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Described herein is a facile and efficient methodology for diversity-oriented one-pot multicomponent synthesis of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 via knoevenagel condensation/Michael/cyclization and then aminomethylation reaction. A wide variety of products with varying degrees of substitution around it, were obtained smoothly with high efficiency (up to overall yield 73% and >20:1 diastereoselectivity). In particular, their biological activities against these three cell lines K562, A549 and PC-3 have been evaluated. These results suggested that most of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 showed equipotent or more potent than the positive control of Cisplatin (up to 3.4 times). [ABSTRACT FROM AUTHOR]

A facile and efficient methodology was developed for the synthesis of isoxazole-fused spiropyrrolidine oxindoles 3–5 via a 1,3-dipolar cycloaddition reaction of 3-methyl-4-nitro-5-alkenyl-isoxazoles with azomethine ylides (thermally generated in situ from isatin derivatives and proline or thioproline or sarcosine). Products bearing adjacent quaternary-tertiary centers were smoothly obtained in high yields (up to 90% yield) with good diastereoselectivity (up to 20:1). Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3, human lung cancer cells A549 and human leukemia cells K562 by the MTT-based assays using the commercially available standard drug Cisplatin as a positive control. These results suggested that most of isoxazole-fused spiropyrrolidine oxindoles 3–5 showed considerable cytotoxicities to these three cell lines K562, A549 and PC-3, and that isoxazole-fused spiropyrrolidine oxindoles may be potential leads for further biological screening. [ABSTRACT FROM AUTHOR]

A new methodology was developed for the synthesis of spirocyclic oxindoles bearing polyfunctional dihydropyrrole units via an organocatalytic tandem Michael/cyclization sequence. Products bearing adjacent quaternary–tertiary stereocenters were smoothly obtained in high yields (up to 97% yield) with excellent diastereoselectivities up to >20/1. [ABSTRACT FROM AUTHOR]

The first Lewis base-catalysed allylic sulfuration of Morita–Baylis–Hillman (MBH) adducts derived from ketones (isatins) has been developed, which affords C3-quaternary oxindole derivatives bearing thio-group at 3-position in good to excellent yield (up to 98% yield) under mild reaction conditions. Significantly, the potential utility of the protocol also has been demonstrated by gram-scale synthesis of 3-alkylthio-2-oxindole ( 3ae ), a low catalyst loading (0.3 mol %) and facile conversion of resulting product ( 3ad ) into functionalized pyrrolidinone ( 5ad ). [ABSTRACT FROM AUTHOR]

Inspired by the chemistry and biology of fluorine-containing molecules, chromanones and pyrrolidinyl spirooxindoles, herein we report a highly diastereoselective [3 + 2] cycloaddition reaction of commercially available 3-carboxylic acid chromones and N-2,2,2-trifluoroethylisatin ketimines as azomethine ylide precursors in the presence of the catalyst DMAP, which enabled diversity-oriented synthesis of a series of potentially bioactive scaffolds containing CF 3 , chromanone and pyrrolidinyl spirooxindole with high efficiency (up to 87% yield and 15:1 diastereomeric ratio). The high efficiency of the cycloaddition relies on the use of a carboxylic acid-activation and then decarboxylation strategy for the less reactive chromones. In particular, this is the first construction of CF3-containing multiple rings-fused pyrrolidinyl spirooxindoles, bearing four contiguous stereogenic centers including one tetra substituted carbon, which might be valuable in medicinal chemistry. Image 1 • The first construction of CF 3 -containing multiple rings-fused pyrrolidinyl spirooxindoles. • The use of a carboxylic acid-activation and then decarboxylation strategy. • Diversity-oriented synthesis of a series of potentially bioactive scaffolds, which might be valuable in medicinal chemistry [ABSTRACT FROM AUTHOR]

