Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function.

OSBP ligands from the ORPphilin family are chemically complex natural products with promising anticancer properties. Here, we describe macarangin B, a natural racemic flavonoid selective for OSBP, which stands out from other ORPphilins due to its structural simplicity and distinct biological activity. Using a bioinspired strategy, we synthesized both (,,) and (,,)-macarangin B enantiomers, enabling us to study their interaction with OSBP based on their unique optical properties.

A Fast and Efficient Molecular Networking Approach for Reactivity of Natural Products Exploration in Plant Extracts: Application to Diterpene Esters from .

Natural products represent a rich source of bioactive compounds, covering a large chemical space. Even if challenging, this diversity can be extended by applying chemical modifications. However, these studies generally require multigram amounts of isolated natural products and face frequent testing failures.

Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein.

Schweinfurthins (SWs) are naturally occurring prenylated stilbenes with promising anticancer properties. They act through a novel mechanism of action similar to that of other families of natural compounds. Their known target, oxysterol-binding protein (OSBP), plays a crucial role in controlling the intracellular distribution of cholesterol.

Metabolic adjustments in response to ATP spilling by the small DX protein in a strain.

ATP wasting is recognized as an efficient strategy to enhance metabolic activity and productivity of specific metabolites in several microorganisms However, such strategy has been rarely implemented in species whereas antibiotic production by members of this genus is known to be triggered in condition of phosphate limitation that is correlated with a low ATP content. In consequence, to assess the effects of ATP spilling on the primary and specialized metabolisms of , the gene encoding the small synthetic protein DX, that has high affinity for ATP and dephosphorylates ATP into ADP, was cloned in the integrative vector pOSV10 under the control of the strong E promoter. This construct and the empty vector were introduced into the species yielding A37 and A36, respectively.

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites.

Membrane contact sites (MCSs) are heterogeneous in shape, composition, and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs that involve the endoplasmic reticulum (ER). Although the VAP-FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs.

In vitro evaluation of NA1-115-7-loaded nanoemulsions, an MCL-1-specific inhibitor of natural origin, intended to treat B-cell lymphoproliferative disorders after oral administration.

MCL-1, an anti-apoptotic member of the BCL-2 protein family, is overexpressed in many types of cancer and contributes to chemotherapy resistance. The drimane derivative NA1-115-7 is a natural compound isolated from Zygogynum pancheri that can be considered as a very promising lead for treating MCL-1-dependent hematological malignancies. As this drug suffers from low stability in acidic conditions and poor aqueous solubility, we evaluated the potential oral use of NA1-115-7 by encapsulating it in lipid nanoemulsions (NA-NEs) prepared by spontaneous emulsification.

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline.

Quinoline derivatives and especially quinolones are considered as privileged structures in medicinal chemistry and are often associated with various biological properties. We recently isolated a series of original monoterpenyl quinolones from the bark of . As this extract was found to have a significant inhibitory activity against a species, we decided to study the anti-leishmanial potential of this type of compound.

NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes.

The overexpression of antiapoptotic members (BCL-2, BCL-xL, MCL-1, etc.) of the BCL-2 family contributes to tumor development and resistance to chemotherapy or radiotherapy. Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax).

Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL-1.

Drimane sesquiterpenoid dialdehydes are natural compounds with antiproliferative properties. Nevertheless, their mode of action has not yet been discovered. Herein, we demonstrate that various drimanes are potent inhibitors of MCL-1 and BCL-xL, two proteins of the BCL-2 family that are overexpressed in various cancers, including lymphoid malignancies.

Isolation of Picrotoxanes from Using Taxonomy-Based Molecular Networking.

A unique collection of 292 extracts from 107 New Caledonian Euphorbiaceae species was profiled by LC-MS and the metabolite content organized by molecular networking. Based on the assumption that taxon-specific molecules are more likely to be structurally novel, taxonomic data were mapped on spectral networks to detect genus-specific clusters. Using this approach, a group of compounds unique to the genus was highlighted.

Anti-diabetic and lipid-lowering effects of drimane sesquiterpenoids isolated from Zygogynum pancheri.

Recently, it has been shown that drimane-type sesquiterpenoids isolated from Zygogynum pancheri, a species native to New Caledonia, possessed significant α-amylase inhibitory activities. To further explore their antidiabetic potential, we investigated the effect of 1β-O-(E-cinnamoyl)-6α-hydroxy-9epi-polygodial (D) and 1β-E-O-p-methoxycinnamoyl-bemadienolide (L), two of the most active compounds of the series, on diabetic model rats. Compounds D and L (2 mg kg/day) were daily and orally administrated for 30 days to streptozotocin (STZ) (150 mg/kg) induced male diabetic Wistar rats.

Molecular and cellular dissection of the oxysterol-binding protein cycle through a fluorescent inhibitor.

ORPphilins are bioactive natural products that strongly and selectively inhibit the growth of some cancer cell lines and are proposed to target intracellular lipid-transfer proteins of the oxysterol-binding protein (OSBP) family. These conserved proteins exchange key lipids, such as cholesterol and phosphatidylinositol 4-phosphate (PI(4)P), between organelle membranes. Among ORPphilins, molecules of the schweinfurthin family interfere with intracellular lipid distribution and metabolism, but their functioning at the molecular level is poorly understood.

Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2.

A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins.

Cytotoxic lignans from fruits of Cleistanthus tonkinensis.

Seven new lignans, cleistonkinins A- E (1-5), cleistonkisides A and B (6-7) were isolated from the fruits of Cleistanthus tonkinensis (Euphorbiaceae), together with five known aryltetralin lignans, cleisindoside B (8), cleistantoxin (9), cleisindoside D (10), neocleistantoxin (11) and polygamain (12). Their structures were established from spectral analysis, including mass spectrometry and 2D-NMR. The absolute configurations of 4-7 were determined by analysis of their experimental CD spectra and comparison with calculated electronic circular dichroism (ECD) spectra.

Cytotoxic Phenolic Compounds from Fruit Glandular Trichomes of .

A new flavonoid, macatanarin D (), together with five known stilbenes (), was isolated from fruit glandular trichomes of . Their structures were elucidated on the basis of spectroscopic methods and through comparison with data reported in the literature. All isolated compounds were evaluated for their cytotoxic activities against KB and MCF-7 cell lines.

Isolation of phenanthrenes and identification of phorbol ester derivatives as potential anti-CHIKV agents using FBMN and NAP from Sagotia racemosa.

In an effort to identify inhibitors of Chikungunya virus (CHIKV) replication, a systematic study of 594 extracts of plant species originating from the French Guiana plateau region was performed in a virus-cell-based assay for CHIKV assay. The extract obtained from the stem bark of Sagotia racemosa was selected for its potent antiviral activity. Using a classical bioassay-guided procedure, three undescribed degraded diterpenoids, i.

Investigation of Premyrsinane and Myrsinane Esters in Euphorbia cupanii and Euphobia pithyusa with MS2LDA and Combinatorial Molecular Network Annotation Propagation.

The species Euphorbia pithyusa and Euphorbia cupanii are two closely related Mediterranean spurges for which their taxonomic relationships are still being debated. Herein, the diterpene ester content of E. cupanii was investigated using liquid chromatography coupled to tandem mass spectrometry.

Collected mass spectrometry data on monoterpene indole alkaloids from natural product chemistry research.

This Data Descriptor announces the submission to public repositories of the monoterpene indole alkaloid database (MIADB), a cumulative collection of 172 tandem mass spectrometry (MS/MS) spectra from multiple research projects conducted in eight natural product chemistry laboratories since the 1960s. All data have been annotated and organized to promote reuse by the community. Being a unique collection of these complex natural products, these data can be used to guide the dereplication and targeting of new related monoterpene indole alkaloids within complex mixtures when applying computer-based approaches, such as molecular networking.

Antiviral Compounds from Codiaeum peltatum Targeted by a Multi-informative Molecular Networks Approach.

