Challenging Approach to the Development of Novel Estrogen Receptor Modulators Based on the Chemical Properties of Guaiazulene.

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.

Photoswitchable inhibitors of human ß-glucocerebrosidase.

Light-switchable inhibitors of the enzyme ß-glucocerebrosidase (GCase) have been developed by anchoring a specific azasugar to a dihydroazulene or an azobenzene responsive moiety. Their inhibitory effect towards human GCase, before and after irradiation are reported, and the effect on thermal denaturation of recombinant GCase and cytotoxicity were studied on selected candidates.

Synthesis of Azulene Derivatives from 2H-Cyclohepta[b]furan-2-ones as Starting Materials: Their Reactivity and Properties.

A variety of synthetic methods have been developed for azulene derivatives due to their potential applications in pharmaceuticals and organic materials. Particularly, 2H-cyclohepta[b]furan-2-one and its derivatives have been frequently used as promising precursors for the synthesis of azulenes. In this review, we describe the development of the synthesis of azulenes by the reaction of 2H-cyclohepta[b]furan-2-ones with olefins, active methylenes, enamines, and silyl enol ethers as well as their reactivity and properties.

Development of Heterocycle-Substituted and Fused Azulenes in the Last Decade (2010-2020).

Azulene derivatives with heterocyclic moieties in the molecule have been synthesized for applications in materials science by taking advantage of their unique properties. These derivatives have been prepared by various methods, involving electrophilic substitution, condensation, cyclization, and transition metal-catalyzed cross-coupling reactions. Herein, we present the development of the synthetic methods, reactivities, and physical properties for the heterocycle-substituted and heterocycle-fused azulenes reported in the last decade.

Antitumor Effects and Tumor-specificity of Guaiazulene-3-Carboxylate Derivatives Against Oral Squamous Cell Carcinoma In Vitro.

AIM: The aim of this study was to investigate the antitumor potential of guaiazulene-3-carboxylate derivatives against oral malignant cells. MATERIALS AND METHODS: Twelve guaiazulene-3-carboxylate derivatives were synthesized by introduction of either with alkyl group [1-5], alkoxy group [6, 7], hydroxyl group [8, 9] or primary amine [10-12] at the end of sidechains. Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against 3 human oral mesenchymal cell lines to that against 4 human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50value against OSCC cell lines. Cell cycle analysis was performed by cell sorter. RESULTS: [6, 7] showed the highest TS and PSE values, and induced the accumulation of both subG1 and G2/M cell populations in HSC-2 OSCC cells. Quantitative structure-activity relationship analysis demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the 3D shape, electric state and ionization potential. CONCLUSION: Alkoxyl guaiazulene-3-carboxylates [6, 7] can be potential candidates of lead compound for developing novel anticancer drugs.

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis.

The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

Azulene-based compounds for targeting orexin receptors.

A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 µM range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold.

Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue tryptophan analogue ß-(1-azulenyl)-l alanine and its incorporation into argyrin C.

The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid ß-(1-azulenyl)-l alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of ß-(1-azulenyl)-l alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon ß-(1-azulenyl)-l alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.

Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core.

The hamigeran family of natural products has been the target of numerous synthetic efforts because of its biological activity and interesting structural properties. Herein, we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members because of their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products.

Metal-Catalyzed C-H Bond Activation of 5-Membered Carbocyclic Rings: A Powerful Access to Azulene, Acenaphthylene and Fulvene Derivatives.

Azulene, acenaphthylene and fulvene derivatives exhibit important physical properties useful in materials chemistry as well as valuable biological properties. Since about two decades ago, the metal-catalyzed functionalization of such compounds, via C-H bond activation of their 5-membered carbocyclic ring, proved to be a very convenient method for the synthesis of a wide variety of azulene, acenaphthylene and fulvene derivatives. For such reactions, there is no need to prefunctionalize the 5-membered carbocyclic rings. In this review, the progress in the synthesis of azulene, acenaphthylene and fulvene derivatives via metal-catalyzed C-H bond activation of their 5-membered carbocyclic ring are summarized.

