Concise Synthesis of 11-Noriridoids via Pauson-Khand Reaction.

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.

Design, synthesis and bioactive evaluation of geniposide derivatives for antihyperuricemic and nephroprotective effects.

Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

Semi-synthesis as a tool for broadening the health applications of bioactive olive secoiridoids: a critical review.

Covering: 2005 up to 2020Olive bioactive secoiridoids are recognized as natural antioxidants with multiple beneficial effects on human health. Nevertheless, the study of their biological activity has also disclosed some critical aspects associated with their application. Firstly, only a few of them can be extracted in large amounts from their natural matrix, namely olive leaves, drupes, oil and olive mill wastewater. Secondly, their application as preventive agents and drugs is limited by their low membrane permeability. Thirdly, the study of their biological fate after administration is complicated by the absence of pure analytical standards. Accordingly, efficient synthetic methods to obtain natural and non-natural bioactive phenol derivatives have been developed. Among them, semi-synthetic protocols represent efficient and economical alternatives to total synthesis, combining efficient extraction protocols with efficient catalytic conversions to achieve reasonable amounts of active molecules. The aim of this review is to summarize the semi-synthetic protocols published in the last fifteen years, covering 2005 up to 2020, which can produce natural olive bioactive phenols scarcely available by extractive procedures, and new biophenol derivatives with enhanced biological activity. Moreover, the semi-synthetic protocols to produce olive bioactive phenol derivatives as analytical standards are also discussed. A critical analysis of the advantages offered by semi-synthesis compared to classical extraction methods or total synthesis protocols is also performed.

Recent Advances in Iridoid Chemistry: Biosynthesis and Chemical Synthesis.

Iridoids are a large family of monoterpenoids found in traditional medicinal plants and show significant effects for the human species. In addition to their wide range of biological activities, such as neuroprotective and antitumor activities, the cis-fused bicyclic ring systems of iridoids are still attractive as synthetic targets to apply novel synthetic methodologies. Accordingly, recent progress regarding the biosynthesis and chemical synthesis of iridoids is covered in this minireview. Identification of new enzymes for the iridoid biosynthesis in Catharanthus roseus and ingenious synthetic strategies for the construction of the iridoid skeleton are described.

Synthesis and biological evaluation of geniposide derivatives as potent and selective PTPlB inhibitors.

Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTP1B inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC50 values of 0.35 and 0.41 µM, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity.

Multicomponent Domino Reaction in the Asymmetric Synthesis of Cyclopentan[c]pyran Core of Iridoid Natural Products.

The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which were determined through 2D homo and heteronuclear NMR and n.O.e. experiments on different compounds specially designed for this purpose, such as a dioxane obtained from a diol. Due to their pharmaceutical properties, including sedative, analgesic, anti-inflammatory, CNS depressor or anti-conceptive effects, this methodology to produce the abovementioned iridoid derivatives, is an interesting strategy in terms of new drug discovery as well as pharmaceutical development.

Synthesis of [3 H] and [14 C]genipin.

[3 H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp2 CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [3 H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [14 C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [14 C]cyanide.

Total syntheses of several iridolactones and the putative structure of noriridoid scholarein A: an intramolecular Pauson-Khand reaction based one-stop synthetic solution.

A simple and general approach towards the total syntheses of several iridolactones such as (±)-boschnialactone, (±)-7-epi-boschnialactone, (±)-teucriumlactone, (±)-iridomyrmecin, (±)-isoboonein, (±)-7-epi-argyol, (±)-scabrol A, (±)-7-epi-scabrol A, and (±)-patriscabrol as well as the putative structure of scholarein A is delineated. The synthetic strategy features a diastereoselective intramolecular Pauson-Khand reaction (IPKR) to construct the iridoid framework followed by some strategic synthetic manipulations to access the targeted monoterpenes including those having diverse oxy-functionalization patterns and with 3-5 contiguous stereogenic centres in a highly stereocontrolled manner. Also, the present endeavour includes the first total synthesis of scabrol A.

Discovery of Glycosylated Genipin Derivatives as Novel Antiviral, Insecticidal, and Fungicidal Agents.

