Search

Abstract: A series of 5,6-dihydroxypyrimidine analogs were synthesized and evaluated for their anti-HIV activity in vitro. Among all of the analogs, several compounds exhibited significant anti-HIV activity, especially 1b and 1e, which showed the most potent anti-HIV activity with EC50 values of 0.14 and 0.15μM, and TI (therapeutic index) values of >300 and >900, respectively. Further docking studies revealed that the representative compounds 1e and 3a could meet the HIV-1 integrase inhibition minimal requirements of a chelating domain (two metal ions) and an aromatic domain (π–π stacking interactions). [Copyright &y& Elsevier]

Abstract: Seven previously unreported daphnane-type diterpene esters named acutilobins A–G, together with 12 known ones, were isolated from EtOAc extract of Daphne acutiloba Rehd. Their structures were elucidated based on the spectroscopic data. The cytotoxic and anti-HIV-1 activities of these daphnane-type diterpene esters were evaluated through bioassays. Fourteen of these isolates exhibited definite cytotoxic activities against the five human tumor cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480. Additionally, anti-HIV-1 activities were observed in 13 daphnane-type diterpene esters, among which acutilobins A–G exhibited significant anti-HIV-1 activities with EC50 below 1.5nM and SI over 10,000. Particularly, genkwanineVIII showed the strongest activity with EC50 0.17nM and SI 187,010. [Copyright &y& Elsevier]

Duan Teng Yimu decoction is a Chinese herbal medicine compound with proven therapeutic effects on inflammasome-related diseases, such as rheumatoid arthritis. This decoction consists of three Chinese herbal medicines, including Leonurus japonicus (L. japonicus), which promotes the blood circulation and exhibits detumescence activity, traditionally curing gynecologic and inflammasome diseases. To explore the anti-inflammasome activity and the underlying mechanisms of action of the compounds from L. japonicus. A series of compounds were isolated from L. japonicus. Their anti-inflammasome activities were evaluated in macrophages that were co-stimulated by lipopolysaccharide (LPS) and NLRP3 inflammasome inducers. NLRP3 inflammasome formation and apoptosis speck like containing a CARD (ASC) oligomerization were evaluated by immunofluorescent microscopy and Western blot analysis. The regulation of autophagy after treatment of this compound was also evaluated. Lastly, in vivo activity of Leojaponin was analyzed in a mouse acute gouty arthritis model. Here we show that Leojaponin, a diterpenoid compound from L. japonicus , suppressed lactate dehydrogenase and IL-1β release in Nigericin-stimulated macrophages in a pyroptosis model. Leojaponin inhibits NLRP3 inflammasome activation in both J774A.1 cells and bone marrow-derived macrophages in a dose dependent manner. Moreover, Leojaponin suppressed NLRP3-mediated ASC specks formation and ASC oligomerization. These activities of Leojaponin depend on restoration of autophagy via promoting RAPTOR phosphorylation. Furthermore, Leojaponin ameliorated monosodium urate (MSU)-induced acute gouty arthritis in vivo. Our findings suggest that Leojaponin inhibits NLRP3 inflammasome activation through enhancing autophagy via RAPTOR phosphorylation, thereby highlighting Leojaponin as a potent drug for inflammasome-related diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

The combination of photodynamic therapy (PDT) and chemotherapy is a prospective strategy to improve antitumor efficacy. Herein, a series of novel cytotoxic chlorin-based derivatives as dual photosensitizers (PSs) and histone deacetylase inhibitors (HDACIs) were synthesized and investigated for biological activity. Among them, compound 15e showed definite HDAC2 and 10 inhibitory activities by up-regulating expression of acetyl-H4 and highest phototoxicity and dark-toxicity, which was more phototoxic than Talaporfin as a PS while with stronger dark-toxicity compared to vorinostat (SAHA) as a HDACI. The biological assays demonstrated that 15e was liable to enter A549 cells and localized in mitochondria, lysosomes, golgi and endoplasmic reticulum (ER) etc. multiple organelles, resulting in higher cell apoptosis rate and ROS production compared to Talaporfin. Moreover, it could induce tumor cell autophagy as a dual PS and HDACI. All results suggested that compound 15e could be applied as a potential dual cytotoxic drug for PDT and chemotherapy. [Display omitted] • The dual-mode cytotoxic chlorin-based derivatives as PSs and HDACIs were synthesized. • HDAC inhibitory activities of target compounds were investigated. • Photo-cytotoxicity and dark-cytotoxicity for target compounds were evaluated. • Compound 15e exhibited the strongest PDT and chemotherapy efficacies. • Dual-mode cytotoxic mechanism of compound 15e was further studied. [ABSTRACT FROM AUTHOR]

