Design, Synthesis, Antifungal Evaluation, Structure-Activity Relationship (SAR) Study, and Molecular Docking of Novel Spirotryprostatin A Derivatives.

Phytopathogenic fungi cause plant diseases and economic losses in agriculture. To efficiently control plant pathogen infections, a total of 19 spirotryprostatin A derivatives and 26 spirooxindole derivatives were designed, synthesized, and tested for their antifungal activity against ten plant pathogens. Additionally, the intermediates of spirooxindole derivatives were investigated, including proposing a mechanism for diastereoselectivity and performing amplification experiments. The bioassay results demonstrated that spirotryprostatin A derivatives possess good and broad-spectrum antifungal activities. Compound 4d exhibited excellent antifungal activity in vitro, equal to or higher than the positive control ketoconazole, against Helminthosporium maydis, Trichothecium roseum, Botrytis cinerea, Colletotrichum gloeosporioides, Fusarium graminearum, Alternaria brassicae, Alternaria alternate, and Fusarium solan (MICs: 8-32 µg/mL). Compound 4k also displayed remarkable antifungal activity against eight other phytopathogenic fungi, including Fusarium oxysporium f. sp. niveum and Mycosphaerella melonis (MICs: 8-32 µg/mL). The preliminary structure-activity relationships (SARs) were further discussed. Moreover, molecular docking studies revealed that spirotryprostatin A derivatives anchored in the binding site of succinate dehydrogenase (SDH). Therefore, these compounds showed potential as natural compound-based chiral fungicides and hold promise as candidates for further enhancements in terms of structure and properties.

Transamidation of thioamides with nucleophilic amines: thioamide N-C(S) activation by ground-state-destabilization.

Thioamides are 'single-atom' isosteres of amide bonds that have found broad applications in organic synthesis, biochemistry and drug discovery. In this New Talent themed issue, we present a general strategy for activation of N-C(S) thioamide bonds by ground-state-destabilization. This concept is outlined in the context of a full study on transamidation of thioamides with nucleophilic amines, and relies on (1) site-selective N-activation of the thioamide bond to decrease resonance and (2) highly chemoselective nucleophilic acyl addition to the thioamide CS bond. The follow-up collapse of the tetrahedral intermediate is favored by the electronic properties of the amine leaving group. The ground-state-destabilization concept of thioamides enables weakening of the N-C(S) bond and rationally modifies the properties of valuable thioamide isosteres for the development of new methods in organic synthesis. We fully expect that in analogy to the burgeoning field of destabilized amides introduced by our group in 2015, the thioamide bond ground-state-destabilization activation concept will find broad applications in various facets of chemical science, including metal-free, metal-catalyzed and metal-promoted reaction pathways.

Verbascoside: An Efficient and Safe Natural Antibacterial Adjuvant for Preventing Bacterial Contamination of Fresh Meat.

Inappropriate and disproportionate antibiotic use contributes immensely to the development of antibiotic resistance in bacterial species associated with food contamination. Therefore, alternative strategies to treat multidrug-resistant (MDR) bacterial infections are urgently needed. In this study, verbascoside was shown to exhibit excellent antibacterial activity and synergistic effects in combination with cell wall synthesis-inhibiting antibiotics, indicating that it can be used as an adjuvant to restore or increase the activity of antibiotics against resistant pathogens. In a mechanistic study, higher concentrations of verbascoside resulted in a longer lag phase and a lower specific exponential-phase growth rate of bacteria. Furthermore, verbascoside exerted its antimicrobial activity through multiple mechanisms, including cell membrane dysfunction, biofilm eradication and changes in cell morphology. The promising antibacterial activity and in vitro safety assessment results suggested that verbascoside can be used as a food additive for fresh meat preservation. Treatment with medium and high doses of verbascoside caused significant bacterial death in meat samples, slowed the spoilage rate, and extended the shelf life. Collectively, verbascoside is expected to be useful as an antibiotic adjuvant to prevent or treat resistant bacteria-related infections and an alternative novel antimicrobial additive in the food industry.

Mechanochemical Solvent-Free Suzuki-Miyaura Cross-Coupling of Amides via Highly Chemoselective N-C Cleavage.

