A screening strategy to identify novel immunomodulators

<p>Understanding the immunomodulatory activities of compounds is important to identify the unintended adverse immunomodulatory effects of therapeutic compounds in development and to select novel compounds that may provide benefit for those diagnosed with immunemediated disorders. In both these cases, it is desirable to identify compounds with immunomodulatory activity early in the drug discovery process in a medium-throughput format. A screening strategy has been designed to fulfil these needs. The first step in designing the strategy was to select informative assays and optimise individual assays to suit medium-throughput drug discovery. These individual assays investigated effects on a broad range of functions associated with innate and adaptive immune cells including macrophages (activation, cytokine production, phagocytosis and motility), helper T cells (activation and cytokine production), cytotoxic T cells (degranulation and cytokine production), and B cells (antibody production and cytokine production). Cost effectiveness and ease-of-use were important considerations during assay design and optimisation. Using a compound set comprised of positive controls (i.e. compounds known to alter specific immune functions), a data set was generated to guide the strategy design. Assays were ordered to efficiently use resources and reduce the generation of less informative data. Additionally, using data collected from this compound set, strategies to assess and identify immunomodulatory activity were built and analysed. A second set of compounds was used to validate the screening strategy, and this screen highlighted new and novel activities for these known compounds that suggests they possess additional immunomodulatory effects. Once validated, several novel compounds were run through the screen, including a traditional Samoan medicine, a heparan sulfate mimetic, and a novel anti-cancer agent; unique immunomodulatory activities were discovered. Finally, a hierarchical cluster analysis was used to cluster compounds sharing similar activity profiles and suggested the potential to develop further statistical methods to provide insight into compound characterisation. Together, this research has developed and validated a novel, medium throughput drug discovery system that can facilitate the identification of the immunomodulatory activities of compounds in the drug discovery environment.</p>

A screening strategy to identify novel immunomodulators

<p>Understanding the immunomodulatory activities of compounds is important to identify the unintended adverse immunomodulatory effects of therapeutic compounds in development and to select novel compounds that may provide benefit for those diagnosed with immunemediated disorders. In both these cases, it is desirable to identify compounds with immunomodulatory activity early in the drug discovery process in a medium-throughput format. A screening strategy has been designed to fulfil these needs. The first step in designing the strategy was to select informative assays and optimise individual assays to suit medium-throughput drug discovery. These individual assays investigated effects on a broad range of functions associated with innate and adaptive immune cells including macrophages (activation, cytokine production, phagocytosis and motility), helper T cells (activation and cytokine production), cytotoxic T cells (degranulation and cytokine production), and B cells (antibody production and cytokine production). Cost effectiveness and ease-of-use were important considerations during assay design and optimisation. Using a compound set comprised of positive controls (i.e. compounds known to alter specific immune functions), a data set was generated to guide the strategy design. Assays were ordered to efficiently use resources and reduce the generation of less informative data. Additionally, using data collected from this compound set, strategies to assess and identify immunomodulatory activity were built and analysed. A second set of compounds was used to validate the screening strategy, and this screen highlighted new and novel activities for these known compounds that suggests they possess additional immunomodulatory effects. Once validated, several novel compounds were run through the screen, including a traditional Samoan medicine, a heparan sulfate mimetic, and a novel anti-cancer agent; unique immunomodulatory activities were discovered. Finally, a hierarchical cluster analysis was used to cluster compounds sharing similar activity profiles and suggested the potential to develop further statistical methods to provide insight into compound characterisation. Together, this research has developed and validated a novel, medium throughput drug discovery system that can facilitate the identification of the immunomodulatory activities of compounds in the drug discovery environment.</p>

Construction and Properties of Ag-I Polymeric Clusters Attach With Nitrogen Heterocyclic Transition Metal Moiety

Two silver cluster compounds {[Co(1,10′-phen)3]2‧[Ag8I12]} (1) and {[Co(2, 2′-bipy)3]‧[Ag10I11]‧(OH)‧3DMF‧2H2O} (2) (1,10′-phen=1,10′-phenanthroline, 2, 2′-bipy=2,2′-bipyridine) were designed and synthesized by solvent evaporation method. The two silver cluster compounds were characterized by elemental analysis, infrared spectroscopy, ultraviolet spectroscopy, thermogravimetric analysis and X-ray powder diffraction. The crystal structures of compounds 1 and 2 were determined by X-ray crystallography diffraction. Through the electrostatic interaction between the metallic Ag cluster moiety and the metallic Co cluster moiety, form stable interlaced layered super molecular structures. In order to explore functional properties, the catalytic reduction of p-nitrophenol and electrochemical behavior of compounds 1 and 2 were explored. The results show that compounds 1 and 2 can efficiently catalyze the reduction of p-nitrophenol in the aqueous solution, and the reduction and removal rate can reach more than 90%.

Redox Potential and Crystal Chemistry of Hexanuclear Cluster Compounds

Most of TM6-cluster compounds (TM = transition metal) are soluble in polar solvents, in which the cluster units commonly remain intact, preserving the same atomic arrangement as in solids. Consequently, the redox potential is often used to characterize structural and electronic features of respective solids. Although a high lability and variety of ligands allow for tuning of redox potential and of the related spectroscopic properties in wide ranges, the mechanism of this tuning is still unclear. Crystal chemistry approach was applied for the first time to clarify this mechanism. It was shown that there are two factors affecting redox potential of a given metal couple: Lever’s electrochemical parameters of the ligands and the effective ionic charge of TM, which in cluster compounds differs effectively from the formal value due to the bond strains around TM atoms. Calculations of the effective ionic charge of TMs were performed in the framework of bond valence model, which relates the valence of a bond to its length by simple Pauling relationship. It was also shown that due to the bond strains the charge depends mainly on the atomic size of the inner ligands.