The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 microM) vs 9 (IC50 > 200 microM). Structure-activity studies of a series of carbocyclic analogues 6a-i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (-)-quinic acid is also described.

Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.

BACKGROUNDLycium ruthenicum Murray (LRM), a perennial shrub plant belonging to the Solanaceae family, is rich in anthocyanins, which have anti‐inflammatory, antioxidant, lipid‐lowering, intestinal flora regulating, and other pharmacological qualities. This study was primarily aimed to investigate the inhibitory effect of different anthocyanin purities from LRM on angiotensin‐I‐converting enzyme (ACE) activity in vitro. Moreover, the inhibitory mechanism was further analyzed by molecular docking technology.RESULTSTwo main anthocyanin isomers were identified by ultra‐performance liquid chromatography–tandem mass spectrometry and proton/carbon‐13 nuclear magnetic resonance, namely petunidin‐3‐O‐[rhamnopyranosyl‐(trans‐p‐coumaroyl)]‐5‐O‐(β‐d‐glucopyranoside) (trans‐Pt3R5G) and petunidin‐3‐O‐[rhamnopyranosyl‐(cis‐p‐coumaroyl)]‐5‐O‐(β‐d‐glucopyranoside) (cis‐Pt3R5G), with a molar ratio of 9:1. Three purification grades of Pt3R5G all showed excellent inhibitory effects on ACE, with the half maximal inhibitory concentration (IC50) values being 0.562, 0.421, and 0.106 mg·mL−1. Increasing the purity may reduce the IC50 within a certain concentration range. An enzymatic kinetic experiment showed that the inhibitory effect of Pt3R5G on ACE was reversible and non‐competitive: Pt3R5G and substrate were not in competition for the active sites of ACE. Molecular docking technology further revealed the possible mechanism was that Pt3R5G and ACE amino acid residues were interacting by hydrogen bonds to exert the inhibitory effect.CONCLUSIONThe results indicated that Pt3R5G from LRM was highly effective at inhibiting ACE activity in vitro, with the hydrogen bonds of Pt3R5G and ACE amino acid residues exerting the inhibition. As a potential plant‐based ACE inhibitor, Pt3R5G can be used as a functional ingredient for antihypertensive effects. © 2023 Society of Chemical Industry.