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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.)

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.)

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.)

Phytochemical investigation of the leaves and twigs of Croton yanhuii led to the isolation of seven highly modified nor-clerodane diterpenoids (1-7), including three new ones, croyanoids A-C (1-3), along with four known analogues (4-7). Compound 1 incorporates a 5,12-epoxy ring, forming a unique cage-like, 6/6/6/5-fused tetracyclic ring system. Their structures were established by extensive spectroscopic analysis, and the absolute configurations of 1-4 were determined by a combination of circular dichroism (CD) analysis and single-crystal X-ray diffraction. All compounds were tested in an array of bioassays, but were inactive. Crotoeurin A (7), a nor-clerodane dimer with a high yield of 0.2‰ isolated in current study, was considered as a chemotaxonomic marker for this species., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The first phytochemical investigation from the stems of Croton krabas resulted in the isolation of three new ent-clerodane diterpenoids, crotonkrabases A-C (1-3), along with two known compounds, 12-oxohardwickiic acid (4) and crotonpyrone B (5). Their structures were elucidated using extensive spectroscopic methods. The structure of 3 was unambiguously proven by X-ray crystallography. Furthermore, the absolute configurations of compounds 1-3 were identified by NOESY and the comparison of their experimental ECD spectra with those of calculated ECD spectra reported in the literature. Compounds 1, 2, and 5 showed antibacterial activities against two Gram-positive bacteria (Bacillus cereus and Bacillus subtilis); whereas compound 4 exhibited weak antibacterial against B. cereus. In addition, compound 4 showed potent α-glucosidase inhibitory activity, which was lower than the reference standard acarbose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This current study presents the phytochemical analysis of Croton velutinus, describing phenylpropanoids obtained from this species. The fractionation of the roots hexane extract led to the isolation of four new phenylpropanoids derivatives, velutines A-D (1-4) and three known (5-7). Their structures were established based on spectroscopic (1D-2D NMR; HRMS and IR) analysis. Cytotoxic, trypanocidal and anti-inflammatory activities of compounds 1-7 were evaluated. Only compounds 2 and 5 showed cytotoxic activity against cancer cell lines (B16F10, HL-60, HCT116, MCF-7 and HepG2), with IC 50 values ranging from 6.8 to 18.3 μM and 11.1 to 18.3 μM, respectively. Compounds 2 and 5 also showed trypanocidal activity against bloodstream trypomastigotes with EC 50 values of 9.0 and 9.58 μM, respectively. Finally, the anti-inflammatory potential of these compounds was evaluated on cultures of activated macrophages. All compounds exhibited concentration-dependent suppressive activity on the production of nitrite and IL-1β by macrophages stimulated with LPS and IFN-γ. These results indicate phenylpropanoids esters (2 and 5) from C. velutinus as promising cytotoxic, trypanocidal and anti-inflammatory candidates that warrants further studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cyperenoic acid (1) is one of the major sesquiterpenes isolated from Croton crassifolius, which exhibited potent anti-angiogenic activity. Traditional structural modification of 1 is difficult to perform by chemical technology due to the remarkable stability of the patchoulane skeleton. In order to overcome chemical synthesis difficulties and obtain structurally diverse derivations, microbial transformation of 1 by using Cunninghamella elegans AS 3.2028 was studied for the first time. Five new hydroxylated products 2-6 were obtained. Furthermore, cytotoxicity and anti-angiogenic activities of all the biotransformation products were evaluated by MTT assay and ELISA in HepG2 and MCF-7 cells. These results indicated that hydroxylated modification products 2-4 significantly inhibited VEGF release, which suggest the potential use of hydroxylated modification products for cancer therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Two new clerodane diterpenoids (1-2), one new clerodane diterpenoid alkaloid (3), as well as thirteen known compounds were isolated from Croton crassifolius. The structures of new compounds were established by a combination of spectroscopic methods, including HRMS, (1)H NMR, (13)C NMR, (1)H (1)H COSY, HSQC, HMBC, NOESY and X-ray crystallographic analysis. Compound 3 is firstly reported as the clerodane-type diterpenoid alkaloid in natural products. All of the compounds were evaluated for in vitro cytotoxic activities against CT26.WT cell using the MTT method., (Copyright © 2015 Elsevier B.V. All rights reserved.)

One new 9,10-seco-abietane derivative, crotontomentosin A (1), four new abietane-type diterpenoids, crotontomentosins B-E (2-5), one new ent-halimane-type diterpenoid, crotontomentosin F (6), along with five known diterpenoids (7-11) and one known sesquiterpenoid (12) were obtained from the twigs and leaves of Croton caudatus Geisel. var. tomentosus Hook. The structures of the compounds were established on the basis of extensive spectroscopic data. Compounds 1-4 and 11 exhibited moderate to weak inhibitory activity against the proliferation of the Hela, Hep G2, MDA-MB-231, or A549 cell lines selectively., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A bioassay-guided purification of an EtOAc extract of the leaves of Croton mauritianus using a chikungunya virus-cell-based assay led to the isolation of 12-O-decanoylphorbol-13-acetate (1) and the new 12-O-decanoyl-7-hydroperoxy-phorbol-5-ene-13-acetate (2), along with loliolide, vomifoliol, dehydrovomifoliol, annuionone D and bluemol C. The planar structure and the relative configuration of compound 2 were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Compounds 1 and 2 inhibited chikungunya virus-induced cell death in cell culture with EC50s of 2.4±0.3 and 4.0±0.8 μM, respectively., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Nerve growth factor (NGF) and analog reagents to promote the neurite outgrowth of nerve cells against the neuron degeneration are expected to be potentially useful for the medical treatment of Alzheimer's disease. In our focus on the discovery of bioactive diterpenes, we investigated the chemical constituents of the plant Croton yanhuii. This investigation led to the isolation and identification of two novel clerodane diterpenes (1 and 2). Their structures were elucidated on the basis of extensive 1D and 2D NMR (COSY, HMQC, HMBC, and NOESY) and mass (ESIMS and HR-ESIMS) spectroscopic data analyses. Further biological screenings showed that both of the compounds enhanced NGF-mediated neurite outgrowth from PC12 cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The bark of Croton campestris provided three furano-clerodane named, respectively, velamone, velamolone acetate and velamolone. Fractions containing these diterpenoids were investigated for their molluscicidal activity against Bulinus truncatus, one of the aquatic snail vectors of schistosomiasis. A dichloromethanic extract of root barks, rich in furano-clerodane and molluscicidal at 20ppm was promising as natural molluscicide. Enriched fraction with velamone gave 80% mortality from 25ppm, while its LD(100) was at 50ppm. The LD(80) was ca. at 45ppm, while LD(100) was at 60ppm for the enriched fraction containing velamolone acetate. The velamolone-enriched fraction was less efficient and gave a mortality of 90% at 90ppm. The pure compounds, velamone and velamolone acetate were active at 100% at 3 and 6ppm, respectively. Velamolone showed a molluscicidal activity at 20ppm.