Nine undescribed limonoids, 18(13 → 14)- abeo -15β,21-dihydroxy-24,25,26,27-tetranor-3,7-dioxoapotirucalla-1,9(11),13(17),20(22)-tetraen-23,21-olide (Toonaone A), 21-hydroxy-24,25,26,27-tetranor-3,7,15-trioxoapotirucalla-1,9(11),20(22)-trien-23,21-olide (Toonaone B), 7α,21-dihydroxy-12α-isobutyryl-24,25,26,27-tetranor-3,15-dioxoapotirucalla-1,20(22)-dien-23,21-olide (Toonaone C), 7,8- seco -7-methyl ester-11β-acetoxy-14β,15β-epoxy-21-hydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,8(30),20(22)-trien-23,21-olide (Toonaone D), 7,8- seco -7-methyl ester-11β-acetoxy-14β,15β-epoxy-23-hydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,8(30),20(22)-trien-21,23-olide (Toonaone E), 7,8- seco -7-methyl ester-11β-acetoxy-14β,15β-epoxy-6β,21-dihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,8(30),20(22)-trien-23,21-olide (Toonaone F), 7,8- seco -7-methyl ester-14β,15β-epoxy-8α,21-dihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,20(22)-dien-23,21-olide (Toonaone G), 7,8- seco -7-methyl ester-14β,15β-epoxy-6β,8α,21-trihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,20(22)-dien-23,21-olide (Toonaone H), 7,8- seco -7-methyl ester-14β,15β-epoxy-6β,8α,21-trihydroxy-24,25,26,27-tetranor-3-oxoapotirucalla-1,20(22)-dien-21,23-diimide (Toonaone I), and five known analogues were isolated from the twigs of Toona ciliata M. Roem. (Meliaceae). Toonaone A possesses the first rare 18(13 → 14)- abeo -limonoid skeleton reported from the genus Toona. Their structures were elucidated using spectroscopic data analyses and quantum chemistry calculations. Biological evaluation showed that toonaone C, toonaone D, toonaone G, toonaciliatavarin F, and toonaciliatavarin G exhibited significant anti-NLRP3 inflammasome activity with IC 50 values ranging from 3.74 to 18.7 μM. GMDMD, IL-1β, and caspase-1 analyses suggested that toonaone D inhibited NLRP3 inflammasome activation and blocked macrophage pyroptosis. [Display omitted] • Nine undescribed limonoids and five analogues were isolated from of Toona ciliate. • Toonaone A possesses a rare 18(13. → 14)-abeo-limonoid skeleton. • Spectroscopic analyses and quantum chemistry calculations were used to elucidate structures. • Some compounds could significantly inhibit NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

• Twenty-four new limonoids were obtained from Toona ciliata. • Their structures were determined by spectroscopic analysis, quantum chemistry calculations, and X-ray diffraction. • Several compounds showed significant anti-NLRP3 inflammasome activity. Twenty-four new limonoids, toonaolides A−X (1 – 24), characterized with an α , β -unsaturated- γ -lactone A-ring were isolated from the twigs of Toona ciliata. Their structures and absolute configurations were elucidated by spectroscopic data, X-ray diffraction crystallography, and quantum chemistry calculations. Most of the isolated compounds (except 9 , 18 , and 24 which possessed the maleimide ring) featured the rare 21-hydroxybutenolide or 23-hydroxybutenolide moieties. In particular, compound 1 has an unprecedented limonoid architecture with 6/6 cis -fused A/B ring system and 2 has an unusual tetrahydrofuran ring B skeleton, featuring a 7/5/6/5 ring system. The biological evaluation showed that compounds 9 , 11 , 12 , 14 , and 18 exhibited significantly anti-NLRP3 inflammasome activity with IC 50 values ranging from 3.2 to 9.7 μM. Analysis of IL-1 β and caspase-1 expression revealed that compounds 11 and 12 are selective inhibitors of NLRP3 inflammasome, which could ameliorate cell pyroptosis by blocking NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e 6 , a second-generation photosensitizer (PS), for tumor photodynamic therapy (PDT). Herein, the novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives 3a , 3b , 3c and 8 were synthesized and their photophysical properties and in vitro bioactivities such as phototoxicity against A549, HeLa and melanoma B16–F10 cells, reactive oxygen species (ROS) production and subcellular localization were evaluated. In addition, preferred target compounds were also investigated for their in vivo pharmacokinetic in SD rats and in vivo antitumor efficacies in C57BL/6 mice bearing melanoma B16–F10 cells. Apparently, simultaneous introduction of amino acid residue and n -hexyloxy chain in chlorin e 6 made a significant improvement in photophysical properties, ROS production, in vitro and in vivo PDT efficacy. Encouragingly, all target compounds showed higher in vitro phototoxicity than Talaporfin, and that 3c (152-Lys) exhibited strongest phototoxicity and highest dark toxicity/phototoxicity ratio, followed by 8 (131-Asp), 3a (152-Asp) and 3b (152-Glu). Moreover, in vivo PDT antitumor efficacy of 3a , 3c and 8 was all better than that of Talaporfin, and that both 3c and 8 had stronger PDT antitumor efficiency than 3a. The overall results suggested that these novel 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives, especially 3c and 8 , might be potential antitumor candidate drugs for clinical treatment of melanoma by PDT. Image 1 • The 31-hexyloxy chlorin e 6 -based 152- or 131-amino acid derivatives were synthesized. • In vitro photodynamic activity and mechanism of target compounds were investigated. • In vivo antitumor potency and pharmacokinetic of target compounds were evaluated. • In vitro and in vivo PDT antitumor efficacy of 3a , 3c , 8 were better than Talaporfin. • In vitro and in vivo PDT antitumor efficacy of 3c and 8 were superior to 3a. [ABSTRACT FROM AUTHOR]

