ARENE AND AZA-HETEROCYCLE FUNCTIONALIZATION VIA ORGANIC PHOTOREDOX CATALYSIS

Over the last decade, photoredox catalysis has emerged as a powerful tool in organic synthesis that provides access to open-shell, one-electron, intermediates. In general, these one-electron intermediates have complementary reactivity compared to traditional two-electron pathways, and, accordingly, have been used to accomplish difficult synthetic transformations. Moreover, photoredox catalysis uses mild reaction conditions with high functional group tolerance, and has accordingly become a popular late-stage functionalization strategy.Chapter 1 serves as a general introduction to organic photoredox catalysis which covers the photophysical and electrochemical properties of organic chromophores. In particular, the properties of acridinium salts as potent photooxidants in the generation of alkene or arene cation radicals and alpha -amino radicals is covered in more detail.Chapter 2 and 3 cover the application of acridinium salts as photooxidants in arene functionalization with carbon nucleophiles. Chapter 2 describes a selective carbon–oxygen (C–O) bond functionalization via a cation radical-accelerated-nucleophilic aromatic substitution (CRA-SNAr) of alkoxy arenes with acetone cyanohydrin, an inexpensive and commercially available cyanide source, generating the desired benzonitriles. Computational studies provide a model for predicting regioselectivity and chemoselectivity in competitive C–H and C–O cyanation of methoxyarene cation radicals. Chapter 3 reports a C–H functionalization of arene cation radicals generated via organic photoredox catalysis with diazoacetates serving as nucleophiles. Computational and experimental studies support a unique mechanism involving cation radical-meditated aromatic cyclopropanation followed by oxidative ring-opening.Chapter 4 covers a two-step acridinium catalyzed procedure for the synthesis of beta-functionalized aza-heterocycles. First, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C–C, C–O and C–N aza-heterocycles at the beta-position. The utility of this transformation was highlighted with the functionalization of several pharmaceutically relevant molecules, including in the synthesis of an orexin antagonist.Doctor of Philosoph

NHD2-15, a novel antagonist of Growth Factor Receptor-Bound Protein-2 (GRB2), inhibits leukemic proliferation.

The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a KD value of 119 ± 2 μM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML

Multiple Myeloma, Version 1.2020 Featured Updates to the NCCN Guidelines

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma