Latest ArticlesAn efficient water-based bismuth-mediated addition reaction of carbonyl compound with cyclic allylic halide was developed. The reactions proceeded smoothly in aqueous DMF in the presence of ammonium iodide to afford the corresponding syn-homoallylic alcohols in moderate to good yields with excellent diastereoselectivities (>99:1 syn:anti). Reversal of product diastereoselectivity was observed when heteroaryl aldehyde possessing an adjacent chelating nitrogen atom was employed as substrate.
A selective ring-opening [3+2] cyclization reaction of benzo[d]isoxazoles with 2-bromo-propanamides has been developed. The azaoxyallyl cation intermediates are employed as C~O 3-atom synthon to build oxa-heterocycles via the selectivity of suitable cyclization partners. This transformation provides rapid access to highly functionalized 2-hydroxyaryl-oxazolines under mild conditions and excellent regioselectivity.
A seven-step total synthesis of α-cyclopiazonic acid is reported from a commercially available 4-bromoindole. Salient feature of the work is the rapid formation of tetracyclic skeleton via a bioinspired [3+2] annulation to form the C/D rings.
In this study, we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors. MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation. In addition, all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L, and also possessed good PARP-1 inhibitory activities. Subsequent mechanistic studies showed that compound 9a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells. Our study suggested that 9a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.
Seven 2, 6-disubstituted N-(2-phenoxy)ethyl imidazo[1, 2-a]pyridine-3-carboxamide series containing various amine moieties were designed and synthesized as new anti-TB agents. Many of them show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and two MDR-MTB clinical isolates (MIC: < 0.002-0.030 μg/mL). Compounds 2f, 5e and 5g display acceptable safety and pharmacokinetic profiles, opening a new direction for further development.
Polymyxin B (PB), as the last-line of defense against multidrug-resistant Gram-negative bacteria, has caused resistance to P. aeruginosa recently. Fortunately, synergistic treatment could preserve the last class of antibiotics and reduce the emergency of drug resistance. Here, we performed a screen of 970 approved drugs synergized with PB against the P. aeruginosa DK2, which is severely resistant to PB, MIC = 512 μg/mL. Encouragingly, we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint (2 μg/mL). Especially, gemifloxacin achieved the highest synergistic effect with PB, leading to a 4096-fold MIC reduction (reduced from 512 μg/mL to 0.125 μg/mL). Furthermore, synergistic effect was also observed in the combination of gemifloxacin and colistin. Finally, outer membrane permeabilization assay showed that gemifloxacin could increase the permeability of bacterial cell membranes for P. aeruginosa which partly explained the synergy mechanism. These results indicate that fluoroquinolones represent attractive synergists to address the emerging threat of polymyxin-resistant infections.
Targeting bromodomain-containing protein 4 (BRD4) has been proved to be an effective strategy for cancer therapy. To date, numerous BRD4 inhibitors and degraders have been identified, some of which have advanced into clinical trials. In this work, a focused library of new [1, 2, 4]triazolo[1, 5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4. WS-722 inactivated BRD4 (BD1/BD2), BRD2 (BD1/BD2) and BRD3 (BD1/BD2) broadly with the IC50 values less than 5 μmol/L. Besides, WS-722 inhibited growth of THP-1 cells with an IC50 value of 3.86 μmol/L. Like (+)-JQ1, WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability. Docking studies showed that WS-722 occupied the central acetyl-lysine (Kac) binding cavity and formed a hydrogen bond with Asn140. In THP-1 cells, WS-722 showed target engagement to BRD4. Cellular effects of WS-722 on THP-1 cells were also examined, showing that WS-722 could block c-MYC expression, induce G0/G1 phase arrest and p21 up-regulation, and promote differentiation of THP-1 cells. BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines. The [1, 2, 4]triazolo[1, 5-a] pyrimidine is a new template for the development of new BRD4 inhibitors.
Four new seco-dibenzocyclooctadiene lignans, kadlongilignans A-D (1-4), consisting of a rare 6, 7-seco-(1), two 15, 16-seco-(2 and 3) and a 9, 10-seco-dibenzocyclooctadiene (4) lignans, were isolated from the roots of Kadsura longipedunculata. Their structures were elucidated by spectroscopic analysis, including extensive NMR, MS and ECD (electronic circular dichroism) spectra. Compounds 3 and 4 exhibited potent inhibitory activities against NO (nitric oxide) production of LPS (lipopolysaccharide)-induced murine macrophages with the inhibition rates of 36.3% and 26.9%, respectively.
Callicarpa bodinieri is a Chinese traditional medicine herbwith anti-inflammatory activity in clinic. Herein, we report two new 9, 10-seco and etherified abietane diterpenoids bodinieric acids J and K(1 and 2)and one known compound (3) isolated from the leaves and twigs of this plant. Their chemical structures were elucidated by detailed spectrometry data analysis and DP4+ NMR calculation methods. Hypothetical biosynthetic pathways of 1-3 were preliminarily speculated. Compound 3 inhibited inflammasome activation and exhibited blockage of NLRP3 inflammasome activation at non-cytotoxic concentrations in vitro.
A novel meroterpenoid, euphoractone (1), was isolated from the extracts of the roots of Euphorbia fischeriana Steud. Its structure was determined by spectroscopic methods and X-ray crystallography. 1 possesses an unusual ent-abietane-phloroglucinol skeleton. The plausible biosynthetic pathway for 1 was proposed.1 showed inhibitory activities against human lung cancer H23 and H460 cells with the IC50 values of 21.07±3.54 and 20.91±4.07 μmol/L.
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