Synthesis and Evaluation of Novel Neamine-Nucleoside Conjugates as Potential Antibiotic Targets for Escherichia coli 16S Ribosomal RNA.

Based on the nucleobase rich character of the binding pocket of A-site 16S ribosomal RNA of Escherichia coli, it was proposed that the neamine moiety of synthesized Neamine-nucleoside conjugates could bind to the groove of RNA while the nucleobase moiety would bind specifically to the sequence of the 16S rRNA A-site fragment. Thus the designed conjugate compound 5 was found to have the same dissociation constant as neamine for binding to 16S rRNA and the neamine-amino acid substituted nucleoside conjugate 8 and 9 showed 6.3 and 4.

[Treatment of triple negative breast cancer cells with combination of mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901].

MEK inhibition activates PI3K/AKT/mTOR pathway in triple negative breast cancer (TNBC) cell lines. Combination of PI3K inhibitor and MEK1/2 inhibitor is not appropriate for PI3K inhibitor insensitive TNBC cell lines. This study was designed to investigate the effects of dual treatments with mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901 in MDA-MB-435 cell line.

Preparation and In Vitro Evaluation of a MRI Contrast Agent Based on Aptamer-Modified Gadolinium-Loaded Liposomes for Tumor Targeting.

The aim of this study was to prepare aptamer-modified liposomes loaded with gadolinium (Gd) to enhance the effective diagnosis for tumor by MRI. A modified GBI-10 (GBI-10) was used to prepare targeted liposomes (GLs). Liposomes with GBI-10 aptamer (GLs) and without aptamer (non-targeted liposomes (NLs)) were also prepared as controls.

Effects of sericin on the testicular growth hormone/insulin-like growth factor-1 axis in a rat model of type 2 diabetes.

This study investigated the effects of sericin on the testicular growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in rats with type 2 diabetes mellitus. Forty rats were randomly assigned to normal control, type 2 diabetes mellitus, sericin and metformin treated groups. Type 2 diabetes was established by repeated intraperitoneal injection of streptozotocin, and identified by blood glucose ≥16.

In vitro study of novel gadolinium-loaded liposomes guided by GBI-10 aptamer for promising tumor targeting and tumor diagnosis by magnetic resonance imaging.

Novel gadolinium-loaded liposomes guided by GBI-10 aptamer were developed and evaluated in vitro to enhance magnetic resonance imaging (MRI) diagnosis of tumor. Nontargeted gadolinium-loaded liposomes were achieved by incorporating amphipathic material, Gd (III) [N,N-bis-stearylamidomethyl-N'-amidomethyl] diethylenetriamine tetraacetic acid, into the liposome membrane using lipid film hydration method. GBI-10, as the targeting ligand, was then conjugated onto the liposome surface to get GBI-10-targeted gadolinium-loaded liposomes (GTLs).

[Design and synthesis of photoaffinity biotin labelled 2'-O-propargyl-guanosine].

Photoaffinity labeling is widely applied to demonstrate targets of small molecule ligands. In this paper, biotin photoaffinity labeled molecule with propargyl group 1 has been designed and synthesized, followed it's labeling of N2-acetyl-2'-O-propargyl guanosine 9 by "click chemistry". This technology presents delight development potential in labeling of second messenger cyclic nucleotide, antisense oligonucleotide or siRNA.

Aprepitant in the prevention of vomiting induced by moderately and highly emetogenic chemotherapy.

Chemotherapy is a major therapeutic approach for malignant neoplasms; however, due to the most common adverse events of nausea and vomiting, scheduled chemotherapeutic programs may be impeded or even interrupted, which severely impairs the efficacy. Aprepitants, 5-HT3 antagonists and dexamethasone are primary drugs used to prevent chemotherapy-induced nausea and vomiting (CINV). These drugs have excellent efficacy for control of acute vomiting but are relatively ineffective for delayed vomiting.

Olanzapine for preventing nausea and vomiting induced by moderately and highly emetogenic chemotherapy.

Nausea and vomiting are common adverse events in chemotherapy. In spite of the serious effects on the quality of life and further treatment, they remain overlooked by physicians, and no standard treatment has been developed. Neurokinin-1 (NK-1) receptor antagonists and palonosetron are the major agents in the standard regimen for treating moderately and highly emetogenic chemotherapy-induced nausea and vomiting (CINV).

Observation of surface dark solitons in nonlocal nonlinear media.

We investigated surface dark solitons (SDSs) at the interface between a self-defocusing nonlocal nonlinear medium and a linear medium, both theoretically and experimentally. We demonstrate that fundamental and higher-order SDSs can exist when the linear refractive index of the self-defocusing medium is much greater than that of the linear medium. The fundamental and second-order solitons are observed at the interface between air and a weakly absorbing liquid.

A novel approach to improve the pharmacokinetic properties of 8-chloro-adenosine by the dual combination of lipophilic derivatisation and liposome formulation.

8-Chloro-adenosine (8CA) has shown promise in hematologic and solid tumor models and is in a phase I clinical trial. However, 8CA is intensively metabolized shortly after i.v.

Synthesis and properties of novel L-isonucleoside modified oligonucleotides and siRNAs.

