Making cycles, bicycles and macrocycles

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Copper-Catalyzed Decarboxylative C—N Cross-Coupling for N-Arylation

A novel approach for N-arylation utilizing aryl carboxylic acids as stable, inexpensive and widely available arylating reagents was developed. Employing a simple copper(II)-phenanthroline catalyst system, several benzoic acids bearing suitable ortho-substitutions undergo decarboxylative C—N cross-coupling effectively with various N-nucleophiles

Continuous Flow Coupling and Decarboxylation Reactions Promoted by Copper Tubing

A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, and decarboxylation reactions using a commercially available copper tube flow reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd), ligands, or reagents, and in greater than 90% yield in most cases examined

Evolution of a New Class of VEGFR‑2 Inhibitors from Scaffold Morphing and Redesign

Anti-VEGF therapy is a clinically validated treatment for age-related macular degeneration (AMD). We have recently reported the discovery of oral VEGFR-2 inhibitors that are selectively distributed to the ocular tissues. Herein we report a further development of those compounds and in particular the validation of the hypothesis that aminoheterocycles such as aminoisoxazoles and aminopyrazoles could also function as effective “hinge” binding moieties leading to a new class of KDR (kinase insert domain containing receptor) inhibitors

A Reliable Synthesis of 3-Amino-5-Alkyl and 5-Amino-3-Alkyl Isoxazoles

A reliable procedure to access a wide range of 3-amino-5-alkyl and 5-amino-3-alkyl isoxazoles was developed. Reaction temperatures and pH were key factors in the regioselectivity of the two reactions

Discovery of Oral VEGFR-2 Inhibitors That Provide Sustained Ocular Retention and Efficacy in Models of Wet-AMD

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) has been well established. Identification of suitable VEGFR-2 inhibitors would provide alternative dosing opportunities beyond intravitreal injection. To identify such inhibitors, we employed a high–throughput in vivo screening strategy with a model of choroidal neovascularization and iterative compound design to provide VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds, when dosed orally, provided good efficacy and preferential ocular tissue distribution while minimizing systemic exposure

Serine Is an Essential Metabolite for Effector T Cell Expansion.

During immune challenge, T lymphocytes engage pathways of anabolic metabolism to meet the demands of clonal expansion and development of effector functions. Here we report a critical role for the non-essential amino acid serine in effector T cell responses. Upon activation, T cells upregulate enzymes of the serine, glycine, one-carbon (SGOC) metabolic network, and rapidly increase processing of serine into one-carbon metabolism. We show that T cell proliferation is highly dependent on extracellular serine, and that serine is required for optimal T cell expansion even in glucose concentrations sufficient to support T cell activation, bioenergetics, and effector function. Restricting dietary serine impairs pathogen-driven expansion of T cells in vivo, without affecting overall immune cell homeostasis. Mechanistically, we demonstrate that serine supplies glycine and one-carbon units for de novo nucleotide biosynthesis in proliferating T cells, and that one-carbon units from formate can rescue T cells from serine deprivation. Our data implicate serine as a key immunometabolite that directly modulates adaptive immunity by controlling T cell proliferative capacity