Neuroprotective effects of kukoamine A on 6-OHDA-induced Parkinson’s model through apoptosis and iron accumulation inhibition

Objective: Parkinson’s disease(PD) is characterized by the loss of dopaminergic neurons in substantia nigra(SN). Our previous study demonstrated kukoamine A(KuA) to exhibit strong neuroprotective effects through antioxidative stress, and autophagy in MPTP/MPP+-induced PD models in vivo and in vitro. It is necessary to evaluate the efficacy of the anti-PD effects under various models.Methods: In the present study, total chemical synthesis was used to obtain KuA, which performed low content in Lycii Cortex. Then, 6-OHDA-induced PD model of PC12 cells was used to investigate the effects of KuA on PD.Results: Our results demonstrated that KuA ameliorated cell loss and mitochondrial membrane potential(MMP) loss, and inhibited Bax/Bcl-2 ratio increase that were induced by 6-OHDA. Iron accumulation in SN is thought to participate in neuronal death in PD, which subsequently resulted in oxidative stress and overexpression of a-synuclein caused by iron metabolism protein disorder. In our study, KuA could chelate cellular iron content and decrease iron influx. Moreover, KuA could upregulate the expression of ferroportin1 and Hephaestin, downregulate the expression of DMT1, TfR, and Ferritin to maintain cellular iron homeostasis avoiding neuronal death from cellular iron deposition. Moreover, KuA could decrease the expression of a-synuclein in cells. All the results indicated that KuA protected against neurotoxininduced PD due to the apoptosis inhibition and iron homeostasis maintaining.Conclusion: KuA treatment might represent a neuroprotective treatment for PD.

Discovery of novel dual inhibitors of VEGFR and PI3K kinases containing 2-ureidothiazole scaffold

A series of compounds possessing 2-（3-phenyl）ureidothiazol-4-formamide derivatives with a 2-ureidothiazole scaffold were designed and synthesized. Some compounds demonstrated inhibition of cell proliferation against both MDA-MB-231 and Hep G2 cell lines using Sorafenib as the positive control.Compounds 6i showed a good to moderate inhibition on VEGFR-2 and PI3Ka which was proved by further molecular docking study. This study suggests that compound 6i is a potential dual inhibitor of VEGFR-2 and PI3Ka and is applicable for further investigation.

Synthesis and antiproliferative activity of novel 4-substituted-phenoxy-benzamide derivatives

A series of novel 4-substituted-phenoxy-benzamide derivatives bearing an aryl cycloaliphatic amine moiety were synthesized and evaluated for antiproliferative activity against SW620, HT29 and MGC803 cancer cell lines in vitro. The pharmacological data demonstrated that the majority of target compounds exhibited moderate efficacy in HT29 and MGC803 cell lines. Compound 10 c showed promising inhibition of hedgehog（Hh） signaling pathway in an Hh-related assay. In addition, the superposition pattern of 10 c showed a good fit for a pharmacophoric model generated by Hh inhibitors and provided a basis for further structural optimization.

Design,synthesis and biological evaluation of sulfenimine cephalosporin sulfoxides as β-lactamase inhibitors

A series of sulfenimine cephalosporin sulfoxide derivatives （Ta-v） were designed, synthesized and evaluated for their inhibitory activity against TEM-1 and cephalosporinase in cell-free systems. Some of the tested compounds showed enhanced inhibitory activity against class C β-lactamase cephalospor- inase compared with the tazobactam. The most promising compounds 7c and 7n （IC50 ~ 7.6 and 8.6 μmol/L, respectively） were further investigated in combination with cefradine against a variety of clinical isolated fi-lactamase-producing bacterial strains.