Li-Dong Shao

Construction of Tetracyclic 3-Spirooxindole through Cross-Dehydrogenation of Pyridinium: Applications in Facile Synthesis of (±)-Corynoxine and (±)-Corynoxine B

A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivatives with 3-substituted pyridines. As examples of the application of this new methodology, two potentially medicinal natural products, (±)-corynoxine and (±)-corynoxine B, were efficiently synthesized in five scalable steps.

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz–enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B’s effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

Hupehenols A-E, Selective 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD1) Inhibitors from Viburnum hupehense

Five selective 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) competitive inhibitors, hupehenols A-E (1-5), were isolated from Viburnum hupehense. The structure elucidation indicated that compounds 1-5 are new 20,21,22,23,24,25,26,27-octanordammarane triterpenoids. Their structures were established on the basis of NMR spectroscopic and mass spectrometric analysis. Hupehenols A-E (1-5) showed inhibition against human 11β-HSD1, with hupehenols B (2) and E (5) having IC50 values of 15.3 and 34.0 nM, respectively. Moreover, hupehenols C (3) and D (4) are highly selective inhibitors of human 11β-HSD1 when compared to murine 11β-HSD1.

Vibsatins A and B, Two New Tetranorvibsane-Type Diterpenoids from Viburnum tinus cv. variegatus

Vibsatins A (1) and B (2), a pair of 14,15,16,17-tetranorvibsane-type diterpenoids that feature a bicyclo[4.2.1]nonane moiety formed by a new C-13/C-2 bond, were isolated from the twigs and leaves of Viburnum tinus cv. variegatus. The structures and absolute configurations were elucidated by a combination of NMR spectra, optical rotation, and X-ray diffraction experiments. A possible biogenetic pathway is also proposed. Moreover, vibsatin A (1) enhanced the neurite outgrowth of NGF-mediated PC12 cells at a concentration of 10 μM.

One-Step Semisynthesis of a Segetane Diterpenoid from a Jatrophane Precursor via a Diels–Alder Reaction

A novel segetane diterpenoid (1) and four jatrophane diterpenoids (2-5) were isolated from an acetone extract of Euphorbia peplus. Due to quantity limitations, we prepared 1 via a Diels-Alder reaction, an approach motivated by this compounds biosynthetic pathway and successfully performed X-ray analysis of 1. Furthermore, in an in vitro activity test, 1 exhibited moderate anti-inflammatory activity, whereas both its precursor (2) and the relevant intermediate (2a, IC50 = 1.56 μM) exhibited significant anti-inflammatory activity.

Three Minor Diterpenoids with Three Carbon Skeletons from Euphorbia peplus

Euphorbia peplus has been used in traditional medicine to treat asthma and psoriasis. Three highly modified diterpenoids, namely, pepluacetal (1) and pepluanol A-B (2-3), have been isolated and identified from this plant. Compounds 1-3 exhibit unprecedented 5/4/7/3, 5/6/7/3, and 5/5/8/3 ring systems, respectively. Their structures with absolute configurations were determined by spectroscopic analyses, X-ray crystallography, and electronic circular dichroism calculations. Since Kv1.3 is a validated target for the treatment of autoimmune diseases, such as multiple sclerosis, type-1 diabetes, asthma, and psoriasis, Kv1.3 was studied in terms of its response to the new compounds. All three compounds inhibit Kv1.3, with compound 3 being the most effective with an IC50 value of 9.50 μM.

Design, Synthesis, and Biological Activities of Vibsanin B Derivatives: A New Class of HSP90 C-Terminal Inhibitors

Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of interaction of the HSP90β CTD with GST-tagged cyclophilin 40 (Cyp40) by ViB derivatives, suggest that ViB can directly bind to the HSP90 C-terminus. On the basis of the docking predictions and primary structure-activity relationships (SARs), a series of ViB analogues devised with focus on the C18 position, along with compounds derivatized at the C4, C7, and C8 positions, were designed and chemically synthesized. Compound 12f (IC50 = 1.12 μM against SK-BR-3) exhibits great potency with drug-like properties. Overall, our findings demonstrate that compounds with the vibsanin B scaffold are a new class of HSP90 C-terminal inhibitors with considerable potential as anticancer agents.

Synthesis of l-Ascorbic Acid Lactone Derivatives

A small focused library which comprised of l-AA lactone derivatives was built with a facile method. This reported method was optimized by modifying the acidity of the solvent. As a result, 12 l-AA lactones were synthesized. Among these lactones, lactones 8–12 were new compounds. The cytotoxicity of these synthetic compounds were investigated.

Synthesis of hupehenols A, B, and E from protopanaxadiol

Hupehenols A–E (3–7) are bioactive octanordammarane triterpenoids, among which hupehenols B (4) and E (7) are the most potent and selective human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors (IC50 = 15 and 34 nM, respectively). Herein, the hupehenols were synthesized from protopanaxadiol, the main component of Panax notoginseng. The different synthetic attempts resulted in the stereoselective synthesis of hupehenols A, B, and E for further biological exploration. Notable features of the synthesis included a regioselective epoxide-opening reaction, regioselective acetylation, and a late-stage stereoselective oxa-Michael addition. Semi-synthetic derivatization of these natural products led to the determination of their absolute configurations, a better understanding of their inherent reactivity patterns, and the required C-17 configuration for murine 11β-HSD1 inhibition. These studies provide the basis for the synthesis of 11β-HSD1 inhibitors as potential targets for the treatment of type 2 diabetes.

Collective formal synthesis of (±)-rhynchophylline and homologues

A collective formal synthesis approach to bioactive oxindole alkaloids, including (±)-rhynchophylline, (±)-isorhynchophylline, (±)-mitraphylline, (±)-formosanine, (±)-isomitraphylline, and (±)-isoformosanine, is completed in a protecting-group free manner. Besides multigram-scaled operations, the notable feature of the synthesis is the application of two one-pot, sequential transformations. Namely, two key tetracyclic intermediates pyridinium salt 9 and monoester 14 were prepared by a one-pot N-alkylation/cross-dehydrogenative coupling sequence and a one-pot Michael/Karpocho sequence with minimal purification, respectively.