Two new triterpenes mayteneri A (1), mayteneri B (2), and seven known compounds (3-9) were isolated from stems of Maytenus hookeri Loes. The chemical structures of compounds 1 and 2 were established by 1D, 2D NMR, HRESIMS analysis, and calculating electronic circular dichroism (ECD). The structures of known compounds 3-9 were determined by comparison of their spectral with those reported. Compounds 4-7 showed significant inhibitory activity for NLRP3 inflammasome, with the IC50 values of 2.36–3.44 μM. [ABSTRACT FROM AUTHOR]

Leonurus japonicus (motherwort) has been widely used to treat gynecological disorders, in which estrogen is often dysregulated, for a long time in China and other Asian countries. However, the chemical constituents and mechanisms underlying the activity of this medicinal plant are not fully understood. Seventeen of forty-six tested natural products from L. japonicus showed stimulatory or inhibitory effects on estrogen biosynthesis with different potency in human ovarian granulosa-like KGN cells. Luteolin-7-methylether (XLY29) potently inhibited 17β-estradiol production (IC 50 : 5.213 μM) by decreasing the expression of aromatase, the only enzyme in vertebrates that catalyzes the biosynthesis of estrogens, but had no effect on the catalytic activity of aromatase. XLY29 decreased the expression of aromatase promoter I.3/II, and suppressed the phosphorylation of cAMP response element-binding protein. XLY29 potently inhibited phosphorylation of p38 mitogen-activated protein kinase and AKT but had no effect on phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. XLY29 also decreased the serum 17β-estradiol level and disturbed estrous cycle in mice. These results suggest that modulation of estrogen biosynthesis is a novel effect of L. japonicus , and XLY29 warrants further investigation as a new therapeutic means for the treatment of estrogen-related diseases. [ABSTRACT FROM AUTHOR]

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e 6 -based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e 6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e 6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O 2 and excellent antitumor efficacy in vitro and in vivo. [Display omitted] • The conjugates of chlorin e 6 with Dasatinib or Imatinib were synthesized. • In vitro PDT antitumor activities of all target compounds were investigated. • In vivo antitumor potency and mechanism of preferred compound 10b were evaluated. • In vitro PDT antitumor efficacy of 10b was better than chlorin e 6 and talaporfin. • In vivo PDT antitumor efficacy of 10b was superior to chlorin e 6. [ABSTRACT FROM AUTHOR]

Two new compounds, including a norsesquiterpenoid, annuionone H (1), and a quassinoid, picraqualide G (2), along with eleven known compounds (3–13), were isolated from the twigs and leaves of Picrasma quassioides. Comprehensive spectroscopic analyses and NMR calculation with DP4+ analysis were used to identify their structures. Moreover, of all these compounds, compound 4 showed a week inhibition rate in the anti-inflammatory screening results against mouse macrophage J774A.1 cell. [ABSTRACT FROM AUTHOR]

Two new compounds verboncin A (1) and verboncin B (4) and 14 known compounds (2–3 and 5–16) were isolated from Verbena bonariensis, and these 14 compounds were first obtained from this plant. Their chemical structures were established by one and two-dimensional NMR and HRESIMS analysis and the results were compared with literature values. The absolute configuration of 1 was determined by calculating electronic circular dichroism (ECD). The cytotoxicity of some of the compounds against MCF-7, HCT-116, MDA-MB-231, and SW620 human cancer cell lines were evaluated, in which compound 4 showed negligible cytotoxic activity with an IC50 value of 68.08 ± 0.35 µM against the MCF-7 cell line. [ABSTRACT FROM AUTHOR]

Fourteen undescribed seco -type diterpenoids, named nudifloids A-N, together with ten known analogs, were isolated from the leaves of Callicarpa nudiflora. Nudifloids A-N had a characteristic 3,4- seco -labdane-type diterpenoid skeleton, whereas nudifloids A-C and K–N were 3,4- seco -norditerpenoids. Nudifloid A was the first example of a 3,4- seco -12,13,14,15,16-quartnor-labdane diterpenoid, with a seven-membered lactone ring formed through esterification between C-3 and C-11. Nudifloids B and C were a pair of highly modified 3,4- seco -labdane nor-diterpenoid epimers, of which C-2 and C-18 were cyclized together to form a cyclohexene fragment. The structures of these undescribed diterpenoids were established by spectroscopic analysis and reference data. The anti-inflammatory activity of diterpenoids in rich yield was evaluated by analyzing the inhibition of lipopolysaccharide plus nigericin-induced pyroptosis in J774A.1 cells. Nudifloids D and E exhibited prominent anti-NLRP3 inflammasome activity, with IC 50 values of 1.80 and 1.59 μM, respectively. Cell permeability assays revealed that nudifloid D inhibited pyroptosis, which could ameliorate inflammation by blocking the activation of the NLRP3 inflammasome. Guiding by anti-inflammatory activity, fourteen undescribed 3,4- seco -labdane diterpenoids were isolated from the leaves of Callicarpa nudiflora , and evaluated the anti-inflammatory activity of abundant diterpenoids. [Display omitted] • Bioassay-guided isolation of C. nudiflora to obtain twenty-four seco -diterpenoids. • Of which, fourteen undescribed 3,4- seco -labdane diterpenoids were determined. • Nudifloid A exhibits the first example with a seven-numbered lactone ring. • Nudifloids D and E exhibited prominent inflammatory inhibitory activity. [ABSTRACT FROM AUTHOR]

6-(cyclohexylmethyl)-5-ethyl-2-((2-oxo-2-phenylethyl)thio)pyrimidin-4(3H)-one (DB-02) is a member of the newly reported synthetic anti-HIV-1 compounds dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines, S-DACOs. In vitro anti-HIV-1 activity and resistance profile studies have suggested that DB-02 has very low cytotoxicity (CC50>1mM) to cell lines and peripheral blood mononuclear cells (PBMCs). It displays potent anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 2.40 to 41.8 nM). Studies on site-directed mutagenesis, genotypic resistance profiles revealed that V106A was the major resistance contributor for the compound. Molecular docking analysis showed that DB-02 located in the hydrophobic pocket with interactions of Lys101, Val106, Leu234, His235. DB-02 also showed non-antagonistic effects to four approved antiretroviral drugs. All studies indicated that DB-02 would be a potential NNRTI with low cytotoxicity and improved activity. [ABSTRACT FROM AUTHOR]

Two new flavonoids, 8,2′-diprenyl-3,5,7,5′-tetrahydroxyflavone (1) and 8-(1-methoxy-2,3-dihydroxy-3-methylbutyl)naringenin (2), along with twelve known compounds (3–14), were isolated from the leaves of Macaranga pustulata. The structures of the new compounds 1 and 2 were established by detailed spectroscopic data analysis and ECD computational methods. The inhibitory effects of compounds 1–6 against NLRP3 inflammasome activation as well as the cytotoxic activities of compounds 1–4 against MCF-7 and HCT-116 cancer cell lines were investigated. Compound 3 showed weak cytotoxicity against HCT-116 (IC50 = 55.747 ± 3.212 μM). [ABSTRACT FROM AUTHOR]

An easily prepared fluoro-functionalized ionic covalent organic framework (F-iCOF) has been implemented into MALDI-TOF MS, enabling the highly selective enrichment and sensitive determination of perfluorinated sulfonate (PFS) contaminants in a rapid and convenient manner. The good thermal stability and excellent optical absorption properties of F-iCOF makes it a brilliant matrix with no background noise. Moreover, benefitting from the large surface area, appropriate pore size, good water dispersibility, and abundant fluorine atom and cationic characteristic of F-iCOF, it exhibited superior adsorption capacity and enrichment selectivity towards PFSs. Good signal responses for PFSs were obtained in the presence of various interfering compounds such as BSA, HA, or even more than 100-fold excess of glutamic acid and similar in structure sodium alkyl sulfonates, highlighting the specific selectivity of F-iCOF. Calibration curves for potassium perflurobutane sulfonate (PFBSK) in tap water and whole blood were established with good linear correlation in the range 1–500 pg mL−1. The limits of detection and quantification for PFBSK were as low as 0.04 pg mL−1 and 0.05 pg mL−1, respectively, which are comparable or better than the existing methods for the determination of PFSs. [ABSTRACT FROM AUTHOR]

One new ionone glycoside, named centrantheroside F (1), together with 9 known compounds (2-10), were isolated from the roots of Centranthera grandiflora. Their structures were determined by spectroscopic data analyses and comparing with the literature data. The absolute configuration of 1 was confirmed via 2 D NMR and electronic circular dichroism (ECD). All isolated compounds were evaluated for their inhibitory activity on lipopolysaccharide (LPS)-induced nitric oxide (NO) production. [ABSTRACT FROM AUTHOR]