Antisense oligonucleotides and siRNAs are potential therapeutic agents and their chemical modifications play an important role to improve the properties and activities of oligonucleotides. Isonucleoside is a type of nucleoside analogue, in which the nucleobase is moved from C-1 to other positions of ribose. In this report, a novel isonucleoside 5 containing a 5'-CH(2)-extended chain at the sugar moiety was synthesized, thus isoadenosine 5a and isothymidine 5b were incorporated into a DNA single strand and siRNA.

[Design, synthesis and biological assay of novel tripeptidic tetrazoles as inhibitors of 20S proteasome].

Ubiquitin-proteasome pathway (UPP) is one of the ways utilized for selective degradation of many proteins in cells, and the 20S proteasome takes the functional machinery where hydrolysis of targeted proteins takes place. Based on existing peptide inhibitors, a series of novel tripeptidic tetrazoles have been designed, synthesized, and the structures have been confirmed with 1H NMR, MS and elemental analysis. Among them, three compounds (6b, 6d and 6h) showed inhibitory activities of ChT-L of 20S proteasome.

[Activity of cyclic diguanylate (c-di-GMP) in bacteria and the study of its derivatives].

Cyclic diguanylate (c-di-GMP) is a ubiquitous second messenger present in a wide variety of bacteria, which is responsible for cell differentiation, biofilm formation, pathogenic factor generation, and so on. The level of c-di-GMP in bacteria is regulated by two opposing active domains, diguanylate cyclase (DGC) and phosphodiesterase (PDE), which are present in the same bifunctional protein, and in charge of the synthesis and the degradation of c-di-GMP, respectively. The target of c-di-GMP in the bacterial cell consists of PilZ domain and GEMM riboswitch, the only riboswitch that involved in signal transduction.

Synthesis, physicochemical and biological properties of oligonucleotides incorporated with amino-isonucleosides.

Antisense oligonucleotides (ASONs) and siRNAs have been applied extensively for the regulation of cellular and viral gene expression, and RNAi is currently one of the most promising new approaches for anti-tumor and anti-viral therapy. In order to improve bioactivity properties and physicochemical properties of siRNA, we synthesized a novel class of ASONs incorporated with amino-isonucleoside ( and ) for investigation on basic physicochemical properties. Then we designed amino-isonucleoside ( , and ) incorporated siRNA .

Design, synthesis and biological characterization of novel inhibitors of CD38.

Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14).

Trifluoromethylated cyclic-ADP-ribose mimic: synthesis of 8-trifluoromethyl-N(1)-[(5''-O-phosphorylethoxy)methyl]-5'-O-phosphorylinosine-5',5''-cyclic pyrophosphate (8-CF(3)-cIDPRE) and its calcium release activity in T cells.

A convenient trifluoromethylation method was firstly applied to the synthesis of 8- CF(3)-purine nucleosides. On the basis of this method, new protection and deprotection strategies were developed for the successful synthesis of the trifluoromethylated cyclic-ADP-ribose mimic, 8-CF(3)-cIDPRE 1. Using intact, fura-2-loaded Jurkat T cells compound 1 and 2',3'-O-isopropylidene 8-CF(3)-cIDPRE 14 were characterized as membrane-permeant cADPR agonists.

Solid-phase synthesis and evaluation of TAR RNA targeted beta-carboline-nucleoside conjugates.

Four types of beta-carboline-nucleoside conjugates were synthesized. The binding affinities of these beta-carboline-nucleoside conjugates , and to TAR RNA were evaluated by affinity capillary electrophoresis. The data of binding affinities to TAR RNA show that conjugates and are stronger binders than the parent compound .

Studies on the synthesis of neamine-dinucleosides and neamine-PNA conjugates and their interaction with RNA.

Two types of neamine derivatives, neamine-dinucleotide conjugates 8a-g and neamine-PNA conjugates 12a-c and 14a-d, were synthesized. Compound 8a-g were synthesized by the condensation of azido-neamine with dinucleotide-5'-carboxylic acids, followed by reduction and deprotection. Compound 12a-c and 14a-d were synthesized by the similar strategy.

Studies on aminoisonucleoside modified siRNAs: stability and silencing activity.

A novel class of aminoisonucleoside was synthesized and incorporated into a luciferase gene-targeting siRNA. Structural and functional analyses of such a kind of siRNAs indicated that sense strand modifications with aminoisonucleoside at the 3' or 5' terminal, such as ssIso-1 and ssIso-2, have less effect on RNA duplex thermal and serum stabilities, and their functional activities are also comparable to their native siRNAs. In contrast, antisense strand modifications with aminoisonucleoside at the corresponding positions, such as asIso-2 or asIso-1, bring a striking negative effect on RNA duplex stability but still maintain around 40-50% of gene knockdown.

Synthesis and biological evaluation of 6-substituted purine and 9-beta-d-ribofuranosyl purine analogues.

6-Substituted purine and 9-beta-d-ribofuranosyl purine analogues were synthesized and their biological activities were evaluated. CD Spectra and thermal melting studies showed that compounds 8, 9, 10 could interact with RNA and DNA in solution. Compound 8 and 10 may bind with RNA single strand and interfere the formation of RNA duplex.