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 Ingenane Diterpenoids from as Antiadipogenic Agents.

Thirteen new diterpenoids, euphylonanes A-M (-), and eight known ones were isolated from the whole plants of . Compounds and are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound represents the first example of a 9,10-epoxy tigliane, while - are typical ingenanes varying with substituents.

New halimane and clerodane diterpenoids from Croton cnidophyllus.

Three new halimane furanoditerpenoids (1-3) and three new clerodane furanoditerpenoids (4-6), along with seven known terpenoids including four pimarane diterpenoids (7-10) and three norisoprenoids (11-13) were isolated from the 95% EtOH extracts of the plants of Croton cnidophyllus. The 2D structures including absolute configuration of new furanoditerpenoids (1-6) were elucidated by analysis of their HRMS and NMR data as well as comparison of experimental and calculated ECD curves. Bioassay revealed that two compounds (8 and 9) possessed certain inhibitory effects against NO production stimulated by LPS, with IC values of 19.

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).

Discovering a New Okadaic Acid Derivative, a Potent HIV Latency Reversing Agent from PL11: Isolation, Structural Modification, and Mechanistic Study.

Marine toxins (MTs) are a group of structurally complex natural products with unique toxicological and pharmacological activities. In the present study, two common shellfish toxins, okadaic acid (OA) () and OA methyl ester (), were isolated from the cultured microalgae strain PL11. OA can significantly activate the latent HIV but has severe toxicity.

Biscroyunoid A, an Anti-Hepatic Fibrotic 19--Clerodane Diterpenoid Dimer with a C-16-C-12' Linkage from .

Biscroyunoid A (), a 19--clerodane diterpenoid dimer featuring a unique C-16-C-12' linkage and containing an unusual 4,7-dihydro-5-spiro[benzofuran-6,1'-cyclohexane] motif, together with its biosynthetic precursor, croyunoid A (), were isolated from . Their structures were determined by spectroscopic, computational, and single-crystal X-ray diffraction methods. Compound exerted an antihepatic fibrosis effect in LX-2 cells via inhibition of TGFβ-Smad2/3 signaling.

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.

New benzofuran neolignans with neuroprotective activity from .

A pair of undescribed dihydrobenzofuran neolignan enantiomers, (+/-)-phybrenan A (/), two new benzofuran neolignans, phybrenan B and C ( and ), along with four known neolignans (-) were obtained from the plants of P. T. Li.

Euphylonoids A and B, Two Highly Modified Jatrophane Diterpenoids with Potent Lipid-Lowering Activity from .

Euphylonoids A () and B (), two highly modified jatrophane diterpenoids, were isolated from . represents a new 9(10→18)--8,12-cyclojatrophane skeleton containing a cage-like 3,8-dioxatricyclo[5.1.

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.

Crotonianoids A-C, Three Unusual Tigliane Diterpenoids from the Seeds of and Their Anti-Prostate Cancer Activity.

Crotonianoids A-C (-), three unusual tigliane diterpenoids, were isolated from the seeds of . Compound is a 13,14:13,15--tigliane featuring a unique spiro[bicyclo[5.3.

Homo/Hetero-Dimers of Aromatic Bisabolane Sesquiterpenoids with Neuroprotective Activity from the Fungus Aspergillus versicolor A18 from South China Sea.

Chromatographic fractionation of the EtOH extracts of the marine-derived fungus Aspergillus versicolor A18 has led to the isolation of 11 homo/hetero-dimers of aromatic bisabolane sesquiterpenoids including eight diphenyl ether-coupled aromatic bisabolanes (1a/1b and 5−10) and three homodimers (2−4), together with their monomers including three aromatic bisabolanes (11−13) and two diphenyl ethers (14 and 15). Their structures and absolute configurations were elucidated by extensive spectroscopic analysis including HRESIMS, 1D/2D NMR, calculated ECD, and the optical rotatory data. Among the four new compounds, (+/−)-asperbisabol A (1a/1b), asperbisabol B (2), and asperbisabol C (3), the enantiomers 1a and 1b represent an unprecedented skeleton of diphenyl ether-coupled aromatic bisabolane sesquiterpenoids with a spiroketal core moiety.

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.

HACE1 negatively regulates neuroinflammation through ubiquitylating and degrading Rac1 in Parkinson's disease models.

Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses.

BaGeSbSe: An Infrared Nonlinear Optical Crystal with a V-Shaped Se Group Possessing a Large Contribution to the SHG Response.

The quaternary selenide BaGeSbSe was prepared by a high-temperature solid state reaction method. BaGeSbSe crystallizes in an acentric orthorhombic space group 2 with the lattice constants = 9.370(11) Å, = 25.

TLR2 Potentiates SR-Marco-Mediated Neuroinflammation by Interacting with the SRCR Domain.

Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes.

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.

Highly modified nor-clerodane diterpenoids from Croton yanhuii.

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.

Structural Elucidation of Three 9,11- Tetracyclic Triterpenoids Enables the Structural Revision of Euphorol J.

Compounds -, the rare examples of 9,11- euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from . Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as . - showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC values in the range of 2.

Three new terpenoids from .

Two new triterpenoids, 3-hydroxytirucall-7,25-dien-24-one () and 3-acetoxytirucall-7,23,25-triene (), along with one new sesquiterpenoid, alloaromadendrane-12,14-dioic acid (), were isolated from the vines and leaves of Pierre. Their structures were established on the basis of extensive spectroscopic data.

Crotonpenoids A and B, Two Highly Modified Clerodane Diterpenoids with a Tricyclo[7.2.1.0]dodecane Core from : Isolation, Structural Elucidation, and Biomimetic Semisynthesis.

Crotonpenoids A () and B (), two highly modified clerodane diterpenoids featuring a new 10-(butan-2-yl)-1,6,12-trimethyltricyclo[7.2.1.

Cytotoxic Pregnane Steroidal Glycosides from Chonemorpha megacalyx.

Three new C pregnane steroids, chonemorphols A-C (1, 3, and 4), 11 new C steroidal glycosides, chonemorphosides A-K (2 and 5-14), and 11 known compounds (15-25) were obtained from the vines and leaves of Chonemorpha megacalyx Pierre. Their structures were established using extensive spectroscopic data. The X-ray crystallographic data of 1 and 3 permitted definition of their absolute configurations.