[Display omitted] • Seven new meroterpenoids and two new polyketides were isolated from the fungus Paraphaeosphaeria sp. C-XB-J-1. • Compounds 1 and 7 exhibited significant anti-inflammatory activity. • Compounds 4 and 7 showed potential inhibitory effects on the SARS-CoV-2 Mpro. Seven new meroterpenoids, paraphaeones A-G (1 – 7), and two new polyketides, paraphaeones H-I (8 – 9), along with eight known compounds (10 – 17), were isolated from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1. The structures of 1 – 9 were identified through the analysis of 1H, 13C, and 2D NMR spectra, assisted by HR-ESI-MS data. Compounds 1 and 7 exhibited a dose-dependent decrease in lactate dehydrogenase levels, with IC 50 values of 1.78 μM and 1.54 μM, respectively. Moreover, they inhibited the secretion of IL-1 β and CASP-1, resulting in a reduction in the activity levels of NLRP3 inflammasomes. Fluorescence microscopy results indicated that compound 7 concentration-dependently attenuated cell pyroptosis. Additionally, compounds 4 and 7 showed potential inhibitory effects on the severe acute respiratory syndrome coronavirus-2 main protease (SARS-CoV-2 Mpro), with IC 50 values of 10.8 ± 0.9 μM and 12.9 ± 0.7 μM, respectively. [ABSTRACT FROM AUTHOR]

Ethyl acetate fraction of Toddalia asiatica was fractionated to yield fifteen previously undescribed prenylated coumarins, asiaticasics A-O (1 – 15) along with nine (16 – 24) known derivatives. The structures of these undescribed coumarins were established by spectroscopic analysis and reference data. Biological activity evaluation showed that compound 3 with the IC 50 value of 2.830 μM and compound 12 with the IC 50 value of 0.682 μM owned anti-inflammatory activity by detecting the rate of lactate dehydrogenase release in pyroptosis J774A.1 cells. The results showed that the expression of Caspase-1 and IL-1 β was decreased in a dose-dependent manner in the compound 12 treatment group, suggesting that compound 12 may reduce pyroptosis by inhibiting NLRP3 inflammasome. To further determine that compound 12 treatment can inhibit macrophage pyroptosis, morphological observation was performed and the results were consistent with the bioactivity evaluation. [Display omitted] • Twenty-four coumarins were isolated from the ethyl acetate fraction of Toddalia asiatica. • Fifteen coumarins that have not been described before. • Two undescribed compounds showed low IC 50 values and could exert effective anti-inflammatory effects. • Compound 12 inhibited pyroptosis in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Four new diterpenoids (1–4) and four known diterpenoids (5–8) were purified from the whole plant of Euphorbia helioscopia L. Compounds 1 and 2 were jathophanes diterpenoids with a 5/12 polycyclic systems, compound 3 was rhamofolane diterpenoid with a 5/10 bicyclic skeleton and compound 4 was a rare class of euphorbia diterpenes featuring an unusual 5/10 fused ring system. Anti-inflammatory activity tests were conducted on the separated compounds, indicating that compound 4 had significant inhibitory effect on NLRP3 inflammasome with an IC 50 value of 7.75 μM. Further, the inhibitory effect of 4 was determined using immunofluorescence assays. [Display omitted] • Four new diterpenoids (1–4) and four known diterpenoids (5 - 8) were purified from the whole plant of Euphorbia helioscopia L. • Compound 3 was rhamofolane diterpenoid with a 5/10 bicyclic skeleton and 4 was a rare class of euphorbia diterpenes featuring an unusual 5/10 fused ring system • Compound 4 showed strong activity with IC 50 values of 7.75 μM. Frther, the inhibitory effects of 4 on protein levels were determined using immunofluorescence assays. [ABSTRACT FROM AUTHOR]

Abstract: Schilancidilactones A (1) and B (2), two novel tetranortriterpenoids possessing an unprecedented skeleton, have been isolated from the stems of Schisandra lancifolia. Their structures were elucidated on the basis of extensive spectroscopic analysis. The relative configurations of 1 were further determined by single-crystal X-ray crystallography. Compounds 1 and 2 were tested for their cytotoxicity against four tumor cell lines NB4, A549, SH-SY5Y, and PC-3, and compound 1 was further tested for its anti-HIV-1 activity. [Copyright &y& Elsevier]

Nine previously undescribed clerodane-type diterpenoids (1–9), named caseabalanspenes A-I , along with six know compounds (10–15), were isolated from the twigs and leaves of Casearia velutina. Spectroscopic data (1D and 2D NMR) analysis permitted the definition of their structures and then determination of the molecular formula of the compound by high resolution mass spectrometry (HR-ESI-MS). It is worth noting that compound 7 contains N- heterocycle. Compounds 1–8 were tested the anti-inflammasome activity, and compound 3 exhibited potent activity and decreased LDH level in a dose-dependent manner, with IC 50 values of 2.90 μM. [Display omitted] • Nine undescribed clerodane diterpenoids were isolated from Casearia velutina. • Their structures were determined by 1D, 2D-NMR and HR-ESI-MS analyses. • The structure of compound 7 contains an N-heterocycle. • Compound 3 exhibited NLRP3-inflammasome inhibitory activity with IC 50 values of 2.90 μM. [ABSTRACT FROM AUTHOR]

Vitex negundo var. Cannabifolia (Sieb. et Zucc.) Hand.-Mazz. leaves and twigs were used to isolate a new phenyldihydronaphthalene-type lignan (1) along with twenty known compounds. Comprehensive spectroscopic techniques such as UV, IR, NMR, HR-ESI-MS, ORD and ECD were used to identify their structures. Quantum chemical computations were used to assign the absolute configurations (AC) of (1). Using DP4+ analysis, the computed chemical shifts were used to pinpoint relative configuration. Compounds (1–6) were tested for biological activities. Compound (5) significantly decreased the release of lactate dehydrogenase (LDH) by 38% at a concentration of 10 μM, demonstrating that compound (5) had significant anti-inflammatory effects on the activation of the NLRP3 inflammasome, while no compound was found potent at a concentration of 200 μM against tyrosinase. Additionally, the chemotaxonomic significance of the isolated compounds was studied. [Display omitted] • One new phenyldihydronaphthalene-type lignan along with twenty known compounds from Vitex negundo var. Cannabifolia. • Spectroscopic analyses and quantum chemistry calculations were used to elucidate structures. • Compound 5 inhibited the release of lactate dehydrogenase (LDH) by 38% at a concentration of 10 μM. • Chemotaxonomic significance of the isolated compounds was discussed. [ABSTRACT FROM AUTHOR]

Plants belonging to the genus Leonurus , also named motherwort, are traditionally used for anti-gynecological disorder in East Asia, and for sedative in Europe. Chemical investigation of the genus Leonurus not only enriched the natural products library, but also enlarged the pharmacological application of this traditional herb. In this review, we systematically summarized the structures of 259 compounds isolated from the genus Leonurus , featured with 147 labdane diterpenoids. The reported bioactivity studies up to 2017 are presented in the second part, with the main focus on the isolated compounds and also concerning the extracts. In addition to the traditional uterine contraction and sedative activity, recently the cardiovascular protection effect of leonurine has drawn most attention. Other than that, neuroprotection, anti-inflammation, anti-cancer, anti-platelet aggregation and many other activities have been assigned to various compounds from the genus Leonurus . Among 70 bioactivity references cited in this review, 57% of them were concentrated on two alkaloids (leonurine and stachydrine), whereas only 20% are about the 147 diterpenoids. Anti-inflammation is the major bioactivity discovered so far for the labdane diterpenoids from the genus Leonurus , whose further therapeutic potential still remains for exploration. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eleven new highly oxidized abietane diterpenoids were identified from Orthosiphon wulfenioides. • Compounds 1 – 4 , 6 and 8 exhibited potent inhibitory effects on NLRP3 inflammasome, and the IC 50 value of compound 1 was 0.23 μM. • Compound 1 inhibited cell pyroptosis via suppressing the expressions of Caspase-1 and IL-1β. Wulfenioidones A − K (1 – 11) were abietane diterpenoids with highly oxidized 6/6/6 aromatic tricyclic skeleton isolated from the whole plant of Orthosiphon wulfenioides , and their planar structures and absolute configurations were elucidated by spectroscopic data interpretation, electronic circular dichroism calculation as well as X-ray crystallography analysis. Bioactivity screening indicated that compounds 1 – 4 , 6 and 8 exhibited lactate dehydrogenase (LDH) inhibition effect with IC 50 values ranging from 0.23 to 3.43 μM by preventing the mononuclear macrophage cell pyroptosis induced by double signal stimulation of LPS and nigericin. Western Blot analyses of Caspase-1 and IL-1β down-regulation exhibited that compound 1 could selectively inhibit NLRP3 inflammasome, and the cell morphological observation further supported that compound 1 prevented macrophage cell pyroptosis. [ABSTRACT FROM AUTHOR]

Eleven undescribed 16,17-dinor-abietane diterpenoids, caseazins A-K (1 − 11), and ten known diterpenoids (12 − 21) were isolated from the twigs and leaves of Casearia kurzii (Flacourtiaceae). Caseazins A-K were the first abietane -type dinorditerpenoids to have been isolated from the plant of Casearia kurzii. Their chemical structures were elucidated using a combination of 1D and 2D NMR spectroscopy and mass spectrometry. The absolute configurations of 5 and 10 were established by electronic circular dichroism calculations. Moreover, compounds 2 , 3 , 13 , 14 , and 18 exhibited anti-inflammatory activity with IC 50 values of 0.17, 0.36, 6.55, 1.30, and 4.53 μM, respectively. IL-1β and caspase-1 analyses suggested that compound 14 inhibited NLRP3 inflammasome activation and blocked macrophage pyroptosis. Diterpenoids from Casearia kurzii with NLRP3 inflammasome inhibitory activity were reported in this research. [Display omitted] • Eleven undescribed dinorditerpenoids were isolated from Casearia kurzii. • The compound 14 showed potent inhibitory activity against pyroptosis by blocking NLRP3 inflammasome activation. Their structures were established by elucidated by NMR, HRESIMS and ECD analyses. [ABSTRACT FROM AUTHOR]

