Discovery of a highly potent and orally available importin-1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-1 inhibitor to afford an improved analog -Br with better tolerability (>25 folds) and oral bioavailability.

Discovery of the First Raptor (Regulatory-Associated Protein of mTOR) Inhibitor as a New Type of Antiadipogenic Agent.

Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, (5/7/6 carbon ring with orthoester and chlorine functionalities).

Diversity of sesquiterpenoids from Stellera chamaejasme with neuroprotective effects.

Chromatographic fractionation of the 95% EtOH extract of the roots of Stellera chamaejasme yielded 20 sesquiterpenoids of four different types, guaiane-, carotane-, sesquicarane-, and alpiniane-types. Among them, sesquistrachanoids A-F were previously undescribed ones, whose structures including absolute configurations were elucidated by spectroscopic methods, the Mo(OAc)-induced ECD experiment, and analysis of experimental and calculated 1D NMR and ECD data. Sesquistrachanoid A is a 2,3-seco-guaiane-type sesquiterpenoid with a α-pyrone core and sesquistrachanoid B is the first example of 8,9-seco-guaiane-type sesquiterpenoid featured with an 1,8-δ-lactone core.

-Abietane Diterpenoids from and Their Cytotoxic Activities.

The roots of have been used as a traditional Chinese medicine for the treatment of tuberculosis and ringworm. In the current study, diterpenoids from the ethyl acetate extract of the roots and their cytotoxic effects against five cancer lines were investigated. Two new -abietane diterpenoids, euphonoids H and I (-), as well as their two analogues (-) were first isolated from this source.

, the Hmong Medicinal Flora: A Comprehensive Review of Its Phytochemical, Pharmacological and Pharmacokinetic Characteristics.

, known as "Tou Hua Liao" (Chinese name), is a crucial source of Hmong medicinal plants that has benefited human health for a long time. This folk-medicinal plant is widely distributed in the south-west of China for the treatment of various urologic disorders including urinary tract infections, pyelonephritis, and urinary calculus. The purpose of this paper was to provide a systematic and comprehensive overview of the traditional usages, botany, phytochemistry, pharmacology, pharmacokinetics and clinical applications of this flora.

Systematic elucidation of the bioactive alkaloids and potential mechanism from Sophora flavescens for the treatment of eczema via network pharmacology.

Ethnopharmacology Relevance: Sophora flavescens is a frequently used traditional Chinese medicine (TCM) for the treatment of skin disorders, diarrhea, vaginal itching and inflammatory diseases. In particular, the root of S. flavescens combination with other herbs mainly treat eczema ailment in the clinical applications.

Discovery of Highly Potent Daphnane Diterpenoids Uncovers Importin-β1 as a Druggable Vulnerability in Castration-Resistant Prostate Cancer.

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 .

Tigliane and rhamnofolane glycosides from Euphorbia wallichii prevent oxidative stress-induced neuronal death in PC-12 cells.

Tigliane and rhamnofolane diterpenoids bearing glycosyl substituents are rarely found in nature. In the current study, seven new tigliane glycosides, euphorwallsides A - G (1-7), and five new rhamnofolane glycosides, euphorwallsides H - L (8-12), were isolated from the whole plants of Euphorbia wallichii. Their structures were elucidated by a combination of spectroscopic, computational, and chemical means.

An unusual indole-diterpenoid with C-17 norcassane skeleton from Euphorbia fischeriana induces HEL cell cycle arrest and apoptosis.

Two new polycyclic diterpenoids, euphkanoids H and I (1 and 2), along with 6 known analogues (2-8) were isolated from the roots of Euphorbia fischeriana, a traditional Chinese medicine. Their structures were identified by spectral methods, and the absolute configurations of 1 and 2 were determined by ECD calculation and single crystal X-ray diffraction, respectively. Compound 1 represents the first example of C-17 norcassane indole-diterpenes.

Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity.

Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types.

Euphohyrisnoids A and B, Two Highly Rearranged Lathyrane Diterpenoids from .

Euphohyrisnoids A () and B (), two highly rearranged lathyrane diterpenoids featuring a unique tetracyclo[10.2.2.

Presegetane diterpenoids from Euphorbia sieboldiana as a new type of anti-liver fibrosis agents that inhibit TGF-β/Smad signaling pathway.

