Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2.

Unpublished data from our labs led us to hypothesize that activated protein C (aPC) may initiate an anti-inflammatory signal in endothelial cells by modulating both the integrin αVβ3 and protease-activated receptor 2 (PAR2), which may exist in close proximity on the cellular surface. To test this hypothesis and to probe the possible inflammation-related pathway, we designed and synthesized dual-targeting ligands composed of modified versions of two αVβ3 ligands and two agonists of PAR2. These novel ligands were connected copper-catalyzed alkyne-azide cycloadditions with polyethylene glycol (PEG) spacers of variable length.

Design and Evaluation of Heterobivalent PAR1-PAR2 Ligands as Antagonists of Calcium Mobilization.

A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1-PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists.

Characterization of Protease-Activated Receptor (PAR) ligands: Parmodulins are reversible allosteric inhibitors of PAR1-driven calcium mobilization in endothelial cells.

Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the PAR1 antagonist RWJ-58259 that is suitable for the preparation of tagged or conjugate compounds.

Studies at the ionizable position of cephalosporins and penicillins: hydroxamates as substitutes for the traditional carboxylate group.

Classically, β-lactams need an ionizable group to potentiate antibacterial activity. Sets of cephalosporins and penicillins featuring different substituted hydroxamates in place of the traditional carboxylate group have been synthesized and tested for antibiotic activity. Many of the compounds exhibited anti-bacterial activities with notable MIC values in the range of 6-0.

Alternate "Drug" Delivery Utilizing β-Lactam Cores: Syntheses and Biological Evaluation of β-Lactams Bearing Isocyanate Precursors.

The synthesis of a small set of β-lactams containing isocyanate precursors is described. The release of the isocyanate precursor in model hydrolysis experiments was substantiated by trapping experiments, thus confirming that β-lactams can be designed that are capable of releasing alternatively reactive species. Preliminary biological assessments are also briefly discussed.

Design, syntheses, and anti-tuberculosis activities of conjugates of piperazino-1,3-benzothiazin-4-ones (pBTZs) with 2,7-dimethylimidazo [1,2-a]pyridine-3-carboxylic acids and 7-phenylacetyl cephalosporins.

Tuberculosis (TB) remains one of the most threatening diseases in the world and the need for development of new therapies is dire. Herein we describe the rationale for the design and subsequent syntheses and studies of conjugates between pBTZ and both the imidazopyridine and cephalosporin scaffolds. Overall some compounds exhibited notable anti-TB activity in the range of 2-0.

Syntheses and Biological Evaluations of Highly Functionalized Hydroxamate Containing and -Methylthio Monobactams as Anti-Tuberculosis and β-Lactamase Inhibitory Agents.

Both the resurgence of tuberculosis (TB) and antibiotic resistance continue to threaten modern healthcare and new means of combating pathogenic bacterial infections are needed. The syntheses of monobactams possessing hydroxamate and -methylthio functionality are described, as well as their anti-TB, β-lactamase inhibitory, and general antimicrobial evaluations. A number of compounds exhibited significant anti-TB and β-lactamase inhibitory activity, with MIC values in the range of 25 to < 0.

Syntheses and evaluation of substituted aromatic hydroxamates and hydroxamic acids that target Mycobacterium tuberculosis.

Tuberculosis (TB) continues to remain one of the most threatening diseases in the world. With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains, the need to develop new therapies is dire. The syntheses of a focused library of hydroxamates and hydroxamic acids is described, as well as anti-TB activity in the microplate alamar blue assay (MABA).