Eight new highly oxygenated lanostane triterpenes, gibbosic acids A–H ( 1 – 8 ), along with three known ones ( 9 – 11 ), were isolated from the fruiting body of Ganoderma gibbosum . The structures of new isolates were assigned by NMR and HRESIMS experiments. The absolute configurations of 1 were further confirmed by single crystal X-ray diffraction data and computational ECD methods. Immunoregulatory effect and anti-inflammatory activities of these compounds were screened in murine lymphocyte proliferation assay and in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, respectively. Compound 2 exhibited immunostimulatory effect both in lymphocyte proliferation assay without any induction and ConA-induced mitogenic activity of T-lymphocyte, and the proportion of lymphocyte proliferation at the concentration of 0.1 μM are 20.01% and 21.40%, respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • Three unique ent -clerodane diterpenoid dimers were isolated from Callicarpa arborea. • The absolute configuration of 1 was deduced by single-crystal X-ray diffraction. • The absolute configuration of 2 and 3 was confirmed by NMR calculations with DP4 + analysis and ECD calculations. • The compound 2 and 3 showed potent cytotoxicity against MCF-7 and HCT-116 cell lines. Callicarpnoids A–C (1 – 3), three new ent -clerodane diterpenoid dimers formed via a [4 + 2] hetero Diels-Alder cycloaddition, appeared as a third example of this type of dimers, were isolated from the stems of Callicarpa arborea Roxb.. Their structures were elucidated by comprehensive spectroscopic analysis, and the absolute configurations were confirmed by single-crystal X-ray diffraction and electronic circular dichroism (ECD) calculations, as well as DP4 + analysis. Cytotoxicity test in two cell lines indicated that compounds 2 and 3 had significant cytotoxic effect against breast cancer cell (MCF-7) and colorectal cancer cell (HCT-116) with IC 50 ranging from 5.2 to 7.2 μ M, comparable to those of the positive control. Furthermore, the western blot analysis revealed that the protein expression levels of Bax were increased following compounds 2 and 3 treatment, whereas the expression levels of caspase 8, caspase 3, caspase 9 and Bcl 2 were decreased in a dose-dependent manner, indicating that compounds 2 and 3 may induce apoptosis via both intrinsic and extrinsic pathways in MCF-7 and HCT-116 cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • 66 ent -clerodane diterpenoids, including 52 new compounds, were isolated from Callicarpa arborea. • Their bioactivity against pyroptosis were evaluated, and the typical α,β-unsaturated-γ-hemiacetal lactone ring was a key active segments from SAR analysis. • Compound 1 showed potent inhibitory activity against pyroptosis by blocking NLRP3 inflammasome activation. • Compound 1 treatment markedly reduced infiltration of CD11b+F4/80+ macrophages into lung and protected lung injury in LPS- induced septic mice. Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent -clerodane diterpenoids from Callicarpa arborea , shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent -clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1 – 25) or a 6/6- (26 – 66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1β secretion in J771A.1 cells, revealed 28 compounds with an IC 50 below 10.5 μM. Compound 1 was the most potent with an IC 50 of 0.68 μM and inhibited the J774A.1 macrophage pyroptosis by blocking the NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An in vivo study further revealed that compound 1 decreased infiltration of CD11b + F4/80 + macrophages into lung and attenuated the lipopolysaccharide (LPS)-induced lung injury. Taken together, this study indicated the potential of compound 1 as a candidate for pyroptosis-related inflammation treatment, as well as provided the chemical and pharmacological basis for the further development of Callicarpa genus as a herbal medicine. [ABSTRACT FROM AUTHOR]

A phytochemical investigation to obtain bioactive substances as lead compounds or agents for anti-inflammatory led to the obtainment of eleven previously undescribed clerodane diterpenoids, named caseatardies A-K (1 − 11), and four known clerodane diterpenoids (12 – 15) from the twigs and leaves of Casearia tardieuae. The structural elucidation of these clerodane diterpenoids was based on 1D and 2D-NMR spectroscopy (COSY, HSQC, HMBC and ROESY) as well as high resolution mass spectrometry (HR-ESI-MS). The relative configurations were defined by ROESY correlations. The anti-inflammatory activity of all the isolated compounds was screened and compound 15 decreased LDH level in a dose-dependent manner, showing IC 50 value of 2.89 μM. [Display omitted] • Eleven new clerodane diterpenoids with conjugated diene side chain at C-9 were isolated from Casearia tardieuae. • The compound 15 showed potent inhibitory activity against pyroptosis by blocking NLRP3 inflammasome activation. • Their structures were established by elucidated by 1D, 2D-NMR and HR-ESI-MS analyses. [ABSTRACT FROM AUTHOR]