Although cross-coupling reactions of amides by selective N-C cleavage are one of the most powerful and burgeoning areas in organic synthesis due to the ubiquity of amide bonds, the development of mechanochemical, solid-state methods remains a major challenge. Herein, we report the first mechanochemical strategy for highly chemoselective, solvent-free palladium-catalyzed cross-coupling of amides by N-C bond activation. The method is conducted in the absence of external heating, for short reaction time and shows excellent chemoselectivity for σ N-C bond activation. The reaction shows excellent functional group tolerance and can be applied to late-stage functionalization of complex APIs and sequential orthogonal cross-couplings exploiting double solventless solid-state methods. The results extend mechanochemical reaction environments to advance the chemical repertoire of N-C bond interconversions to solid-state environmentally friendly mechanochemical methods.

Controllable Strategy for Metal-Organic Framework Light-Driven [2 + 2] Cycloaddition Reactions via Solvent-Assisted Linker Exchange.

Flexible olefinic trans-1,2-bis(4-pyridyl)ethene linkers were postsynthetically introduced into the metal-organic frameworks (MOFs) containing parallel rigid 4,4'-bipyridine linkers with a spacing of less than 4.2 Å by the linker exchange strategy, and then, the MOF satisfied Schmidt criteria could be obtained. Eventually, MOF products connected by cyclobutane derivatives were formed by the photochemical [2 + 2] cycloaddition reaction under UV irradiation.

Metal-Free Synthesis of 2-Substituted Quinolines via High Chemoselective Domino Condensation/Aza-Prins Cyclization/Retro-Aldol between 2-Alkenylanilines with ß-Ketoesters.

A highly chemoselective domino condensation/aza-Prins cyclization/retro-aldol between 2-alkenylanilines with ß-dicarbonyl compounds under metal-free conditions was accomplished, giving a large category of valuable 2-substituted quinolines in good yields with excellent functional group toleration. This newly established process, adopting ß-ketoesters as masked C1 synthons via C-C cleavage, could even be simplified into a three-component [3 + 2 + 1] domino version consisting of exceedingly low-priced commercial starting materials. The synthetic application of products was exemplified by several intriguing chemical operations.

Synthesis of C6-Substituted Isoquinolino[1,2-b]quinazolines via Rh(III)-Catalyzed C-H Annulation with Sulfoxonium Ylides.

We report the synthesis of C6-substituted isoquinolino[1,2-b]quinazolinones via rhodium(III)-catalyzed C-H annulation with sulfoxonium ylides and evaluation of the cytotoxic activity of the scaffold. This C-H activation approach enables the most straightforward and convergent synthesis of C6-substituted isoquinolino[1,2-b]quinazolines reported to date. This operationally simple method is compatible with a wide variety of the sulfoxonium ylide and arene C-H activation coupling partners, permitting access to diverse isoquinolino[1,2-b]quinazolines. This method shows a high atom economy, generating H2O and dimethyl sulfoxide (DMSO) as by-products. This method is scalable and operates with exquisite N-lactam cyclization selectivity, thus enabling expedient access to new heterocyclic analogues featuring promising cytotoxic properties.

Two Natural Alkaloids Synergistically Induce Apoptosis in Breast Cancer Cells by Inhibiting STAT3 Activation.

Breast cancer has become a worldwide threat, and chemotherapy remains a routine treatment. Patients are forced to receive continuous chemotherapy and suffer from severe side effects and poor prognosis. Natural alkaloids, such as piperine (PP) and piperlongumine (PL), are expected to become a new strategy against breast cancer due to their reliable anticancer potential. In the present study, cell viability, flow cytometry, and Western blot assays were performed to evaluate the suppression effect of PP and PL, alone or in combination. Data showed that PP and PL synergistically inhibited breast cancer cells proliferation at lower doses, while only weak killing effect was observed in normal breast cells, indicating a good selectivity. Furthermore, apoptosis and STAT3 signaling pathway-associated protein levels were analyzed. We demonstrated that PP and PL in combination inhibit STAT3 phosphorylation and regulate downstream molecules to induce apoptosis in breast cancer cells. Taken together, these results revealed that inactivation of STAT3 was a novel mechanism with treatment of PP and PL, suggesting that combination application of natural alkaloids may be a potential strategy for prevention and therapy of breast cancer.

Synthesis of Amides by Mild Palladium-Catalyzed Aminocarbonylation of Arylsilanes with Amines Enabled by Copper(II) Fluoride.