A series of novel genipin glycoside derivatives incorporating 11 glycosidic moieties at either the 1 or 10 position of genipin were designed and synthesized. These compounds exhibited moderate to excellent inhibitory activities against tobacco mosaic virus. Especially, the in vitro and in vivo activities of compounds 6e, 7c, 7d, 7f, 7h, and 7i were comparable to that of ribavirin. In particular, compound 7c, the mannosyl derivative of genipin at the 10 position, showed the best activity. The series of genipin glycosyl derivatives also displayed fungicidal activities against 14 kinds of phytopathogenic fungi, especially for Rhizoctonia cerealis and Sclerotinia sclerotiorum. Moreover, compound 6h exhibited good insecticidal activity against diamondback moth; compounds 7b, 7c, and 7g exhibited moderate insecticidal activity against three kinds of Lepidoptera pests (oriental armyworm, cotton bollworm, and corn borer); and compound 7e showed excellent larvacidal activities against mosquito.

New semi-synthetic analogs of oleuropein show improved anticancer activity in vitro and in vivo.

Oleuropein is a glucosylated seco-iridoid present in olive fruits and leaves. Due to its broad spectrum of biological activities, including anticancer properties, oleuropein has attracted scientific attention for the past 20 years. The promising antiproliferative activity of an olive leaf extract enriched in oleuropein against a series of human cancer cell lines, prompted us to proceed with the semi-synthesis of 51 analogs of oleuropein. Following their initial screening against the estrogen receptor negative breast cancer cell line SKBR3, 7 analogs were shown to display significant cytotoxicity and were further tested against 6 additional solid tumor-derived and leukemic cell lines. The analog with the most promising antitumor activity (24) was selected for more detailed studies. 24 was non-toxic to peripheral blood mononuclear cells derived from healthy blood donors when tested at concentrations close to its half maximal inhibitory concentration. In vivo administration of 24 in melanoma-bearing mice resulted in reducing tumor size in a dose-dependent manner and in inducing anti-melanoma-reactive immune responses. Our results suggest that analog 24, emerging from the initial structure of oleuropein, represents a promising lead structure for further optimization.

Synthesis of an Iridoid-Inspired Compound Collection and Discovery of Autophagy Inhibitors.

Iridoids comprise a large group of monoterpenoid natural products displaying a diverse array of biological activities ranging from neurotrophic to anti-inflammatory and anti-tumorigenic properties. Therefore, the development of concise synthesis routes to compound collections inspired by the structural features of these natural products is of particular relevance for chemical biology and medicinal chemistry. Herein we describe a samarium diiodide-mediated synthesis of a small, focused iridoid-inspired compound collection. Characterization of these iridoid analogues in biological assays revealed novel small-molecule inhibitors of autophagy.

Synthesis and antitumor activity evaluation of lamiridosin A derivatives.

A series of lamiridosin A derivatives were synthesized through simple procedures. Their antitumor activities were evaluated against EC9706, MGC803, and B16 cell lines in vitro. Several compounds showed potent antitumor activity, especially compound 10, with IC50 value of 2.36 µmol/L against MGC803 cell lines, is more potent than marketed positive drug 5-fluorouridine (5-FU).

Genipin Derivatives Protect RGC-5 from Sodium Nitroprusside-Induced Nitrosative Stress.

CHR20 and CHR21 are a pair of stable diastereoisomers derived from genipin. These stereoisomers are activators of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). In the rat retinal ganglion (RGC-5) cell model these compounds are non-toxic. Treatment of RGC-5 with 750 µM of sodium nitroprusside (SNP) produces nitrosative stress. Both genipin derivatives, however, protect these cells against SNP-induced apoptic cell death, although CHR21 is significantly more potent than CHR20 in this regard. With Western blotting we showed that the observed neuroprotection is primarily due to the activation of protein kinase B (Akt)/eNOS and extracellular signal-regulated kinase (ERK1/2) signaling pathways. Therefore, LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or PD98059 (a MAPK-activating enzyme inhibitor) abrogated the protective effects of CHR20 and CHR21. Altogether, our results show that in our experimental setup neuroprotection by the diasteromeric pair is mediated through the PI3K/Akt/eNOS and ERK1/2 signaling pathways. Further studies are needed to establish the potential of these compounds to prevent ntric oxide (NO)-induced toxicity commonly seen in many neurodegenerative diseases.

Divergent synthetic route to new cyclopenta[c]pyran iridoids: syntheses of jatamanin A, F, G and J, gastrolactone and nepetalactone.

Six natural iridoids including jatamanin A, F, G and J, gastrolactone and nepetalactone have been synthesized via the efficient transformation of a core cyclopenta[c]pyran intermediate. Key features of the syntheses include the stereoselective construction of the core cyclopenta[c]pyran skeleton of the iridoid lactones via a Pd(0)-catalyzed intramolecular allylic alkylation, and the facile transformation of the common intermediate into natural iridoids.

Improved Syntheses of (+)-Iridomyrmecin and (-)-Isoiridomyrmecin, Major Components of Matatabilactone.