From a set of 292 Euphorbiaceae extracts, the use of a molecular networking (MN)-based prioritization approach highlighted three clusters (MN1-3) depicting ions from the bark extract of Codiaeum peltatum. Based on their putative antiviral potential and structural novelty, the MS-guided purification of compounds present in MN1 and MN2 afforded two new daphnane-type diterpenoid orthoesters (DDO), codiapeltines A (1) and B (2), the new actephilols B (3) and C (4), and four known 1,4-dioxane-fused phenanthrene dimers (5-8). The structures of the new compounds were elucidated by NMR spectroscopic data analysis, and the absolute configurations of compounds 1 and 2 were deduced by comparison of experimental and calculated ECD spectra.

N-myristoyltransferases inhibitory activity of ellagitannins from Terminalia bentzoë (L.) L. f. subsp. bentzoë.

N-myristoylation (Myr) is an eukaryotic N-terminal co- or post-translational protein modification in which the enzyme N-myristoyltransferase (NMT) transfers a fatty acid (C14:0) to the N-terminal glycine residues of several cellular key proteins. Depending on the cellular context, NMT may serve as a molecular target in anticancer or anti-infectious therapy, and drugs that inhibit this enzyme may be useful in the treatment of cancer or infectious diseases. As part of an on-going project to identify natural Homo sapiens N-myristoyltransferase 1 inhibitors (HsNMT1), two ellagitannins, punicalagin (1) and isoterchebulin (2), along with eschweilenol C (3) and ellagic acid (4) were isolated from the bark of Terminalia bentzoë (L.

MetGem Software for the Generation of Molecular Networks Based on the t-SNE Algorithm.

Molecular networking (MN) is becoming a standard bioinformatics tool in the metabolomic community. Its paradigm is based on the observation that compounds with a high degree of chemical similarity share comparable MS fragmentation pathways. To afford a clear separation between MS spectral clusters, only the most relevant similarity scores are selected using dedicated filtering steps requiring time-consuming parameter optimization.

Natural Inhibitors of the RhoA-p115 Complex from the Bark of Meiogyne baillonii.

In an effort to find potent natural inhibitors of RhoA and p115 signaling G-proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11 317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species Meiogyne baillonii for a chemical investigation. Using a bioguided isolation procedure, three enediyne-γ-butyrolactones (1-3) and two enediyne-γ-butenolides (4 and 5), named sapranthins H-L, respectively, two enediyne carboxylic acid (6 and 7), two depsidones, stictic acid (8) and baillonic acid (9), aristolactams AIa and AIIa (10 and 11), and two aporphines, dehydroroemerine (12) and noraristolodione (13), were isolated from the ethyl acetate extract of the bark.

Structurally Diverse Diterpenoids from Sandwithia guyanensis.

Bioassay-guided fractionation of an EtOAc extract of the trunk bark of Sandwithia guyanensis, using a chikungunya virus (CHIKV)-cell-based assay, afforded 17 new diterpenoids 1-17 and the known jatrointelones A and C (18 and 19). The new compounds included two tetranorditerpenoids 1 and 2, a trinorditerpenoid 3, euphoractines P-W (4-11), and euphactine G (13) possessing the rare 5/6/7/3 (4-7), 5/6/6/4 (8-11), and 5/6/8 (13) fused ring skeletons, sikkimenoid E (12), and jatrointelones J-M (14-17) possessing jatropholane and lathyrane carbon skeletons, respectively. Jatrointelones J (14) and M (17) represent the first naturally occurring examples of C-15 nonoxidized lathyrane-type diterpenoids.

Dual inhibitors of the pro-survival proteins Bcl-2 and Mcl-1 derived from natural compound meiogynin A.

Thirty analogues of natural meiogynin A, a pan-Bcl-2 inhibitor, were prepared in order to elaborate cytotoxic compounds on specific cancer cells overexpressing one or more proteins of the Bcl-2 family. The interaction of all the new analogues with Bcl-xL, Mcl-1 and Bcl-2 proteins was first evaluated by fluorescence polarization assay (FPA) and showed that modulation of the lateral chain has a dramatic impact as subtle changes significantly modify the activity on the target proteins. The acetoxymethyl prodrugs of the two most active compounds were then elaborated to determine their cytotoxicity on B cell lines.