Xu-Wen Li

Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues.

Summary Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.

Design, synthesis and in vitro activity of phidianidine B derivatives as novel PTP1B inhibitors with specific selectivity.

A series of phidianidine B derivatives were synthesized by introducing various heterocyclic rings. Their inhibitory effects on PTP1B and other PTPs (TCPTP, SHP1, SHP2 and LAR) were evaluated. A majority of them displayed significant inhibitory potency and specific selectivity over PTP1B. The SAR and molecular docking analysis were also described.

Bio‐Inspired Formal Synthesis of Hirsutellones A–C Featuring an Electrophilic Cyclization Triggered by Remote Lewis Acid‐Activation

A bio-inspired strategy was used to complete the formal synthesis of the antitubercular hirsutellone B and congeners A and C, through construction of its decahydrofluorene core from a linear polyene strand activated at both ends by a silyl enol ether and an allyl acetate. Our synthesis features a key electrophilic cyclization, starting with the remote activation (by [Yb(OTf)3] or BF3·OEt2) of the allyl acetate and stereoselectively affording the C ring. This was followed by an intramolecular Diels-Alder reaction to get the tricyclic core of the natural product. The stereoselective reduction of the resulting ketone towards the formal intermediate was critical to the success of this strategy.

Xishacorenes A–C, Diterpenes with Bicyclo[3.3.1]nonane Nucleus from the Xisha Soft Coral Sinularia polydactyla

Three new diterpenes, xishacorenes A-C, featuring an undescribed bicyclo[3.3.1]nonane nucleus bearing 1-vinyl and 13-[(E)-4-methylpenta-1,3-dien-1-yl] alkyl chains, and a related monocyclic known compound, were isolated from the Xisha soft coral Sinularia polydactyla. The structures of xishacorenes A-C, including their absolute configurations, were elucidated by extensive spectroscopic analysis and TDDFT ECD calculations. The new compounds exhibit an interesting dose-dependent promotion effect on the ConA-induced T lymphocyte proliferation. A plausible biosynthetic pathway of xishacorenes A-C is proposed.

Structural diversity of terpenoids in the soft coral Sinularia flexibilis, evidenced by a collection from the South China Sea

Eight new terpenoids, including six α-methylene-δ-lactone-bearing cembranoids (1–6), a 15-membered macrocyclic diterpenoid (7), and a biscembranoid (8), were isolated from South China Sea soft coral Sinularia flexibilis, along with five known analogues (9–13). Their structures including relative stereochemistry were elucidated by detailed spectroscopic analyses, chemical reactions and by comparison with literature data. Further, the structures of 8 and 10 were unambiguously confirmed by X-ray diffraction analyses. Compound 7, named epoxyflexibilene, represents the second 15-membered macrocyclic diterpenoid being discovered from marine sources, whereas sinulaflexiolide L (8) is the third member of the extremely rare cembrane dimers connected through C–C single bond. The discovery of these new isolates showed the high chemical diversity and ecological complexity of the animal S. flexibilis collected in different locations. In a bioassay, compound 9 exhibited potent anti-tumor activity targeting the inositol-requiring 1/X-box-binding protein 1 (IRE1/XBP1) signaling pathway.

Chemically Unprecedented Biocatalytic (AuaG) Retro‐[2,3]‐Wittig Rearrangement: A New Insight into Aurachin B Biosynthesis

AuaG is flavin‐dependent monooxygenase responsible for the conversion of aurachin C to aurachin B, a reaction thought to resemble semipinacol migration of the farnesyl substituent. A study of the substrate tolerance of AuaG reveals that it has the peculiar ability to oxidise short‐chain analogues of aurachin D. Unexpectedly, a novel retro‐[2,3]‐Wittig rearrangement was observed with an isoprenyl substrate analogue, thus leading to the 1,1‐dimethylallyl ether. Additionally, we found that saturated‐chain analogues of N‐oxidised aurachin C were not transformed by the C3→C4 semipinacol reaction, as might have been expected for such substrates. Based on this and the unique retro‐[2,3]‐Wittig rearrangement, we discuss an alternative biosynthetic route for the conversion of aurachin C to aurachin B.

Asymmetric Total Synthesis of Distaminolyne A and Revision of Its Absolute Configuration

The first total synthesis of a marine derived polyacetylene, distaminolyne A, and its enantiomer were achieved from the commercially available undec-10-en-1-ol. A key proline-catalyzed asymmetric α-aminooxylation of an aldehyde intermediate was used to introduce the chiral center en route to the enantiomerically pure 1,2-amino alcohols. The absolute configuration of both synthesized enantiomers of distaminolyne A was confirmed by using chiral derivatizing agents, leading to revision of the natural product absolute configuration from 2S to 2R. Antibacterial, pancreatic lipase (PL) inhibitory, and protein-tyrosine phosphatase 1B (PTP1B) inhibitory activities were evaluated.

New laurane-type sesquiterpenoids from the Chinese red alga Laurencia okamurai Yamada

Abstract Two new laurane-type sesquiterpenoids, debromo-3α-hydroperoxy-3-epiaplysin (1) and debromo-3β-hydroperoxyaplysin (2), together with seven known related compounds (3–9), were isolated from the Chinese red alga Laurencia okamurai. Their structures were elucidated by detailed analysis of spectroscopic data and by comparison with the literature. In bioassay, compounds 2, 4, 8, and 9 exhibited significant PTP1B inhibitory activity with IC50 values ranging from 4.9 to 14.9 μg/ml.

New Bicyclic Cembranoids from the South China Sea Soft Coral Sarcophyton trocheliophorum

Nine new bicyclic cembranoids, sarcophytrols M–U(1–9), were isolated from the South China Sea soft coral Sarcophyton trocheliophorum as minor components, along with one known related cembranoid 10. Their structures were elucidated by detailed spectroscopic analysis and chemical conversion. The chemical structures of these metabolites are characterized by the different patterns of the additional cyclization within the 14-member skeleton, which leading to the formation of furan, pyran, oxepane, and peroxyl rings, respectively. Among them, sarcophytrols R and S(6 and 7) share a rare decaryiol skeleton with an unusual C12/C15 cyclization. In addition, the absolute configurations of sarcophytrols M and T(1 and 8) were determined by the modified Mosher’s method. The research of these new secondary metabolites provided a further understanding of the diversity of cyclized cembranoids from the title species.

Further New Highly Oxidative Cembranoids from the Hainan Soft Coral Sarcophyton trocheliophorum

Three new highly oxidative cembranoids, sarcophytrols D–F (1–3), were obtained from the South China Sea soft coral Sarcophyton trocheliophorum, along with two known related ones (4 and 5). Their structures were elucidated by extensive spectroscopic analyses and by comparison with literature data. The discovery of these new secondary metabolites enriched the family of cembranoids deduced from the title animal.Graphical Abstract