A Concise, Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from (R)-(-)-Carvone.

A concise, efficient and scalable synthesis of thapsigargin and nortrilobolide from commercially available (R)-(-)-carvone was developed. Our synthetic strategy is inspired by nature's carbon-carbon bond formation sequence, which facilitates the construction of a highly functionalized sesquiterpene lactone skeleton in five steps via an enantioselective ketone alkylation and a diastereoselective pinacol cyclization. We envision that this strategy will permit the construction of other members of the family, structural analogs and provide a practical synthetic route to these important bioactive agents. In addition, we anticipate that the prodrug Mipsagargin, which is currently in late-stage clinical trials for the treatment of cancer, will also be accessible via this strategy. Hence, the limited availability from natural sources, coupled with an estimated demand of one metric ton per annum for the prodrug, provides a compelling mandate to develop practical total syntheses of these agents.

Antiretroviral (HIV-1) activity of azulene derivatives.

The antiretroviral activity of azulene derivatives was detected for the first time. A series of eighteen diversely substituted azulenes was synthesized and tested in vitro using HIV-1 based virus-like particles (VLPs) and infectious HIV-1 virus in U2OS and TZM-bl cell lines. Among the compounds tested, the 2-hydroxyazulenes demonstrated the most significant activity by inhibiting HIV-1 replication with IC50 of 2-10 and 8-20 µM for the VLPs and the infectious virus, respectively. These results indicate that azulene derivatives may be potentially useful candidates for the development of antiretroviral agents.

Chemo- and Regioselective Functionalization of Nortrilobolide: Application for Semisynthesis of the Natural Product 2-Acetoxytrilobolide.

The difference in reactivity of the hexaoxygenated natural product thapsigargin (1) and the pentaoxygenated nortrilobolide (3) was compared in order to develop a chemo- and regioselective method for the conversion of nortrilobolide (3) into the natural product 2-acetoxytrilobolide (4). For the first time, a stereoselective synthesis of 2-acetoxytrilobolide (4) is described, which involves two key reactions: the first chemical step was a one-pot substitution-oxidation reaction of an allylic ester into its corresponding α,ß-unsaturated ketone. The second process consisted of a stereoselective α'-acyloxylation of the key intermediate α,ß-unsaturated ketone to afford its corresponding acetoxyketone, which was converted into 2-acetoxytrilobolide (4) in a few steps. This innovative approach would allow the synthesis of a broad library of novel and valuable penta- and hexaoxygenated guaianolides as potential anticancer agents.

Divergent pathways to furosesquiterpenes: first total syntheses of (+)-zedoarol and (Rac)-gweicurculactone.

A non-natural hydroxy-elemane was found amenable to divergent transformations, producing either polyunsaturated guaianes under basic, oxygen-free conditions, or oxidized furogermacranes when anionic oxy-Cope reaction quenched by an oxidant is employed. Based on these findings, the first total syntheses of zedoarol and gweicurculactone are reported.

Production of the pepper aroma compound, (-)-rotundone, by aerial oxidation of α-guaiene.

The aroma link between pepper and wine has recently been elucidated to be due to the important aroma compound rotundone. To date, rotundone is the only known impact odorant with a peppery aroma. Although the concentration found in products of natural origin is small, the odor detection threshold is among the lowest of any natural product yet discovered. We report herein the identification of the first known precursor to rotundone, namely, α-guaiene, and that one mechanism of transformation is simple aerial oxidation.

Synthesis of substituted azulenes via Pt(II)-catalyzed ring-expanding cycloisomerization.

Substituted azulenes, valuable structures for electronic devices and pharmaceuticals, have been synthesized by the platinum(II)-catalyzed intramolecular ring-expanding cycloisomerization of 1-en-3-yne with ortho-disubstituted benzene. This novel method provides an alternative route for the efficient synthesis of substituted azulenes. The reaction mechanism of selected catalytic transformations was explored using density functional calculations.

