Mehdi A. Beniddir

Goniomedines A and B: Unprecedented Bisindole Alkaloids Formed through Fusion of Two Indole Moieties via a Dihydropyran Unit

Two novel bisindole alkaloids, goniomedines A (1) and B (2), possessing an unprecedented quebrachamine-pleioarpamine-type skeleton, in which indole moieties are fused via a dihydropyran unit, were isolated from the stem bark of Gonioma malagasy. The structures were elucidated by comprehensive analysis of MS and NMR spectroscopic data. Their absolute configurations were deduced following the comparison of experimental and theoretically calculated ECD spectra and through biogenetic considerations. Goniomedine B (2) exhibited moderate activity against Plasmodium falciparum.

Acridone Alkaloids from Glycosmis chlorosperma as DYRK1A Inhibitors

Two new acridone alkaloids, chlorospermines A and B (1 and 2), were isolated from the stem bark of Glycosmis chlorosperma, together with the known atalaphyllidine (3) and acrifoline (4), by means of bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (4) and to a lesser extent chlorospermine B (2) and atalaphyllidine (3) showed significant inhibiting activity on DYRK1A with IC50s of 0.075, 5.7, and 2.2 μM, respectively. Their selectivity profile was evaluated against a panel of various kinases, and molecular docking calculations provided structural details for the interaction between these compounds and DYRK1A.

A Unified Bioinspired “Aplysinopsin Cascade”: Total Synthesis of (±)-Tubastrindole B and Related Biosynthetic Congeners

Applying a biomimetic approach, the first total synthesis of (±)-tubastrindole B is reported herein. This work features a ring-expansion cascade of a dictazole-type precursor into cycloaplysinopsin-type congeners. Moreover, the isolation of a transient biogenetic intermediate represents a milestone in the biosynthetic understanding of this family of marine alkaloids.

Unified biomimetic assembly of voacalgine A and bipleiophylline via divergent oxidative couplings

Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4-b]indolenine motif instead of a benzofuro[2,3-b]indolenine.

Ilimaquinone and 5-epi-Ilimaquinone: Beyond a Simple Diastereomeric Ratio, Biosynthetic Considerations from NMR-Based Analysis

Dactylospongia metachromia and Dactylospongia elegans collected from French Polynesia were studied with a particular focus on the variation of the diastereomeric ratio between ilimaquinone (4) and 5-epi-ilimaquinone (5). More than 100 samples, covering an area of 4100 km2, were studied to try to clarify this intriguing issue. Nuclear magnetic resonance appeared as the non-destructive, straightforward technique of choice for a relative quantitative study. A random distribution, unique at that point in nature, is observed and leads to biosynthetic considerations. Biological evaluation of both compounds was also performed and showed moderate discrepancies in cytotoxicity and apoptosis induction.

Resolving the (19R) Absolute Configuration of Lanciferine, a Monoterpene Indole Alkaloid from Alstonia boulindaensis

Reinvestigation of the structure of lanciferine (1a) through extensive spectroscopic analysis in conjunction with a detailed computational study led to the unambiguous assignment of its (19 R) absolute configuration, thus leading to the full (2 R, 3 S, 7 S, 15 R, 16 R, 19 R, 20 S) assignment of lanciferine 45 years after its isolation.

DNA‐Templated [2+2] Photocycloaddition: A Straightforward Entry into the Aplysinopsin Family of Natural Products

Biosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)-aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan-derived olefin to light in the presence of salmon testes DNA (st-DNA) reproducibly afforded the corresponding homo-dimerized spiro-fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid-state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA-mediated transformation to be applied to the total synthesis of a natural product.

Theionbrunonines A and B: Dimeric Vobasine Alkaloids Tethered by a Thioether Bridge from Mostuea brunonis

Theionbrunonines A and B (1 and 2), the first examples of monoterpene bisindole alkaloids linked by a thioether bridge, were isolated from the stems of Mostuea brunonis, guided by a molecular networking-based dereplication strategy. Their structures were elucidated by a combination of spectroscopic data and ECD calculations. A plausible biosynthetic pathway for 1 and 2 was postulated. Theionbrunonines A and B (1 and 2) showed moderate antiplasmodial activities in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 μM.

Sulfonic Acid-Containing Flavonoids from the Roots of Phyllanthus acidus

Six new sulfonic acid-containing flavonoids, acidoflavanone (1), acidoauronol (2), 5- O-methylacidoauronol (3), acidoaurone (4), acidoisoflavone (5), and acidoflavonol (6), were isolated from the EtOH extract of the roots of Phyllanthus acidus. Their structures were unambiguously established by interpretation of their HRESIMS and 1D and 2D NMR data, single-crystal X-ray diffraction analysis, and comparison to the literature data. These new structures represent the first examples of sulfonic acid-containing flavanones, auronols, aurones, and isoflavones.

Two new triterpenoids from the roots of Phyllanthus emblica

Two new triterpenes, the seco-friedelane type secofriedelanophyllemblicine and the ursane-derived saponin ursophyllemblicoside were isolated from the roots of the edible fruit-producing Phyllanthus emblica. Their structures were unambiguously elucidated using extensive 1D and 2D NMR analyses, high resolution mass spectrometry and single-crystal X-ray crystallographic analyses along with comparison with literature data. Secofriedelanophyllemblicine represents the first 3,4-secofriedelane bearing a carboxylic acid group substituent at C-20. Ursophyllemblicoside, incorporating the rare 21α hydroxyursolic acid as a sapogenol represents the first example of saponin comprising this aglycone. Secofriedelanophyllemblicine displayed a moderate cytotoxicity against K562 and HepG2 cancer cell lines.