent anti-HIV activities against HIV-1 with IC 50 values ranging from 0.02-8.1 μg/mL and cytotoxicity effects against MT-4 cells ranging from IC 50  = 0.58-174 μg/mL. Hence, hexane soluble extract of 1:1 v/v/ CH 2 Cl 2 /MeOH crude extract of the leaves of C. macrostachyus, that was more potent against HIV-1 at IC 50  = 0.02 μg/mL was subjected to column chromatography leading to the isolation of 2-methoxy benzyl benzoate (1), lupenone (2), lupeol acetate (3), betulin (4), lupeol (5), sitosterol (6) and stigmasterol (7). Lupenone (2), lupeol acetate (3) and betulin (4) exhibited anti-HIV-1 inhibition at IC 50  = 4.7 nM, 4.3 and 4.5 μg/mL respectively. The results obtained from this study support the potential of C. macrostachyus, as a source of anti-HIV constituents., (© 2022. The Author(s).)

One new sesquiterpenoid, 10-epi-lochmolin F (1), together with 13 known sesquiterpenoids, was isolated from the roots of Croton crassifolius. The structures of these compounds were confirmed by UV, IR, MS, and NMR spectroscopic analysis. The absolute configuration of compound 1 was elucidated by analysis of X-ray crystallography. All the 14 isolated sesquiterpenoids were screened for their inhibitory effects on ferroptosis in HT-22 cells. Two compounds 4 and 7 showed certain inhibitory effects against RSL3-induced ferroptosis with EC 50 values of 10.8±2.3 μM and 15.5±0.5 μM, respectively. Here we firstly reported the sesquiterpenoids from C. crassifolius showing inhibitory effect on ferroptosis., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Thirty-five tigliane diterpenoids and two ent -kaurane diterpenoids were isolated from the leaves of Croton damayeshu , and, among them, compounds 1 - 10 were characterized as new tigliane diterpenoids. The structures of compounds 1 - 10 were determined by analysis of their HRESIMS, NMR, and ECD data and by chemical methods. The isolates were assayed for their larvicidal, antifungal, and α-glucosidase inhibitory activities, and compounds 8 - 10 were found to possess larvicidal activities against Plutella xylostella with LC 50 values of 0.19, 0.16, and 0.26 μM, respectively, comparable to the LC 50 of 0.14 μM for the positive control, flubendiamide.

Nowadays, new leishmanicidal drugs are needed and natural products arise as a promising alternative source. Therefore, bioguided fractionation of a hydroethanolic extract from the stem bark of Croton echioides Baill. were conducted based on its antileishmanial activity. Two novel neo -clerodane diterpenoids methyl-15,16-epoxy-3,13(16),14- neo -clerodatrien-17,18-dicarboxylate ( 1 ) and dimethyl-3-oxo-15,16-epoxy-13(16),14- neo -clerodadien-17,18-dicarboxylate ( 2 ) were isolated, as well as four known compounds ( 3-6 ) and lupeol, from the hexane fraction. Their structures were established by NMR analysis. The crude extract, fractions and the compounds ( 1 and 3-6 ) were evaluated for their in vitro antileishmanial activity and cytotoxicity against macrophages J774A.1. The selectivity index (SI) were calculated. The most active compound against promastigote forms of L. amazonensis was the clerodane diterpene 4 , with IC 50 values of 8.3 µM and SI value of 80.9. Our results highlighted stem bark of Croton echioides Baill. as a promising source for the development of a new chemotherapeutic agent to combat leishmaniasis.

