Photoredox-Mediated Dual Catalysis, 1,2-Difunctionalizations, And Reaction Development For Dna-Encoded Library Technology

Reactions for the controlled, catalytic formation of carbon-carbon bonds are crucial for modern organic synthesis. In an idealized sense, they enable a rapid, convergent assembly of molecular complexity. Among such transformations, the formation of C–C bonds at Csp3-hybridized centers is a particularly desirable construct because of its potential to provide access to 3D-rich architectures and, akin to the Suzuki sp2-sp2 coupling, impact the way that novel chemical space is accessed. Toward this goal, metallaphotoredox catalysis has been enlisted as a valuable advance to forge Csp3–Csp2 linkages through single-electron-transfer (SET) under mild reaction conditions. Recent research efforts have broadened the scope of radical progenitors from feedstock chemicals including aliphatic carboxylic acids, aldehydes, bromides, and organosilanes. In subsequent studies, a photochemical/Ni-mediated decarboxylative strategy is accomplished through electron donor-acceptor (EDA) complex activation bypassing the need for stoichiometric metal reductants or exogenous photocatalysts. To facilitate sequential bond formation, net-neutral radical/polar crossover is utilized to achieve the 1,2-dicarbofunctionalization of olefins with organotrifluoroborate nucleophiles. Among the applications in which the ability to accommodate diverse reaction modalities and molecular complexity becomes critical is DNA-Encoded Library (DEL) synthesis. Recently, DEL technology has emerged as an innovative screening modality for the discovery of therapeutic candidates in the pharmaceutical industry. The platform enables a cost-effective, time-efficient, and large-scale assembly and interrogation of billions of small organic ligands against a biological target in a single experiment. To increase chemical diversity, the implementation of photoredox catalysis in DELs, including Ni-catalyzed manifolds and radical/polar crossover, has enabled the construction of novel structural scaffolds. To expand chemical space, a decarboxylative-based hydroalkylation of DNA-conjugated trifluoromethyl-substituted alkenes driven by SET and subsequent hydrogen atom termination through EDA complex activation is detailed. In a further protocol, the coupling of electronically unbiased olefins is achieved through the intermediacy of (hetero)aryl radical species with full retention of the DNA tag integrity. In summary, photoredox catalysis offers new avenues for unique synthetic disconnections toward bioactive molecules. The diverse nature of amenable radical precursors, combined with the mild and modular character of photochemical paradigms, facilitate the generation of chemotypes that possess a high density of pendant functional groups

Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase

Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2

Synergistic Visible-Light Photoredox/Nickel-Catalyzed Synthesis of Aliphatic Ketones via N–C Cleavage of Imides

An electrophilic, imide-based, visible-light-promoted photoredox/Ni-catalyzed cross-coupling reaction for the synthesis of aliphatic ketones has been developed. This protocol proceeds through N–C­(O) bond activation, made possible through the lower activation energy for metal insertion into this bond due to delocalization of the lone pair of electrons on the nitrogen by electron-withdrawing groups. The operationally simple and mild cross-coupling reaction is performed at ambient temperature and exhibits tolerance for a variety of functional groups

Moody, Miss. Jennie L

https://digitalcommons.buffalostate.edu/dabc_cards_5/1225/thumbnail.jp

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1

Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1’s catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications