A rapid and convergent synthesis of the integrastatin core

The tetracyclic core of the integrastatin natural products has been prepared in a convergent and rapidmanner. Our strategy relies upon a palladium(II)-catalyzed oxidative cyclization to form the central [3.3.1]-dioxabicycle of the natural product core. Overall, the core has been completed in only 4 linear steps from known compounds

Regioselective Reactions of Highly Substituted Arynes

The fully regioselective reactivity of four new highly substituted silyl aryl triflate aryne precursors in aryne acyl-alkylation, acyl-alkylation/condensation, and heteroannulation reactions is reported. The application of these more complex arynes provides access to diverse natural product scaffolds and obviates late-stage functionalization of aromatic rings

Sequential Photoactivation of Self-Assembled Monolayers to Direct Cell Adhesion and Migration

Dynamic substrates for cell culture control the spatial and temporal presentation of extracellular matrix ligands that interact with adherent cells. This paper reports a photoactive surface chemistry that can repeatedly activate regions of the substrate for cell adhesion, spreading, and migration. The approach uses self-assembled monolayers presenting the integrin ligand RGD that is caged with a nitrophenyl-based photoprotecting group. The group is also modified with a maltoheptaose oligosaccharide to prevent nonspecific protein adsorption and cell attachment. The peptide is uncaged when irradiated with a laser source at 405 nm on a microscope to reveal micron-size regions for single cell attachment. This method is applied to studies of gap junction-mediated communication between two neighboring cells and requires the patterning of an initial receiver cell population and then the patterning of a second sender population to give a culture wherein each pair of cells are separated by 30 μm. Finally, activation of the region between the cells permits cell–cell contact and gap junction assembly between the sender and receiver cells. This example demonstrates the broad relevance of this method to studying complex phenotypes in cell culture

Measuring Drug Metabolism Kinetics and Drug–Drug Interactions Using Self-Assembled Monolayers for Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry

The competition of two drugs for the same metabolizing enzyme is a common mechanism for drug–drug interactions that can lead to altered kinetics in drug metabolism and altered elimination rates <i>in vivo</i>. With the prevalence of multidrug therapy, there is great potential for serious drug–drug interactions and adverse drug reactions. In an effort to prevent adverse drug reactions, the FDA mandates the evaluation of the potential for metabolic inhibition by every new chemical entity. Conventional methods for assaying drug metabolism (e.g., those based on HPLC) have been established for measuring drug–drug interactions; however, they are low-throughput. Here we describe an approach to measure the catalytic activity of CYP2C9 using the high-throughput technique self-assembled monolayers for matrix-assisted laser desorption-ionization (SAMDI) mass spectrometry. We measured the kinetics of CYP450 metabolism of the substrate, screened a set of drugs for inhibition of CYP2C9 and determined the <i>K</i>_i values for inhibitors. The throughput of this platform may enable drug metabolism and drug–drug interactions to be interrogated at a scale that cannot be achieved with current methods