Seven new diterpenoids, eupholenes A-G (1-7), including two presegetanes (1 and 2), four jatrophanes (3-6), and one paraliane (7), along with 19 known analogues (8-26) were obtained by anti-liver fibrosis bioassay-guided isolation of Euphorbia sieboldiana. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, ECD calculations, and single-crystal X-ray diffractions. Euphorbesulin A (10), a presegetane diterpenoid (5/9/5 ring system), was identified as a promising anti-liver fibrosis agent that could inhibit the expressions of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagen I in TGF-β1-stimulated LX-2 cells at a micromolar level.

Lathyrane Diterpenoids as Novel hPXR Agonists: Isolation, Structural Modification, and Structure-Activity Relationships.

Pregnane X receptor (PXR) that orchestrates the intricate network of xeno- and endobiotic metabolism is considered as a promising therapeutic target for cholestasis. In this study, the human PXR (hPXR) agonistic bioassay-guided isolation of followed by the structural modification led to the construction of a lathyrane diterpenoid library (-). Subsequent assay of this library led to the identification of a series of potent hPXR agonists, showing better efficacy than that of typical hPXR agonist, rifampicin.

Euphorboside A, a cytotoxic meroterpenoid glycoside with an unusual humulene-phloroglucinol skeleton from Euphorbia kansuensis.

Euphorboside A (1), an unusual meroterpenoid glycoside featuring the incorporation of an acylphloroglucinol moiety into a humulene skeleton to form a 6/6/11 ring system, was isolated from the roots of Euphorbia kansuensis. Its structure was elucidated by extensive spectroscopic analysis, chemical methods, and ECD calculations. Compound 1 was screened for the cytotoxicity against nine cancer cell lines, and 1 showed marked inhibitory activities against human colon cancer RKO and human breast cancer MDA-MB-231 cell lines with IC values of 3.

Euphopanes A-C, three new diterpenoids from .

Three new diterpenoids, euphopanes A-C (-), including one -isopimarane (), one -abietane () and one cembrane (), along with five known compounds (-) were isolated from the roots of . Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of compounds - 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 , , and showed significant cytotoxicity against human prostate cancer cells C4-2B with IC values of 14.

Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells.

Eight previously undescribed diterpenoids, euphoroyleans A-H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A-H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities.

Secondary metabolites from Isodon ternifolius (D. Don) Kudo and their anticancer activity as DNA topoisomerase IB and Tyrosyl-DNA phosphodiesterase 1 inhibitors.

Based on DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition of the ethanol extract of the roots of Isodon ternifolius (D. Don) Kudo (Labiatae), its secondary metabolites has been studied. Two new compounds, an ent-abietane diterpenoid isodopene A (1) and a 2,3-seco-triterpene isodopene B (13), along with 25 known compounds were isolated.

Meriolin1 induces cell cycle arrest, apoptosis, autophagy and targeting the Akt/MAPKs pathways in human neuroblastoma SH-SY5Y cells.

Objectives: Meriolins, a kind of chemical hybrid between meridianins and variolins, have lately been determined as kinase inhibitors and reportedly have antitumour activity. However, there is currently no in-depth study for the action mechanism. This study aimed to elucidate the potentially antitumour action mechanism of Meriolin1 on human neuroblastoma (SH-SY5Y) cells.

Euphanoids A and B, two new lathyrane diterpenoids with nitric oxide (NO) inhibitory activity from .

Two new lathyrane diterpenoids, euphanoids A and B ( and ), along with five known compounds (-) were isolated from the roots of . Their structures were elucidated by spectroscopic analysis, and the absolute configuration of was determined by single crystal X-ray diffraction. All of the isolates were screened for the inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.

Euphonoids A-G, cytotoxic diterpenoids from Euphorbia fischeriana.

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.

Euphorkanlide A, a Highly Modified Ingenane Diterpenoid with a C Appendage from Euphorbia kansuensis.

Euphorkanlide A (1), a highly modified ingenane diterpenoid with a C appendage forming an additional hexahydroisobenzofuran-fused 19-membered macrocyclic bis-lactone ring system was isolated from the roots of Euphorbia kansuensis. Its structure was determined by extensive spectroscopic analysis and quantum-chemical calculations. Compound 1 showed significant cytotoxicities against a panel of cancer cell lines (IC < 5 μM).

Two new abietane diterpenoids from the leaves of .

Phytochemical investigation on the leaves of led to the isolation of two new abietane diterpenoids, raserranes A () and B (), and four known phenylpropanoids (-). Their structures were determined by spectroscopic data. Compound represented the rare examples of abietane diterpenoids featuring a 16-methoxycarbonyl group.