Design, Synthesis, and Evaluation of Inhibitors of Pyruvate Phosphate Dikinase

Pyruvate phosphate dikinase (PPDK) catalyzes the phosphorylation reaction of pyruvate that forms phosphoenolpyruvate (PEP) via two partial reactions: PPDK + ATP + P_i → PPDK-P + AMP + PP_i and PPDK-P + pyruvate → PEP + PPDK. Based on its role in the metabolism of microbial human pathogens, PPDK is a potential drug target. A screen of substances that bind to the PPDK ATP-grasp domain active site revealed that flavone analogues are potent inhibitors of the <i>Clostridium symbiosum</i> PPDK. In silico modeling studies suggested that placement of a 3–6 carbon-tethered ammonium substituent at the 3′- or 4′-positions of 5,7-dihydroxyflavones would result in favorable electrostatic interactions with the PPDK Mg-ATP binding site. As a result, polymethylene-tethered amine derivatives of 5,7-dihydroxyflavones were prepared. Steady-state kinetic analysis of these substances demonstrates that the 4′-aminohexyl-5,7-dyhydroxyflavone <b>10</b> is a potent competitive PPDK inhibitor (<i>K</i>_i = 1.6 ± 0.1 μM). Single turnover experiments were conducted using 4′-aminopropyl-5,7-dihydroxyflavone <b>7</b> to show that this flavone specifically targets the ATP binding site and inhibits catalysis of only the PPDK + ATP + P_i → PPDK-P + AMP PP_i partial reaction. Finally, the 4′-aminopbutyl-5,7-dihydroxyflavone <b>8</b> displays selectivity for inhibition of PPDK versus other enzymes that utilize ATP and NAD

Photoaddition Reactions of Acetylpyridines with Silyl Ketene Acetals: SET vs [2 + 2]-Cycloaddition Pathways

Photoaddition reactions of silyl ketene acetals with 2-, 3- and 4-acetylpyridine have been explored. The results show that the acetylpyridines react with an electron rich, dimethyl-substituted silyl ketene acetal via a pathway in which excited state single electron transfer (SET) takes place to produce β-hydroxyesters in high yields. In contrast, photochemical reactions of the acetylpyridines with an electron deficient, nonmethyl-substituted silyl ketene acetal generate oxetanes as major products, which arise via a route involving excited state [2 + 2]-cycloaddition. In addition, an increase in solvent polarity significantly enhances the relative efficiencies of the SET processes versus [2 + 2]-cycloaddition reactions. Importantly, the carbonyl groups rather than the pyridine moieties in the acetylpyridine substrates participate in both types of addition reactions. Finally, the results demonstrate that photoinduced electron transfer (PET)-promoted chemical reactions between acetylpyridines and electron rich silyl ketene acetals in polar solvent serve as useful methods to promote β-hydroxyester forming, Claisen or Mukaiyama condensation reactions under mild conditions

Effects of Alkoxy Groups on Arene Rings of Lignin β‑O‑4 Model Compounds on the Efficiencies of Single Electron Transfer-Promoted Photochemical and Enzymatic C–C Bond Cleavage Reactions

To gain information about how alkoxy substitution in arene rings of β-O-4 structural units within lignin governs the efficiencies/rates of radical cation C1–C2 bond cleavage reactions, single electron transfer (SET) photochemical and lignin peroxidase-catalyzed oxidation reactions of dimeric/tetrameric model compounds have been explored. The results show that the radical cations derived from less alkoxy-substituted dimeric β-O-4 models undergo more rapid C1–C2 bond cleavage than those of more alkoxy-substituted analogues. These findings gained support from the results of DFT calculations, which demonstrate that C1–C2 bond dissociation energies of β-O-4 radical cations decrease as the degree of alkoxy substitution decreases. In SET reactions of tetrameric compounds consisting of two β-O-4 units, containing different degrees of alkoxy substitution, regioselective radical cation C–C bond cleavage was observed to occur in one case at the C1–C2 bond in the less alkoxy-substituted β-O-4 moiety. However, regioselective C1–C2 cleavage in the more alkoxy-substituted β-O-4 moiety was observed in another case, suggesting that other factors might participate in controlling this process. These observations show that lignins containing greater proportions of less rather than more alkoxylated rings as part of β-O-4 units would be more efficiently cleaved by SET mechanisms

Single Electron Transfer-Promoted Photochemical Reactions of Secondary <i>N</i>‑Trimethylsilylmethyl‑<i>N</i>‑benzylamines Leading to Aminomethylation of Fullerene C₆₀

Photoreactions between C₆₀ and secondary <i>N</i>-trimethylsilylmethyl-<i>N</i>-benzylamines were explored to evaluate the feasibility of a new method for secondary aminomethylation of electron acceptors. The results show that photoreactions of C₆₀ with these secondary amines in 10% EtOH-toluene occur to form aminomethyl-1,2-dihydrofullerenes predominantly through a pathway involving single electron transfer (SET)-promoted formation of secondary aminium radicals followed by preferential loss of the α-trimethylsilyl group. The aminomethyl radicals formed in this manner then couple with C₆₀ or C₆₀^•– to form radical or anion precursors of the aminomethyl-1,2-dihydrofullerenes. In contrast to thermal and photochemical strategies developed previously, the new SET photochemical approach using α-trimethylsilyl-substituted secondary amines is both mild and efficient, and as a result, it should be useful in broadening the library of substituted fullerenes. Moreover, the results should have an impact on the design of SET-promoted C–C bond forming reactions. Specifically, introduction of an α-trimethylsilyl group leads to a change in the chemoselectivity of SET-promoted reactions of secondary amines with acceptors that typically favor aminium radical N–H deprotonation, leading to N–C bond formation. Finally, symmetric and unsymmetric fulleropyrrolidines are also generated in yields that are highly dependent on the electronic properties of arene ring substituents in amines, irradiation time, and solvent