Bruce Clapham

Preparation of soluble and insoluble polymer supported IBX reagents.

A series of soluble and insoluble polymer supported versions of the versatile oxidizing reagent IBX has been prepared. Each of the reagents were evaluated for their efficiency in the conversion of benzyl alcohol to benzaldehyde. Results from this study were that the soluble, non-crosslinked polystyrene supported IBX reagent gave the best rate of conversion to benzaldehyde, while the macroporous polymer supported IBX resin provided a superior rate of conversion to benzaldehyde when compared with a gel type resin. The macroporous IBX reagent was also shown to convert a series of alcohols to the corresponding aldehydes and ketones.

The preparation of polymer bound β-ketoesters and their conversion into an array of oxazoles

A series of diverse polymer bound β-ketoesters have been prepared using a transesterification reaction between t-butyl β-ketoesters and a hydroxybutyl functionalized JandaJel resin. Additionally, these highly useful polymer bound substrates have also been prepared using a transesterification reaction with commercially available methyl or ethyl β-ketoesters using lithium perchlorate as a catalyst. The polymer bound β-ketoesters were then converted into the corresponding α-diazo-β-ketoesters using standard diazo transfer conditions and these products were utilized in the synthesis of an array of oxazoles.

Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

Solid-phase synthesis of oligoesters using a JandaJel™ resin

Abstract This communication describes a general method for the solid-phase synthesis of oligomeric esters. A J anda J el™ resin was utilized as the solid support in conjunction with the highly acid labile Rink linker. Ester coupling reactions were performed using buffered reagents and the monomer was protected as its allyl ester. In this manner, ester coupling and deprotection could be performed under essentially neutral conditions, giving rise to products in both excellent yields and purity.

Synthesis and optimization of furano[3,2-d]pyrimidines as selective spleen tyrosine kinase (Syk) inhibitors.

A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model.

Discovering Additional Chemical and Biological Functions for 3-Oxo-N-Acylhomoserine Lactones

Introduction The term quorum sensing has been coined to describe the ability of a population of unicellular bacteria to act as a multicellular organism in a cell-density-dependent manner, that is, a way to sense “how many are out there” [1]. Bacteria use small diffusible molecules to exchange information amongst themselves. An important class of autoinducers is the family of N-acylhomoserine lactones (AHLs) used by Gram negative bacteria. Variation in N-acyl chain length and oxidation state of AHLs provide for bacterial strain specificity in the signaling process and subsequent synchronization of gene expression. Upon reaching a critical threshold concentration, they bind to their cognate receptor proteins, triggering the expression of target genes. Pseudomonas aeruginosa is a common environmental microorganism that has acquired the ability to take advantage of weaknesses in the host immune system to become an opportunistic pathogen in humans [2]. Over the last ten years, significant progress has been made in elucidating the molecular mechanisms underlying P. aeruginosa pathogenicity. Two different AHLs, N-(3-oxododecanoyl) homoserine lactone 1 and N-butyrylhomoserine lactone, have been identified as the main quorum sensing signaling molecules in P. aeruginosa [3]. Importantly, genes regulated by this mechanism control the expression of virulence factors as well as the formation of structures known as biofilms [4]. Recently, we have assigned new roles for these compounds through the demonstration that 1 performs a previously unrecognized role; the autoinducer itself and a corresponding degradation product derived from an unusual Claisen-like condensation reaction function as innate bactericidal agents [5].