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Five tigliane ( 1 - 5 ) and one ingenane ( 6 ) diterpenoids were isolated from the ethanol extract of Euphorbia tirucalli . The structures of these compounds were identified based on analysis of their spectroscopic data. Among them, compound 12- O -(2 E ,4 E ,6 E ,8 E -tetradecatetraenoyl)-13- O -isobutyroyl-4 β -deoxyphorbol ( 1 ) was a new tigliane. The Rho123 effluxion assay showed that tiglianes with a trans -fused 5/7 ring system such as compounds 1 , 2 , and 4 had potent inhibitory activity against P-glycoprotein in HepG2/ADR cells.

Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-β1 inhibitor, daphnane diterpenoid DD1 . DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-β1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-β1 abolished this anti-CRPC effect. These findings suggest that importin-β1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-β1 inhibitor to date can be developed as therapeutics for treatment of this disease.

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.

The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms were related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Three new diterpenoids, euphopanes A-C ( 1 - 3 ), including one ent -isopimarane ( 1 ), one ent -abietane ( 2 ) and one cembrane ( 3 ), along with five known compounds ( 4 - 8 ) were isolated from the roots of Euphorbia pekinensis . Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of compounds 1 - 3 were determined by ECD calculations. All the isolates were screened for the cytotoxicity against three cancer cell lines (C4-2B, C42B/ENZR, and MDA-MB-231), and compounds 1 , 2 , and 4 showed significant cytotoxicity against human prostate cancer cells C4-2B with IC 50 values of 14.3, 16.9, and 15.3 μM, respectively.

Bladder cancer is a clinically heterogeneous disease with a poor prognosis. In the current study, anti-proliferation assay of a Euphorbiaceae diterpenoid library led to the identification of an anti-bladder cancer agent Jolkinolide B (JB). JB showed significant cytotoxicity against a panel of bladder cancer cell lines and suppressed the growth of cisplatin (CDDP)-resistant bladder cancer xenografts in single or combination treatments. Mechanistic study revealed that, besides inducing mitogen-activated protein kinase (MAPK)-related apoptosis, JB could trigger the paraptosis via activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and extracellular signal-regulated kinase (ERK) pathway. The excessive production of ROS could be induced by JB via inhibition of thioredoxin reductase 1 (TrxR1) and depletion of glutathione (GSH). Collectively, JB that targets thioredoxin and GSH systems to induce two distinct cell death modes may serve as a promising candidate in future anti-bladder cancer drug development., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Seven previously undescribed polycyclic diterpenoids, euphonoids A-G, including four ent-abietanes, two ent-atisanes, and one ent-kaurene, along with 26 known analogues were isolated from the roots of Euphorbia fischeriana. The structures of the undescribed compounds were elucidated by spectroscopic analysis, ECD calculations, and single crystal X-ray diffraction. Besides, the structure of a previously reported ent-abietane diterpenoid, fischeriabietane A, was revised. All the isolates were screened for the cytotoxicities against five cancer cell lines. Euphonoid A, fischeriabietane A, 11-oxo-ebracteolatanolide B, caudicifolin, jolkinolide B, and methyl-8,11-3-dihydroxy-12-oxo-ent-abietadi-13,15(17)-ene-16-oate showed significant inhibitory activities against human prostate cancer C4-2B and C4-2B/ENZR cell lines, with IC 50 values being less than 10 μM. The brief structure-activity relationships (SARs) of these diterpenoids were also discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Jatrogricaine A (1), a new diterpenoid possessing a 5/6/6/4 carbon ring system, together with eight known diterpenoids (2-9) were isolated from the stems of Jatropha podagrica. Their structures were elucidated by extensive spectroscopic methods and the absolute configuration of 1 was determined by single crystal X-ray diffraction analysis. All compounds were evaluated for their anti-inflammatory activities in vitro, and compound 3 showed significant inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells with an IC 50 of 13.44 ± 0.28 μmol·L -1 , being comparable to the positive control, quercetin (IC 50 17.00 ± 2.10 μmol·L -1 )., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Bioassay-guided fractionation of the ethanolic extract of the roots of Euphorbia kansui led to the isolation of two new ingenane diterpenoids, euphorkans A (1: ) and B (2: ), together with 16 known analogues (3:  - 18: ). Their structures were determined by combined spectral and chemical methods. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells. Compounds 1:  - 6: and 10:  - 13: exhibited pronounced inhibitory activity with IC 50 values in the range of 2.78 - 10.6 µM, and were more potent than the positive control, quercetin (IC 50  = 15.8 µM). Compounds 1: and 5: were selected for further assays toward the key inflammation mediators TNF- α and IL-6, and showed a significant inhibition in a dose-dependent manner. The preliminary mechanistic study revealed that 1: and 5: inhibited NF- κ B activity, which may exert a role in their anti-inflammatory activity., Competing Interests: The authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Eight previously undescribed diterpenoids, crolaevinoids A-H, including two halimanes, four clerodanes, and two laevinanes, along with six known analogues were isolated from the twigs of Croton laevigatus. The structures of the previously undescribed were elucidated by spectroscopic analysis, and their absolute configurations were determined by combination of a single crystal X-ray diffraction and CD analysis (exciton chirality and Rh 2 (OCOCF 3 ) 4 -induced methods). Crolaevinoids A and B represent the first halimane diterpenoids with a unique lactone bridge between C-12 and C-17. All compounds were evaluated for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells. Furocrotinsulolide A and 3,4,15,16-diepoxy-cleroda-13(16),14-diene-12,17-olide exhibited pronounced inhibition of NO production with IC 50 values of 10.4 ± 0.8 and 6.0 ± 1.0 μM, respectively, being more potent than the positive control, quercetin (IC 50  = 13.1 ± 1.9 μM)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)