A general Pd-catalyzed synthesis of amides by oxidative aminocarbonylation of arylsilanes under mild conditions was accomplished for the first time. The reaction is promoted by a commercially available copper(II) fluoride, which acts as a dual silane activator and mild oxidant, enabling highly efficient aminocarbonylation of versatile arylsilanes at atmospheric CO pressure. The reaction is tolerant of a wide range of arylsilanes and various sensitive halide functional groups as well as a broad scope of amines are compatible with this oxidative process using cheap CO. A significant aspect involves the increased efficiency by the catalyst system. The reaction represents a segue into the powerful Pd-catalyzed oxidative transformations of organosilanes.

Color-Tuning and Near-Sunlight White Emission in Highly Stable Rod-Spacer MOFs with Defective Dicubane Based Lead(II)-Carboxyl Chains.

The active lone pair electron effect and highly flexible coordination geometry of Pb2+ prevented the rational construction of metal-organic frameworks (MOFs) but promoted excellent fluorescence tuning. The regulation on organic and alkali templates facilitated the assemblies of three new Pb-MOFs: [Pb2(pia)2(DMA)]·DMA (1), [Pb2(pia)2(DMF)]·1.5DMF (2), and [Pb2(pia)2(DMF)]·NEt3 (3). They were rigid rod-spacer and double-walls frameworks, which possess defective dicubane [Pb4O6] based metal-carboxyl chains constructed from both semidirected and holodirected Pb2+ ions. These MOFs exhibited thermal stability up to 370 °C and unprecedented chemical stability in H2O and acidic (pH 2) and alkaline (pH 12) aqueous solutions, found for the first time in Pb-MOFs. A single-phase and rare-earth-free white-emitting phosphor, 1, was screen out, which showed a near-sunlight and human-vision-friendly broadband spectrum covering the full visible region, possessing the close-to-pure-white chromaticity coordinates of (0.332, 0.347), a near-daylight color temperature of 5696 K, and a high color rendering index of 95. The replacement of DMF as apical ligand and guest in 2 resulted in an intrinsic single and narrow emission at 562 nm with yellow color. The convenient yellow-and-blue color-tuning until white for 2 was realized by either solution or solid blending with blue-emissive H2pia, benefited from their highly matched excitation spectra. Using large NEt3 as template guest induced great framework distortion for 3 and led to white emission with chromaticity coordinates of (0.302, 0.294), stemming from nonequivalent dual emission at 450 and 545 nm. In-depth structure analysis revealed intra-/interchain Pb···Pb interactions in the lead(II)-carboxyl chains greatly affected the photochemical output.

Regioselective deoxygenative chalcogenation of 7-azindole N-oxides promoted by I2/PEG-200.

We developed a general and sustainable approach for the regioselective deoxygenative chalcogenation of 7-azindole N-oxides; the combination of an internal oxidant and a green solvent has been used successfully for the synthesis of mono- and dichalcogenyl 7-azaindoles which are of pharmaceutical interest. The regioselectivity is tunable by the variation of the reaction conditions. I2/PEG was established as an efficient and reusable catalytic system for C-H chalcogenation. This developed methodology has great potential for practical utility, with a broad substrate scope, green reaction conditions, and operational simplicity.

Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.

Total synthesis and biological evaluation of spirotryprostatin A analogs.

Based on the spirotryprostatin A structure, a series of compounds belonging to spiro-indolyl diketopiperazine structural class were designed and synthesized, which embody an oxindole with an all-carbon quaternary stereocenter. The total synthesis can efficiently be accessed in a seven-step reaction sequence with 18-28% overall yield from commercially available materials, and a highly enantioselective 1,3-dipolar cycloaddition, N-acylation of the resulting stereochemically complex spiro[pyrrolidin-3,3'-oxindole]s core with Fmoc-L-pro-Cl and spontaneous ring closure upon N-deprotection were obtained. The synthesized compounds 13a-e and 15a-e were evaluated for their antibacterial activities. The result showed that compounds 13b and 15b were active only against Gram-positive bacteria, and selective antibacterial activity was exhibited by compounds 13d and 13e against Streptococcus lactis. Further, all the remaining compounds showed a certain degree of antibacterial activity. In addition, the structure-activity relationship is also discussed.

A new p-hydroxybenzoic acid derivative from an endophytic fungus Penicillium sp. of Nerium indicum.

