Exploring structure-activity relationships of tricyclic farnesyltransferase inhibitors using ECLiPS libraries

The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.     

Thermally induced cascade pericyclic reaction pathways from tetraene esters

A novel thermally induced cascade pericyclic transformation of a tetraene ester into a complex tricyclic core is reported. This transformation is high yielding and highly selective.     

Electrochemistry and charge transport in sporopollenin particle arrays

Electrochemical oxidation of hollow sporopollenin particles immobilised on an electrode surface is investigated in aqueous acidic solution. Redox activity is demonstrated to occur via a mixture of 2e^?–2H⁺ and 2e^?–1H⁺ processes, likely due to the oxidation of conjugated phenolics embedded within the surface-shell of the polymer particles. Charge transport over the surface is suggested to be fast based on comparison with an approximate physicochemical model.     

Electrochemical and microfabrication strategies for remotely operated smart chemical sensors: Application of anodic stripping coulometry to calibration-free measurements of copper and mercury

Remote unattended sensor networks are increasingly sought after to monitor the drinking water distribution grid, industrial wastewater effluents, and even rivers and lakes. One of the biggest challenges for application of such sensors is the issue of in-field device calibration. With this challenge in mind, we report here the use of anodic stripping coulometry (ASC) as the basis of a calibration-free micro-fabricated electrochemical sensor (CF-MES) for heavy metal determinations. The sensor platform consisted of a photo-lithographically patterned gold working electrode on SiO₂ substrate, which was housed within a custom stopped-flow thin-layer cell, with a total volume of 2–4 μL. The behavior of this platform was characterized by fluorescent particle microscopy and electrochemical studies utilizing Fe(CN)₆^3−/4− as a model analyte. The average charge obtained for oxidation of 500 μM ferrocyanide after 60 s over a 10 month period was 176 μC, corresponding to a volume of 3.65 μL (RSD = 2.4%). The response of the platform to copper concentrations ranging from 50 to 7500 ppb was evaluated, and the ASC results showed a linear dependence of charge on copper concentrations with excellent reproducibility (RSD ≤ 2.5%) and accuracy for most concentrations (≤5–10% error). The platform was also used to determine copper and mercury mixtures, where the total metallic content was measurable with excellent reproducibility (RSD ≤ 4%) and accuracy (≤6% error).     

Addition curing thermosets endcapped with 4-amino [2.2] paracyclophane

A new family of addition curing polyimides were prepared that contained 4-amino [2.2]-paracyclophane as the endcap. An improved synthesis of the endcap 4-amino-[2.2] cyclophane was accomplished increasing the yield to 60% and simplifying the procedure. DSC and rheological analysis of endcapped polyimide oligomers confirmed that the onset for polymerization of the ethylene bridge was 250°C. ¹³C CP/MAS NMR was used to determine the structural changes of the oligomers after thermal treatment. The cyclophane capped polyimides were successfully compression molded to from void free neat resin specimens. T'_gs as high as 353°C were obtained by thermomechanical analysis for postcured samples. Preliminary thermal stability studies (TGA) suggest that these resins have a high onset of decomposition ranging from 549 to 567°C.