Ten new prenylated flavonoids, named denticulains A-J (1−10), together with seven known prenylated flavonoids (11–17) were isolated from Macaranga denticulata. Their structures were elucidated on the basis of detailed spectroscopic analysis and by comparison with literature data. In addition, compounds 1 and 14 inhibited the proliferation of SW620 and HCT-116 cell lines with an IC 50 value of 46.08 μM and 56.83 μM, respectively. [Display omitted] • Ten new prenylated flavonoids were isolated from Macaranga denticulata. • Some compounds have week anticancer activities. [ABSTRACT FROM AUTHOR]

Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC50s ranging from 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range. [ABSTRACT FROM AUTHOR]

A phytochemical investigation was conducted on Euphorbia helioscopia , resulting in the isolation of thirteen compounds, including nine undescribed diterpenoids, Euphzycopias A − I (1 – 9), of which the skeletons of compounds 1 – 4 were found in E. helioscopia L. Compounds 1 – 3 had 5/7/6 cyclic systems, while compound 4 had a 4/11 polycyclic system with a 4,7-cyclic ether between C-4 and C-7. The anti-inflammasome test using the isolated compounds (1–6, 8–13) showed that the diterpenes from E. helioscopia L. had a strong inhibitory effect on NLRP3 inflammasomes with IC 50 values of 3.34–14.92 μM. [Display omitted] • Nine undescribed diterpenoids were isolated from Euphorbia helioscopia L. • The skeletons of the first four compounds first appeared in the genus Euphorbia L. • Some compounds had significant anti-inflammatory activity on NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

Abstract: A new benzophenone C-glycoside, malaferin A (1), and two new epicatechin derivatives, malaferin B (2) and malaferin C (3), together with five known compounds were isolated from Malania oleifera. In addition, (−)-epicatechin-3-O-benzoate (6) was isolated for the first time from a natural resource. Structures of 1–3 were determined on the basis of their spectroscopic methods, including 1D and 2D NMR techniques. All of the compounds were evaluated for anti-HIV activities. [Copyright &y& Elsevier]

[Display omitted] • Nature-inspired compounds were found to inhibit HDAC and block inflammasome activation. • The active scaffold was discovered by virtual screening. • Derivatives of nigranoic acid and manwuweizic acid derivatives were prepared. As a successful anti-tumor drug target, the family of histone deacetylases (HDACs) is also a critical player in immune response, making the research of anti-inflammatory HDAC inhibitors an attractive new focus. In this report, triterpenoids nigranoic acid (NA) and manwuweizic acid (MA) were identified as HDAC inhibitors through docking-based virtual screening and enzymatic activity assay. A series of derivatives of NA and MA were synthesized and assessed for their biological effects. As a result, hydroxamic acid derivatives of NA and MA showed moderately increased activity for HDAC1/2/4/6 inhibition (the lowest IC 50 against HDAC1 is 1.14 μM), with no activity against HDAC8. In J774A.1 macrophage, compound 1 – 3 , 13 and 17 – 19 demonstrated inhibitory activity against lactate dehydrogenase (LDH) and IL-1β production, without affecting cell viability. Compound 19 increased the histone acetylation level in J774A.1 cells, as well as inhibited IL-1β maturation and caspase-1 cleavage. These results indicated that compound 19 blocks the activation of NLRP3 inflammasome, probably related to HDAC inhibition. This work provided a natural scaffold for developing low-cytotoxic and anti-inflammatory HDAC inhibitors, as well as a class of tool molecules for studying the relationship between HDACs and NLRP3 activation. [ABSTRACT FROM AUTHOR]

Nine new diterpenoids, Rubellacrns A − I (1–9), including five isopimaranes (1–4, 9), four pimaranes (5–8), together with five known isopimarane analogues (10–14), were isolated from Callicarpa rubella. The structures of these compounds were unambiguously established by HR-ESIMS and NMR spectroscopic data, the absolute configurations of compounds 5 and 9 were determined by ECD. All the isolated compounds were tested for their anti-inflammatory effects and compounds 2 and 11–14 showed NLRP3-inflammasome inhibitory activity with IC 50 values ranging from 7.02 to 14.38 μM. Unlabelled Image • Nine new diterpenoids were isolated from Callicarpa rubella. • The absolute configuration of 5 and 9 was deduced by ECD. • The new compound 2 showed potent inhibition of inflammasome activation. [ABSTRACT FROM AUTHOR]

• A novel series of S -DABO derivatives have been designed and synthesized. • Selected compounds displayed potent activity against different HIV-1 strains. • Compound 5r only showed inhibition of HIV-1 DPDP activity unlike classical NNRTIs. • Preliminary SAR and molecular modeling of these novel congeners were investigated. In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2-mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC 50 values are in the range of 0.06–12.95 μM. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b) , which exhibited similar HIV-1 inhibitory potency (IC 50 = 0.06 μM, CC 50 = 96.23 μM) compared with nevirapine (IC 50 = 0.04 μM, CC 50 >200 μM) and most of compounds exhibited submicromolar IC 50 values indicating they were specific RT inhibitors. The compounds 5b , 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization. [ABSTRACT FROM AUTHOR]