A new p-hydroxybenzoic acid derivative named 4-(2'R, 4'-dihydroxybutoxy) benzoic acid (1) was isolated from the fermentation of Penicillium sp. R22 in Nerium indicum. The structure was elucidated by means of spectroscopic (HR-ESI-MS, NMR, IR, UV) and X-ray crystallographic methods. The antibacterial and antifungal activity of compound 1 was tested, and the results showed that compound 1 revealed potent antifungal activity against Colletotrichum gloeosporioides, Alternaria alternata, and Alteranria brassicae with MIC value of 31.2 µg/ml.

One-pot synthesis and antifungal activity against plant pathogens of quinazolinone derivatives containing an amide moiety.

An efficient one-pot, three-component synthesis of quinazolinone derivatives containing 3-acrylamino motif was carried out using CeO2 nanoparticles as catalyst. Thirty-nine synthesized compounds were obtained with satisfied yield and elucidated by spectroscopic analysis. Four phytopathogenic fungi were chosen to test the antifungal activities by minimum inhibitory concentration (MIC) method. Compounds 4ag, 4bb, 4bc showed broad antifungal activities against at least three fungi, and dramatic effects of substituents on the activities were observed. Docking studies were established to explore the potential antifungal mechanism of quinazolinone derivatives as the chitinase inhibitors, and also verified the importance of the amide moiety.

Aza-polycyclic aromatic hydrocarbons from Saruma henryi.

A new azafluoranthene alkaloid, named sarumine (1), along with six known N-containing derivatives of phenanthrenes, 2-7, were isolated from the whole herb of Saruma henryi. Their structures were elucidated on the basis of extensive spectroscopic analysis. Moreover, antimicrobial activities of all compounds were evaluated.

[Chemical Compositions from Stems and Branches of Sorbaria arborea].

OBJECTIVE: To investigate the chemical constituents from the stems and branches of Sorbaria arborea. METHODS: The chemical constituents were isolated and purified by silica gel column chromatography, Sephadex LH-20 column chromatography and recrystallization. Their structures were identified by physicochemical properties and spectra analysis. RESULTS: Ten compounds were isolated and identified as ursolic acid (1), cucurbitacin F (2), (-) -epicatechin (3), daucosterol (4), arbutin (5), 3-O-ß-anthemisol (6), 2,6-dimethoxy-p-hydroquinone-4-O-ß-D-glucopyranoside (7), lupeol (8), betulin (9) and lup-20 (29) -en-3ß, 30-diol (10). CONCLUSION: All the compounds are isolated from this plant for the first time, and compounds 1, 6 - 8 and 10 are obtained from Sorbaria genus for the first time.

Synthesis of Indolyldiketopiperazines with NBS.

Two series of indolyldiketopiperazines were synthesized starting from methyl 1-substituted-1,2,3,4-tetrahydro-ß-carboline-3-carboxylate hydrochlorides via N-bromo-succinimide (NBS) as an important reagent. All eight compounds were characterized by nuclear magnetic resonance (NMR) and elemental analysis. Furthermore, the mechanisms of NBS-reacted rearrangements are also discussed.

[The ameliorate effect of anthocyanin onMouse testis damage].

OBJECTIVE: To study the effect of Anthocyanin (Ay) on Cadmium-Induced Mouse testis Damage. METHODS: Mouse testis damage model were constructed and testis malonaldehyde (MDA) and protein carbonxyl content (PCO), as well as catalase (CAT) and superoxide dismutase (SOD) were determined. RESULTS: The intoxication of cadmium can cause the increase of MDA and PCO content in mouse testis (P < 0.05), however, the activities of SOD and CAT were altered (P < 0.01). CONCLUSION: Ay have the strong potent to scavenge free radicals, owing to its special chemical structures, and act as a protector to inhibit the oxidative stress induced by cadmium.

Palladium-Catalyzed Domino Conversion of Aryl-Thianthreniums with Anhydrides: Rapidly Building Highly Functionalized Fluorenones.

As a class of rising electrophilic coupling reagents, aryl-thianthreniums (aryl-TTs) have been gaining immense attention. Herein, a novel palladium-catalyzed domino annulation of aryl-TTs with anhydrides is proposed to rapidly assemble a collection of highly functionalized fluorenones. This finding presents an innovative reaction pattern of aryl-TTs wherein the domino annulation version is first involved. Heavily compared with the existing conversions with aryl-TTs, this identified process successively functions as four aryl C-H bonds.