Improved syntheses'of iridomyrmecin and isoiridomyrmecin, major components of matatabilactone, are described. The synthesis features a direct transformation of nepetalactol into key intermediates by DIBAL-H reduction and provides an expeditious and straightforward production of iridoid lactones for biological investigations of the Matatabi phenomenon.

Gardenamide A attenuated cell apoptosis induced by serum deprivation insult via the ERK1/2 and PI3K/AKT signaling pathways.

Gardenamide A (GA) is a stable genipin derivative with neuroprotective properties. It rescued pheochromocytoma cell (PC12) sympathetic cultures and retinal neuronal cells from apoptosis insult induced by serum deprivation. GA attenuated the accumulation of intracellular reactive oxygen species (ROS) and the loss of mitochondrial membrane potential. Western blotting with specific phospho-antibodies indicated that GA increased the phosphorylation of both the protein kinase B (Akt) and the extracellular signal-regulated kinase (ERK1/2) in PC12 cells. The GA neuroprotective effect was inhibited by either the specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 or the mitogen-activated protein kinase (MAPK) pathway inhibitor PD98059. These results propose that the neuroprotective effect of GA on PC12 neuronal cell cultures was mediated through both the PI3K/Akt and ERK1/2 signaling pathways. Therefore, GA may serve as a pharmacological tool to investigate neuroprotective mechanisms of neurons afflicted by different insults.

Characterization of mechanics and cytocompatibility of fibrin-genipin annulus fibrosus sealant with the addition of cell adhesion molecules.

There is an unmet clinical need for a biomaterial sealant capable of repairing small annulus fibrosus (AF) defects. Causes of these defects include painful intervertebral disc herniations, microdiscectomy procedures, morbidity associated with needle puncture injury from discography, and future nucleus replacement procedures. This study describes the enhancements of a fibrin gel through genipin crosslinking (FibGen) and the addition of the cell adhesion molecules (CAMs), fibronectin and collagen. The gel's performance as a potential AF sealant is assessed using a series of in vitro tests. FibGen gels with CAMs had equivalent adhesive strength, gene expression, cytomorphology, and cell proliferation as fibrin alone. However, FibGen gels had enhanced material behaviors that were tunable to higher shear stiffness values and approximated human annulus tissue as compared with fibrin alone, were more dimensionally stable, and had a slower in vitro degradation rate. Cytomorphology of human AF cells cultured on FibGen gels exhibited increased elongation compared with fibrin alone, and the addition of CAMs to FibGen did not significantly affect elongation. This FibGen gel offers the promise of being used as a sealant material to repair small AF defects or to be used in combination with other biomaterials as an adhesive for larger defects.

Genipin-cross-linked layer-by-layer assemblies: biocompatible microenvironments to direct bone cell fate.

The design of biomimetic coatings capable of improving the osseointegration of bone biomaterials is a current challenge in the field of bone repair. Toward this end, layer-by-layer (LbL) films composed of natural components are suitable candidates. Chondroitin sulfate A (CSA), a natural glycosaminoglycan (GAG), was used as the polyanionic component because it promotes osteoblast maturation in vivo. In their native state, GAG-containing LbL films are generally cytophobic because of their low stiffness. To stiffen our CSA-based LbL films, genipin (GnP) was used as a natural cross-linking agent, which is much less cytotoxic than conventional chemical cross-linkers. GnP-cross-linked films display an original combination of microscale topography and tunable mechanical properties. Structural characterization was partly based on a novel donor/acceptor Förster resonance energy transfer (FRET) couple, namely, FITC/GnP, which is a promising approach for further inspection of any GnP-cross-linked system. GnP-cross-linked films significantly promote adhesion, proliferation, and early and late differentiation of preosteoblasts.

Discovery of inhibitors of the Wnt and Hedgehog signaling pathways through the catalytic enantioselective synthesis of an iridoid-inspired compound collection.

Cousins you can count on: An iridoid-inspired compound collection was synthesized efficiently by the resolution of cyclic enones in an asymmetric cycloaddition with azomethine ylides. The collection contained novel potent inhibitors of the Wnt and Hedgehog signaling pathways.

Divergent diastereoselective synthesis of iridomyrmecin, isoiridomyrmecin, teucrimulactone, and dolicholactone from citronellol.

The iridoid natural products iridomyrmecin, isoiridomyrmecin, teucriumlactone, and dolicholactone were prepared from citronellol using a divergent diastereoselective approach. Key steps include a highly diastereoselective enamine/enal cycloaddition and the selective reduction of masked aldehyde functionalities by ionic hydrogenation.