Yong Li

Although chiral α-alkenyl quaternary amino acid derivatives have been extensively utilized in organic synthesis, the catalytic asymmetric synthesis of such compounds remains elusive. In this report, we present a highly efficient method for the direct introduction of an alkenyl group at the α carbon of an NH₂-unprotected amino acid ester through a three-component reaction involving readily available aryl (alkenyl) bromide and allyl acetate, facilitated by chiral aldehyde/palladium co-catalysis. A diverse array of α-alkenyl quaternary amino acid esters featuring unconjugated π systems are generated in commendable yields and excellent enantioselectivities, and some of them are used for the synthesis of valuable building blocks.

C ₃₃ H ₃₃ N ₃ O ₄ , monoclinic, P 2 ₁ /c (no. 14), a = 10.9636(14) Å, b = 9.6450(12) Å, c = 27.328(4) Å, β = 99.637(2)°, V = 2848.9 Å ³ , Z = 4, R _gt ( F ) = 0.0463, wR _ref ( F ² ) = 0.1189, T = 296 K.

Inflammation is a protective response by the body aimed at maintaining tissue homeostasis by eliminating pathogenic microbial infection, irritants, or tissue damage. However, dysregulated inflammation is pathological and involved in various diseases such as metabolic disorders, cancer, and neurodegenerative diseases. In this study, multicomponent reaction, an efficient tool for the synthesis of complex compounds with potential biological activities, was employed to synthesize twenty 3,4-dihydro-pyrazine[1,2-b]indazole-1(2H)-one derivatives and two 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one analogues. We next identified compounds 6e and 6r as potential inhibitors for NLRP3 inflammasome-driven pyroptosis through activity-based screening and investigated their potential binding modes with the NLRP3 protein via molecular docking. Further studies on anti-inflammatory activity showed that compounds 6e and 6r also significantly inhibited LPS-induced NO release, among which compound 6e had better anti-inflammatory activity, with an IC₅₀ of 8.55 ± 0.32 μM in inhibiting NO release. Additionally, qPCR analysis indicated that compound 6e notably suppressed the gene transcription of the pro-inflammatory cytokine IL-6. In conclusion, this study identifies compound 6e, featuring a novel 3,4-dihydro-pyrazine[1,2-b]indazole-1(2H)-one scaffold, as a promising hit compound with inhibitory activity against pyroptosis and key inflammatory mediators. These findings highlight this chemotype as a valuable starting point for the development of a new class of anti-inflammatory agents.

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-d]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (10b) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC₅₀) = 112 ± 8 nM] and BRD4-BD1 (IC₅₀ = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, 10b has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.

A facile methodology for the construction of a complex heterocycle indazolo-fused quinoxalinone has been developed via an Ugi four-component reaction (U-4CR) followed by an intramolecular Ullmann reaction. The expeditious process features an operationally simple approach, time efficiency, and a broad substrate scope. Biological activity was evaluated and demonstrated that compound 6e inhibits human colon cancer cell HCT116 proliferation with an IC₅₀ of 2.1 μM, suggesting potential applications for developing a drug lead in medicinal chemistry.

Colorectal cancer (CRC) is the most common intestinal malignancy, and nearly 70% of patients with this cancer develop metastatic disease. In the present study, we synthesized a novel compound, termed N-(3-(5,7-dimethylbenzo [d]oxazol-2-yl)phenyl)-5-nitrofuran-2-carboxamide (compound 275#), and found that it exhibits antiproliferative capability in suppressing the proliferation and growth of CRC cell lines. Furthermore, compound 275# triggered caspase 3-mediated intrinsic apoptosis of mitochondria and autophagy initiation. An investigation of the molecular mechanisms demonstrated that compound 275# induced intrinsic apoptosis, and autophagy initiation was largely mediated by increasing the levels of the intracellular accumulation of reactive oxygen species (ROS) in CRC cells. Taken together, these data suggest that ROS accumulation after treatment with compound 275# leads to mitochondria-mediated apoptosis and autophagy activation, highlighting the potential of compound 275# as a novel therapeutic agent for the treatment of CRC.

In this study, 2-benzyl-10a-(1H-pyrrol-2-yl)-2,3-dihydropyrazino[1,2-a]indole-1,4,10(10aH)-trione (DHPITO), a previously identified inhibitor against hepatocellular carcinoma cells, is shown to exert its cytotoxic effects by suppressing the proliferation and growth of CRC cells. An investigation of its molecular mechanism confirmed that the cytotoxic activity of DHPITO is mediated through the targeting of microtubules with the promotion of subsequent microtubule polymerisation. With its microtubule-stabilising ability, DHPITO also consistently arrested the cell cycle of the CRC cells at the G2/M phase by promoting the phosphorylation of histone 3 and the accumulation of EB1 at the cell equator, reduced the levels of CRC cell migration and invasion, and induced cellular apoptosis. Furthermore, the compound could suppress both tumour size and tumour weight in a CRC xenograft model without any obvious side effects. Taken together, the findings of the present study reveal the antiproliferative and antitumour mechanisms through which DHPITO exerts its activity, indicating its potential as a putative chemotherapeutic agent and lead compound with a novel structure.

Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1H)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1H)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.

Glioblastoma (GBM) is an aggressive malignancy with a high rate of tumor recurrence after treatment with conventional therapies. Parthenolide (PTL), a sesquiterpene lactone extracted from the herb Tanacetum parthenium or feverfew, possesses anticancer properties against a wide variety of solid tumors. In the present study, a series of PTL derivatives were synthesized and screened. An inhibitor, dimethylaminoparthenolide (DMAPT)‑D6, a derivative of the PTL prodrug DMAPT in which the hydrogen of the dimethylamino group is substituted for the isotope deuterium, induced significant cytotoxicity in GBM cells in vitro and induced cell cycle arrest at the S‑phase in a dose‑dependent manner. Furthermore, mechanistic investigation indicated that through increasing the levels of intracellular accumulation of reactive oxygen species (ROS), DMAPT‑D6 triggered DNA damage and finally death receptor‑mediated extrinsic apoptosis in GBM cells, suggesting that DNA damage induced by DMAPT‑D6 initiated caspase‑dependent apoptosis to remove damaged GBM cells. Taken together, these data suggested that ROS accumulation following treatment with DMAPT‑D6 results in DNA damage, and thus, death‑receptor‑mediated apoptosis, highlighting the potential of DMAPT‑D6 as a novel therapeutic agent for the treatment of GBM.