Croton lechleri, commonly known as Dragon's blood, is a tree cultivated in the northwest Amazon rainforest of Ecuador and Peru. This tree produces a deep red latex which is composed of different natural products such as phenolic compounds, alkaloids, and others. The chemical structures of these natural products found in C. lechleri latex are promising corrosion inhibitors of admiralty brass (AB), due to the number of heteroatoms and π structures. In this work, three different extracts of C. lechleri latex were obtained, characterized phytochemically, and employed as novel green corrosion inhibitors of AB. The corrosion inhibition efficiency (IE%) was determined in an aqueous 0.5 M HCl solution by potentiodynamic polarization (Tafel plots) and electrochemical impedance spectroscopy, measuring current density and charge transfer resistance, respectively. In addition, surface characterization of AB was performed by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy techniques. Chloroform alkaloid-rich extracts resulted in IE% of 57% at 50 ppm, attributed to the formation of a layer of organic compounds on the AB surface that hindered the dezincification process. The formulation of corrosion inhibitors from C. lechleri latex allows for the valorization of non-edible natural sources and the diversification of the offer of green corrosion inhibitors for the chemical treatment of heat exchangers.

Purpose: This study was aimed at investigating the protective effect of antioxidant-rich fraction of Croton zambsicus (C-ZAMB) leaves on ocular-gastrointestinal dysfunction in rats exposed to environmental mixed-metal (EOMABRSL)., Materials and Methods: The rats were divided into five ( n  = 10) groups. Group I designates the control which received 0.5 mL of distilled water. Group II and III received 0.5 mL of EOMABRSL for 98 days (non-withdrawal) and 70 days (withdrawal for 28 days), respectively. Group IV received 0.5 mL EOMABRSL for 70 days and 400 mg/kg C-ZAMB fraction for 28 days. Group V received 400 mg/kg C-ZAMB only for 28 days via oral route., Results: Exposure of the animals to EOMARBSL for 98 days and 70 days significantly up-regulated the activities of ocular-gastrointestinal aldolase-reductase, α-amylase, α-glucosidase and eco-5 1 -nucleotidase with corresponding depletion of lactate dehydrogenase activity. Furthermore, exposure to EOMABRSL significantly altered the antioxidant proteins with up-production of MDA content. Apparently, management with 400 mg/kg C-ZAMB fraction significantly inhibited the key markers linked with ocular-gastrointestinal disorders., Conclusion: Hence, this study underscores the biochemical mechanisms for managing ocular-gastrointestinal lesions by 400 mg/kg C-ZAMB fraction on exposure to mixture of environmental metals.

Four new 19-nor-clerodane diterpenoids (1-4), one new 15,16-dinor-ent-pimarane diterpenoid (5) together with four known diterpenoids (6-9) were isolated from whole plants of Croton yunnanensis. The structures of these compounds were determined by extensive spectroscopic methods including 1D, 2D NMR, HR-ESI-MS, and by comparing their NMR data with those of previously reported compounds. The experimental and calculated electronic circular dichroism data were used to define their absolute configurations. The 1 H and 13 C NMR spectra of 6 were completely assigned for the first time. All isolated compounds (1-9) were evaluated for their cytotoxic activities against five human cancer cell lines (including SMMC-7721, HL-60, A-549, MCF-7, and SW-480), and anti-inflammatory activities in LPS-induced RAW264.7 macrophages. Crotonyunnan E (5) exhibited selective cytotoxicities against three tumor cell lines, SMMC-7721 (human hepatoma cells, IC 50 4.47 ± 0.39 μM), HL-60 (human premyelocytic leukemia, IC 50 14.38 ± 1.19 μM), and A-549 (human lung cancer cells, IC 50 27.42 ± 0.48 μM), while none of the compounds showed obviously anti-inflammatory activities at 50 μM level., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Fifteen new labdane-type diterpenoids, sublyratins A-O ( 1 - 15 ), along with four known analogues ( 16 - 19 ) were isolated from the aerial parts of Croton sublyratus . Their structural assignments were challenging due to the stereoisomeric features evident and were achieved by analyzing comprehensively the spectroscopic data and electronic circular dichroism spectra and using X-ray crystallographic analysis. Compounds 9 and 16 - 18 displayed cytotoxic activity against the HL-60 cell line with IC 50 values of 1.5-2.8 μM.