Taxodascaloids A-C (1-3), three uncommon oligomeric terpenoids featuring an oxazoline ring linkage, were purified from the cones of Taxodium ascendens. Compounds 1 and 2, a unique pair of stereoisomers, represented the first identified diterpenoid-monoterpenoid adducts linked by an oxazoline ring. Compound 3 was an uncommon dimeric diterpenoid and composed of a seco-abietane unit and an abietane unit, also containing an oxazoline ring. The planar structures and absolute configurations of these compounds were determined using extensive spectroscopic analysis and X-ray diffraction techniques. Compounds 1 and 2 demonstrated potent anticancer activity against human colon cancer HCT cells, with the IC50 values of 25.7 and 40.1 mu M, respectively. Further research indicated that compound 1 could induce both ferroptosis and apoptosis in HCT-116 cells. Additionally, compound 3 showed notable alpha-glucosidase inhibitory activity in a mixed-type manner with an IC50 value of 2.9 mu M.

Mimicking the transition state of tryptophan (Trp) and O-2 in the enzymatic reaction is an effective approach to design indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. In this study, we firstly assembled a small library of 2substituted benzo-fused five membered heterocycles and found 2-sulfinyl-benzoxazoles with interesting IDO1 inhibitory activities. Next the inhibitory activity toward IDO1 was gradually improved. Several benzoxazoles showed potent IDO1 inhibitory activity with IC50 of 82-91 nM, and exhibited selectivity between IDO1 and tryptophan 2,3-dioxygenase (TDO2). Enzyme binding studies showed that benzoxazoles are reversible type II IDO1 inhibitors, and modeling studies suggested that the oxygen atom of the sulfoxide in benzoxazoles interacts with the iron atom of the heme group, which mimics the transition state of Fe-O-O-Trp complex. Especially, 10b can effectively inhibit the NO production in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and it also shows good anti-inflammation effect on mice acute inflammation model of croton oil induced ear edema.

Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The β 3 AR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of β 1 AR and β 2 AR. Interestingly, several β-blockers, which are antagonists of the β 1 ARs and β 2 ARs, have been reported to exhibit agonist activity at the β 3 AR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of β 3 AR agonists with improved selectivity and reduced off-target effects. In this work, we determined the structures of human β 3 AR in complex with the endogenous agonist epinephrine or with a synthetic β 3 AR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D 3.32 directly contribute to carazolol's distinct activities as an antagonist for the β 2 AR and an agonist for the β 3 AR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective β 3 AR agonists, paving the way for new therapeutic opportunities.

The phytochemical investigation on the n-BuOH fraction of the Cinnamomum camphora extract led to the isolation and identification of 37 secondary metabolites. Among them, compound 1, named as camphodiol A, was a new phenylpropanoid glycoside, while compounds 2-10, 12, 13, 16-25, 27, and 29-37 were firstly isolated from this plant. The isolates were evaluated for their alpha-glucosidase inhibitory activities, and compounds 9, 1225, 27 and 29 showed potent activities with IC50 values ranging from 0.26 to 113.87 mu M. The molecular docking analysis indicated that compound 22 could bind within the active pocket of the alpha-glucosidase through the hydrogen bonding and pi-pi interaction. These results demonstrated that the utilization of C. camphora leaves may have potential beneficial effects for the treatment of diabetes mellitus.

Genistein is an important isoflavone that has been widely used to prevent blood disease and cancer. In this work, a novel genistein electrochemical sensor was developed based on the composite of molecularly imprinted polymer (MIP) and carboxylated multiwalled carbon nanotubes (cMWCNTs). The MIP layer was electropolymerizated on the cMWCNTs modified electrode using carbazole as functional monomer and genistein as template molecule. The morphology and electrochemical performance of MIP/cMWCNTs were characterized by scanning electron microscopy (SEM) and cyclic voltammetry (CV), respectively. A series of experimental conditions were optimized, including the pH value of supporting electrolyte, electropolymerization potential range, molar ratio of functional monomers to template molecules, numbers of cycle, accumulation potential and accumulation time. Under the optimal conditions, the resulting electrochemical sensor (MIP/cMWCNTs/GCE) showed high performance, such as high sensitivity and selectivity towards genistein, a wide linear range (0.02–7.00 μM) and a low limit detection of 0.006 μM (S/N = 3). The electrochemical sensor was applied to determination of genistein in tablets and human urine samples with satisfactory recoveries (97.9%–102.8%), and the accuracy of the sensor was demonstrated with the HPLC method.

The abnormal activation of PI3K signaling pathway leads to the occurrence of various cancers. The PI3Kα is frequently mutated and overexpressed in many human cancers. Therefore, the PI3Kα was considered as a promising target in therapeutic treatment of cancer. In this study, two series of compounds containing 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold were synthesized and evaluated antiproliferative activities against three cancer cell lines, including HCT-116, MDA-MB-231 and SNU638. Compound 7f with the most potent antiproliferative activity was selected for further evaluation on normal cells and PI3K kinase. Studies indicated that compound 7f could decrease the phospho-Akt (T308) in a dose-dependent manner. Four key hydrogen bonding interactions were found in the docking of 7f with PI3K enzyme. All the results suggested that 7f was a potent PI3Kα inhibitor.

The overexpression of EGFR correlates with rapidly progressive disease, resistance to chemotherapy and poor prognosis. In certain human cancers, PI3K works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and PI3K has therapeutic advantage and was an attractive approach against tumors. In this work, based on the molecular docking and previous studies, a series of 4-aminoquinazolines derivatives containing 6-sulfonamide substituted pyridyl group were rationally designed and identified as potent EGFR and PI3K dual inhibitors. The cytotoxicity experiment results showed that this series of compounds could effectively inhibit cell growth. The kinase assay demonstrated that 6c and 6i had high inhibition for EGFR and selectivity for PI3Kα distinguished from other isoforms. Further experiments showed that 6c could induce cell cycle arrest in G1 phase and apoptosis in BT549 cells. The western blot assay indicated that 6c inhibited the proliferation of BT549 cell through EGFR and PI3Kα/Akt signaling pathway. Our study suggested that compound 6c was a potential dual inhibitors of EGFR and PI3Kα.