Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition.

Proline dehydrogenase (PRODH) is a p53-inducible inner mitochondrial membrane flavoprotein linked to electron transport for anaplerotic glutamate and ATP production, most critical for cancer cell survival under microenvironmental stress conditions. Proposing that PRODH is a unique mitochondrial cancer target, we structurally model and compare its cancer cell activity and consequences upon exposure to either a reversible (S-5-oxo: S-5-oxo-2-tetrahydrofurancarboxylic acid) or irreversible (N-PPG: N-propargylglycine) PRODH inhibitor. Unlike 5-oxo, the suicide inhibitor N-PPG induces early and selective decay of PRODH protein without triggering mitochondrial destruction, consistent with N-PPG activation of the mitochondrial unfolded protein response. Fly and breast tumor (MCF7)-xenografted mouse studies indicate that N-PPG doses sufficient to phenocopy PRODH knockout and induce its decay can be safely and effectively administered in vivo Among breast cancer cell lines and tumor samples, PRODH mRNA expression is subtype dependent and inversely correlated with glutaminase (GLS1) expression; combining inhibitors of PRODH (S-5-oxo and N-PPG) and GLS1 (CB-839) produces additive if not synergistic loss of cancer cell (ZR-75-1, MCF7, DU4475, and BT474) growth and viability. Although PRODH knockdown alone can induce cancer cell apoptosis, the anticancer potential of either reversible or irreversible PRODH inhibitors is strongly enhanced when p53 is simultaneously upregulated by an MDM2 antagonist (MI-63 and nutlin-3). However, maximum anticancer synergy is observed in vitro when the PRODH suicide inhibitor, N-PPG, is combined with both GLS1-inhibiting and a p53-upregulating MDM2 antagonist. These findings provide preclinical rationale for the development of N-PPG-like PRODH inhibitors as cancer therapeutics to exploit synthetic lethal interactions with p53 upregulation and GLS1 inhibition.

Mechanism of SmI2 Reduction of 5-Bromo-6-oxo-6-phenylhexyl Methanesulfonate Studied by Spin Trapping with 2-Methyl-2-nitrosopropane.

The radical formed by reduction of 5-bromo-6-oxo-6-phenylhexyl methanesulfonate, an α-bromoketone, with SmI2 was spin trapped with 2-methyl-2-nitrosopropane. Electron paramagnetic resonance spectra of the spin adduct and the adduct formed in the analogous reaction with selectively deuterated substrate identify the radical intermediate in this SmI2 reduction as a carbon-centered radical. This result supports the proposal that the formation of reactive Sm-enolates arises from reduction of the carbon-bromine bond rather than a ketyl radical anion.

Recent Advances in Metal-Free Quinoline Synthesis.

The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. Quinolines were first synthesized in 1879, and since then a multitude of synthetic routes have been developed. Many of these methods, such as the Skraup, Doebner-Von Miller, and Friedlander quinoline syntheses, are well-known but suffer from inefficiency, harsh reaction conditions, and toxic reagents. This review focuses on recent transition metal-free processes toward these important heterocycles, including both novel routes and modifications to established methods. For example, variations on the Skraup method include microwave irradiation, ionic liquid media, and novel annulation partners, all of which have shown increased reaction efficiency and improved yield of the heteroring-unsubstituted quinoline products. Similarly, modifications to other synthetic routes have been implemented, with the quinoline products displaying a wide variety of substitution patterns.

Pyridylalanine (Pal)-peptide catalyzed enantioselective allenoate additions to N-acyl imines proceed via an atypical "aza-Morita-Baylis-Hillman" mechanism.

Mechanistic experiments, including kinetics and hydrogen/deuterium kinetic isotope effects, reveal an "atypical" rate-determining step in a pyridylalanine-peptide catalyzed enantioselective coupling of allenoates and N-acyl imines. Typically, acrylates participate in both the aldehyde-based "Morita-Baylis-Hillman (MBH)" reaction and the imine-based variant (the "aza-MBH") through similar mechanisms, with proton transfer/catalyst regeneration often rate-determining. In contrast, the title reaction exhibits kinetics wherein proton transfer is kinetically silent.

Enantioselective catalysis and complexity generation from allenoates.

Lewis base catalysis of reactions with allenoates using phosphine and amine nucleophiles has emerged as a key platform for the generation of molecular complexity. Investigations in this area have established a range of suitable coupling partners for allenoates, including electron-deficient olefins, imines, and aldehydes. This tutorial review will describe these methodologies, with a special emphasis on recent work regarding asymmetric reactions using chiral Lewis base catalysts.

Pyridylalanine (pal)-peptide catalyzed enantioselective allenoate additions to N-acyl imines.

An amine-catalyzed reaction has been discovered that couples alpha-allenic esters with N-acyl imines in good to excellent yields (up to 88%). Extension of this methodology from the study of achiral pyridine-based catalysis to chiral peptide-based scaffolds is presented. The approach culminated in the identification of a tetrameric peptide sequence containing an embedded pyridylalanine (Pal) residue as an efficient asymmetric catalyst for enantioselective coupling reactions. The unique allenic products are obtained with enantiomer ratios of up to approximately 95:5 (up to >98:2 following recrystallization).