Diastereoselective N-sulfonylaminoalkenylation of azulenes from terminal alkynes and azides via N-sulfonyl-1,2,3-triazoles.

The development of rhodium-catalyzed diastereoselective N-sulfonylaminoalkenylation of azulenes using N-sulfonyltriazoles is described. This procedure can be successfully applied to rhodium-catalyzed diastereoselective N-sulfonylaminoalkenylation of azulenes starting from terminal alkynes and N-sulfonylazides via a three-component semi-one-pot process.

Design and synthesis of novel 1,2,3-triazole derivatives of coronopilin as anti-cancer compounds.

A series of 1,2,3-triazole coronopilin congeners have been designed and synthesized by employing click chemistry approach starting from parthenin and evaluated for their cytotoxicity against a panel of six human cancer cell lines (PC-3, THP-1, HCT-15, HeLa, A-549 and MCF-7). While many compounds exhibited significant anticancer activity, compound 3a, was found to be the most promising analogue in this series with IC50 values of 3.1 µM on PC-3 cell line. Flow-cytometric studies showed that 1,2,3-triazole derivative-3a induce dose dependent apoptosis in the sub G1 phase. This lead molecule-3a was further studied for NF-κB (p65) transcription factor inhibitory activity using Elisa and western blotting analysis which confirmed concentration dependent inhibitory activity against NF-κB, p65 with 80% inhibition in 24 h at 100 µM.

Breakdown of interference rules in azulene, a nonalternant hydrocarbon.

We have designed and synthesized five azulene derivatives containing gold-binding groups at different points of connectivity within the azulene core to probe the effects of quantum interference through single-molecule conductance measurements. We compare conducting paths through the 5-membered ring, 7-membered ring, and across the long axis of azulene. We find that changing the points of connectivity in the azulene impacts the optical properties (as determined from UV-vis absorption spectra) and the conductivity. Importantly, we show here that simple models cannot be used to predict quantum interference characteristics of nonalternant hydrocarbons. As an exemplary case, we show that azulene derivatives that are predicted to exhibit destructive interference based on widely accepted atom-counting models show a significant conductance at low biases. Although simple models to predict the low-bias conductance do not hold with all azulene derivatives, we demonstrate that the measured conductance trend for all molecules studied actually agrees with predictions based on the more complete GW calculations for model systems.

1,2,3-Triazole-containing derivatives of rupestonic acid: click-chemical synthesis and antiviral activities against influenza viruses.

Two series of rupestonic acid derivatives, (1-substituted-1H-1,2,3-triazol-4-yl)methyl 2-((5R,8S,8aS)-3,8-dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octahydroazulen-5-yl)acrylate and N-(1-substituted-1H-1,2,3-triazol-4-yl)methyl 2-((5R,8S,8aS)-3,8-dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octahydroazulen-5-yl)acrylamide were easily and efficiently synthesized via click chemistry. These compounds were tested for their in vitro activities against various strains of influenza A virus (H1N1, oseltamivir resistant H1N1, H3N2) and influenza B virus. The results showed that nine compounds were active against the H1N1 strain of influenza A virus and among them the best one 14a, was as active as the reference drugs, Oseltamivir and Ribavirin. Some of them were also active on the Oseltamivir resistant H1N1 strain. In regards to influenza B virus, twenty-one compounds over thirty were active and seven of them 7b, 8b, 9b, 10a, 11b, 12b, 13b showed better activity than Ribavirin. The structure-activity relationship of these compounds is discussed on the basis of each type of the viruses studied. Furthermore, four best representative compounds 7b, 10a, 12b and 14a were evaluated in a plaque assay experiment using MDCK cells and RBV as control compound and the results showed that 7b, 10a and 12b were better than RBV in inhibiting plaque formation, in good accordance with their anti-influenza B activities.