Advances in Proteasome Enhancement by Small Molecules

The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation

Sensitization of Tumor Cells toward Chemotherapy: Enhancing the Efficacy of Camptothecin with Imidazolines

SummaryActivation of nuclear transcription factor κB (NF-κB) by chemotherapeutic agents was found to protect cells from apoptosis. In light of its central role in regulating the cellular resistance to apoptotic agents, inhibition of NF-κB-mediated gene transcription may sensitize tumor cells to chemotherapeutic agents and enhance their efficacy. We describe herein a noncytotoxic imidazoline scaffold that sensitizes leukemia T cells to the chemotherapeutic agent camptothecin. No significant induction of apoptosis was found when cells were treated with the imidazoline; however, pretreatment of cells with this agent resulted in a drastic enhancement in efficacy of camptothecin (∼75-fold). Elucidation of the potential cellular mechanism revealed that the imidazoline prevents nuclear translocation of NF-κB. These findings indicate that inhibition of NF-κB by this imidazoline may present improved strategies in the chemotherapeutic treatment of cancer

Perspectives On SARS-CoV-2 Main Protease Inhibitors

The main protease (Mpro) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting SARS-CoV-2 Mpro designed by Pfizer are under clinical trials, no SARS-CoV-2 medication is approved due to the long period of drug development. Here, we collect a comprehensive list of 817 available SARS-CoV-2 and SARS-CoV Mpro inhibitors from the literature or databases and analyze their molecular mechanisms of action. The structure–activity relationships (SARs) among each series of inhibitors are discussed. Additionally, we broadly examine available antiviral activity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and animal tests of these inhibitors. We comment on their druggability or drawbacks that prevent them from becoming drugs. This Perspective sheds light on the future development of Mpro inhibitors for SARS-CoV-2 and future coronavirus diseases

Small Molecule Modulation of Proteasome Assembly

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S–20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes

Hydroxyamination of Olefins Using Br-N-(CO₂Me)₂

The hydroxyamination reagent Br-N-(CO₂Me)₂ underwent Markovnikov addition to various olefins in the presence of catalytic BF₃·OEt₂ and provides efficient access to aminoalcohols. The reaction provided the <i>trans</i>-1-bromo, 2-<i>N</i>-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol

Substrate Controlled Regioselective Bromination of Acylated Pyrroles Using Tetrabutylammonium Tribromide (TBABr₃)

Electrophilic bromination of pyrroles bearing carbonyl substituents at C-2 typically results in a mixture of the 4- and 5-brominated species, generally favoring the 4-position. Herein, we describe a substrate-controlled regioselective bromination in which tetra-butyl ammonium tribromide (TBABr₃) reacts with pyrrole-2-carboxamide substrates to yield the 5-brominated species as the predominant (up to >10:1) product