Described herein is a facile and efficient methodology toward the synthesis of Morusin scaffolds and Morusignin L scaffolds 4 – 9 and 12 via a novel three-step approach (Michael addition or prenylation, cyclization and cyclization) and use a rapid, microwave-accelerated cyclization as the key step. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation for anti-osteoporosis activity. These Morusin, Morusignin L and newly synthesized compounds 5b , 6a , 8e , 8f greatly exhibited the highest potency, especially at the 10 −5 mol/L (P < 0.01), and had good in vitro anti-osteoporosis activities using the commercially available standard drug Ipriflavone as a positive control. The mechanisms associated with anti-osteoporosis effects of these compounds may be through the inhibition of TRAP enzyme activity and bone resorption in osteoclasts, and promotion effect of osteoblast proliferation in vitro . The results indicated that Morusin scaffolds and Morusignin L scaffolds may be useful leads for further anti-osteoporosis activity screenings. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). β-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin , and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of β-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo . 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that β-elemene inhibited lung cancer tumor growth and cell vitality in a dose- and time-dependent manner. Not only that, β-elemene could up-regulate ERs-related proteins like PERK, IRE1α, ATF6, ATF4, CHOP and down-regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1α inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of β-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of β-elemene is closely related to the activation of ERs through PERK/IRE1α/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC. [ABSTRACT FROM AUTHOR]

A new methodology was developed for the synthesis of hexahydro-1 H -pyrido[2,3- b ]indol-2-one scaffolds via a sequential Michael addition/amidation/reductive cyclization process. A wide variety of products bearing a hexahydro-1 H -pyrido[2,3- b ]indol-2-one core with varying degrees of substitution around it, which is a key structural skeleton found in a large number of biologically active natural products and pharmaceutical compounds, were obtained smoothly with high efficiency (up to overall yield of 67%). Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3, human lung cancer cells A549 and human leukemia cells K562 by the MTT-based assays, using the commercially available standard drug Cisplatin as a positive control. These results suggested there is a trend that lipophilic groups improve the potency, and also suggested a carbonyl moiety located in the hexahydro-1 H -pyrido[2,3- b ]indol-2-one scaffolds is beneficial for the activity. The results also demonstrated that most of the compounds showed considerable cytotoxicities to these three cell lines K562, A549 and PC-3, and that hexahydro-1 H -pyrido[2,3- b ]indol-2-one scaffolds may be potential leads for further antitumor activity screenings. [ABSTRACT FROM AUTHOR]

A facile and efficient methodology was developed for the synthesis of isoxazole or coumarin-fused 3-quaternary carbon oxindoles and isoxazole-fused pyrrolidinones via DABCO-catalyzed sp 3 C–H activation of 5-methyl-isoxazole or 4-methylcoumarin. Furthermore, the biological activity of the isoxazole or coumarin-fused 3-quaternary carbon oxindoles 3 and 5 has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3 and human leukemia cells K562 by the MTT-based assays using the commercially available standard drug Cisplatin as a positive control. These results suggested that most of the compounds 3 and 5 showed considerable cytotoxicities to these two cell lines K562 and PC-3, and a methyl or an ethyl group of acrylates and an oxindole moiety located in the isoxazole-fused 3-quaternary carbon oxindoles 3 are beneficial for the activity. In addition, the activity of all the afforded isoxazole-fused pyrrolidinones 7 were also evaluated against Gram-positive bacteria Staphylococcus aureus (MTCC96) and Gram-negative bacteria Escherichia coli (ATCC25835) using Penicillin as a standard drug for Gram-positive organism or Streptomycin as standard drug for Gram-negative organism. The results demonstrated that most of the compounds 7 had comparable in vitro inhibitory activity against Gram-positive bacteria Staphylococcus aureus (MTCC96) with the positive control Penicillin. The results also indicated that isoxazole-fused pyrrolidinone analogs had significantly better inhibition ability against Gram-positive bacteria Staphylococcus aureus (MTCC96) than against Gram-negative bacteria Escherichia coli (ATCC25835). [ABSTRACT FROM AUTHOR]

Inspired by the chemistry and biology of fluorine-containing molecules and pyrrolidinyl spirooxindoles, herein we report a highly diastereoselective [3 + 2] cycloaddition reaction of β , γ -unsaturated α -keto esters and N-2,2,2-trifluoroethylisatin ketimines in the presence of the catalyst DABCO. The process enables efficient incorporation of CF 3 groups into pharmaceutically important spiro[pyrrolidin-3,2′-oxindoles], bearing four contiguous stereogenic centers including one tetra substituted carbon, with high efficiency (up to 93% yield and >20:1 diastereomeric ratio). Moreover, using β , γ -unsaturated α -keto esters as the 2C building blocks in this reaction, which are different from other enone substrates such as chalcone and benzalacetone, further expanded their scope of applicability. [Display omitted] • Expanding the scope of substrate applicability. • Potential biologically active molecules. • using β,γ-unsaturated α-keto esters as the 2C building blocks. [ABSTRACT FROM AUTHOR]

The species from Alangium have been used as folk medicine to treat rheumatism, skin diseases, diabetes by the people of Southeast Asia. Previous phytochemical studies have shown this genus are rich sources of alkaloids, glycosides, and terpenoids, which have attracted considerable attention of many researchers due to their markedly diverse and complex architecture. The crude extracts as well as the monomeric compounds from the title genus possess anti-tumor, anti-inflammatory, antibacterial, anti-oxidant pharmacological activities. Besides, some isolates from Alangium exhibited the effects on skeletal, smooth muscle and the nervous system. As a large genus of medicinal plants, the medicinal value of Alangium has been widely reported, but there is no review that provide a systematic summary towards its chemical constituents and pharmacological activities, to our knowledge. This work aims to present a comprehensive overview on the traditional uses, phytochemistry, and pharmacological activities of medicinal plants in the genus Alangium , and to explore the evidence supporting its ethnopharmacological effectiveness. Unlabelled Image • This review presented a systematic review on genus Alangium in the period of 1965–2020. • A detailed description of traditional usage. • Including the structures of more than 300 isolated compounds. • The comprehensive summary of medicinal parts and activities data. [ABSTRACT FROM AUTHOR]

The our previous study synthesized the chrysin-chromene-spirooxindole hybrids 3 , and further found compound 3e had good antitumor activity against A549 cells in vitro through multi-target co-regulation of the p53 signalling pathway to inhibit the proliferation of A549 cells. This study was designed to evaluate the antitumor effects of compound 3e on Lewis lung carcinoma of C57BL/6 mice in vivo. Compound 3e significantly inhibited the growth of transplanted tumors in C57BL/6 mice and induced the apoptosis of tumor cells. Further studies showed that compound 3e activates and expands the anti-cancer activity of p53 by inhibiting the expression of MDM2, Akt and 5-Lox proteins, accordingly promotes the expressions Bax and inhibit the Bcl-2 protein, the release of Cyt c as well, which resulted in the activation of apoptotic pathway in tumor cells eventually. Moreover, Compound 3e inhibited tumor metastasis by down-regulating VEGF, ICAM-1 and MMP-2 protein expression and angiogenesis. These results suggested that compound 3e exerts an effective antitumor activity in vivo through activating the p53 signaling pathway, which could be exploited as a promising candidate for the development of new anti-tumour drugs. [ABSTRACT FROM AUTHOR]

The first example of Ca(OH) 2 -activated p-regioselective synthesis of chrysin-fused chromene was reported through a cascade Michael/cyclization of chrysin and arylidenemalononitrile. The newly synthesized structurally diverse 2-amino 3-cyano chromene-chrysin hybrids 3 were evaluated for their in vitro anticancer activity, and some of the compounds showed stronger anti-proliferative activity against K562, PC-3, A549 and NCI-H1299 than parent compound chrysin, and demonstrated equipotent potency compared with the reference drug of cisplatin. In particular, compound 3h had the highest cytotoxicity towards K562 cells (IC 50 = 6.41 µM). Furthermore, compound 3h induced apoptosis of K562 cells in a concentration-dependent manner, as well as induced the apoptosis possibly through promoting the formation of apoptotic DNA of cancer cell via the intrinsic apoptotic pathway. Thus, our results provide in vitro evidence that compound 3h may be a potential candidate for the development of new anti-tumour drugs. [ABSTRACT FROM AUTHOR]