Search

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.

With the development of medical image equipment, the Computed tomography (CT) scan has greatly increased the detectable area of the human body and improved the detection sensitivity and accuracy of disease monitoring. However, the unbalanced distribution of HU intensity values lowers accuracy and sensitivity of automatic analysis and segmentation based on CT images. As such, we proposed a redistributing method to make the distribution even while ensuring that similar intensities of CT images reflect the same tissue after processed. Our experiments based on the 3D brain tumor CT images proved that this method can significantly speed up the convergence and improve segmentation accuracy as compared to conventional preprocessed methods.

An efficient and rapid method was developed for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene. Copper and palladium-catalyzed sonogashira-type coupling of trimethylsilylacetylene and aryl bromides or iodides in the presence of triethylamine as base under microwave irradiation in acetonitrile afforded the desired 1-aryl-2-(trimethylsilyl)acetylene. The use of microwave was found to significantly improve the reaction yield and shorten the reaction time.

Patients with chronic kidney diseases (CKD) always suffer from anemia with severe impacts on their quality of life. Erythropoiesis-stimulating agents (ESAs) are the main drugs in clinical therapy. However, the side effects and high price of ESAs scare off many patients. Small-molecule inhibitors of hypoxia inducing factor proline hydroxylase domain 2 (HIF-PHD2) solves these problems elegantly in clinical therapy. The strategy of inhibiting HIF-PHD2 to improve renal anemia is via the upregulating of hypoxia inducing factor-2α (HIF-2α) for increased expression of downstream genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). This review introduces the function of small-molecule HIF-PHD2 inhibitors for improving renal anemia and summarizes the small-molecule inhibitors of HIF-PHD2 currently in clinical studies.

OBJECTIVE: To characterize the anatomical features of a large unnamed nerve in the posterior cervical triangle and clarify its relationship with the lesser occipital nerve. METHODS: We dissected 31 adult formalin-fixed cadaver head and neck specimens (62 sides). The lateral cervical region, the anterior cervical region, the sternocleidomastoid region, and the occipital region were dissected to define the anatomical features of the unnamed nerve. RESULTS: This unnamed nerve was identified in the posterior cervical triangle in 96.8% of the specimens. The main trunk of the nerve had a diameter of about 3 mm with a length of around 10 cm. The nerve arose from the anterior branch of the second cervical nerve (C2, C2-3), entered the posterior cervical triangle at 1-3 cm above the accessory nerve, and continued to ascend along or in parallel with the posterior border of the sternocleidomastoid muscle. It passed between the attachments of the sternocleidomastoid and the trapezius to the occiput and divided into 3-5 branches, which innervated the skin area between the lesser and greater occipital nerves. CONCLUSIONS: We identified a large unnamed nerve in the posterior cervical triangle, for which we coined the name "long occipital nerve" based on its unique anatomical features. The discovery of this nerve can be important for local surgery and for diagnosis and treatment of related diseases.

Prolyl hydroxylase domain 2 (PHD2) enzyme, a Fe(II) and 2-oxoglutarate (2-OG) dependent oxygenase, mediates key physiological responses to hypoxia by modulating the levels of hypoxia inducible factor 1-α (HIF1α). PHD2 has been shown to have the therapeutic potentials for conditions including anemia and ischemic disease. Currently, many activity-based assays have been developed for identifying PHD2 inhibitors. Here we report an affinity-based fluorescence polarization method using FITC-labeled HIF1α (556-574) peptide as a probe for quantitative and site-specific screening of small molecule PHD2 inhibitors.

A series of L-shaped ortho-quinone analogs were designed by analyzing the binding mode with NQO1. Metabolic studies demonstrated that compounds 2m, 2n and 2q exhibited higher metabolic rates than β-lapachone. The docking studies, which supported the rationalization of the metabolic studies, constituted a prospective rational basis for the development of optimized ortho-quinone analogs. Besides, good substrates (2m, 2n and 2r) for NQO1 showed higher selective toxicity than β-lapachone toward A549 (NQO1-rich) cancer cells versus H596 (NQO1-deficient) cells. Determination of superoxide (O2(•-)) production and in vitro cytotoxicity evaluation in the presence of the NQO1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling. It was suggested that the L-shaped quinone substrates for NQO1 possessed better specificity and safety than β-lapachone.

A highly regioselective intramolecular cyclization of lapachol mediated by Lewis acids including NbCl5, AlCl3, and FeCl3 was developed for synthesizing β-lapachone in excellent yields without any formation of the isomer α-lapachone. This procedure was efficient, mild, and easily scalable that avoided using highly hazardous concd H2SO4. In the case of ZrCl4 the cyclization was found to give α-lapachone as the main product. A possible mechanism for the Lewis acid mediated cyclization was also discussed.

Concrete is a complex multiphase composite. Along with the hydration reaction, the thermal and mechanical properties of concrete continue to increase, resulting in deformations such as temperature, autogenous volume and shrinkage, and stress and creep after being restrained by themselves and externally, further cracks are formed. Through finite element simulation, the key parts of temperature control and crack prevention of concrete dam can be predicted, and targeted crack prevention measures can be proposed. Therefore based on BIM technology and combined with simulation results, this paper conducts real-time monitoring of concrete temperature and stress during construction. Through comparison and inversion analysis, the whole process dynamic management of temperature and stress during dam construction period is implemented, and temperature control measures are optimized in real time to realize the whole process control of temperature control and crack prevention of concrete dam.

An improved and scalable synthetic method of N-(5-(4-cyanophenyl)-3-hydroxypicolinoyl)glycine, a promising inhibitor of PHD2, is described. The optimized route staring from commercially available 5-bromo-3-nitropicolinonitrile takes only five chemical steps and has a dramatically increased total yield of 37.6% without chromatographic purifications.

An efficient and rapid method was developed for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene. Copper and palladium-catalyzed sonogashira-type coupling of trimethylsilylacetylene and aryl bromides or iodides in the presence of triethylamine as base under microwave irradiation in acetonitrile afforded the desired 1-aryl-2-(trimethylsilyl)acetylene. The use of microwave was found to significantly improve the reaction yield and shorten the reaction time.