Quinolones and their N-oxides as inhibitors of mitochondrial complexes I and III

Abstract4(1H)-quinolones (2-alkyl- (1), 2-alkyl-3-methyl- (2), 2-methyl-3-alkyl- (3), 1-hydroxy-2-methyl-3-alkyl- (4) and 1-hydroxy-2-alkyl- (5)) with n-alkyl side chains varying from C5 to C17 have been synthesized and tested for biological activity in mitochondrial complexes. Whereas all quinolones were efficient inhibitors of electron transport in the cytochrome b/c1-complex from either beef heart or Rhodospirillum rubrum, in complex I from beef heart quinolones 1 and 2 only were highly active. In a Quantitative Structure-Activity Relationship (QSAR) inhibitory activity in the cytochrome b/c1-complexes could be correlated to the physicochemical parameters lipophilicity π and/or to STERIMOL L. Maximal inhibitory potency was achieved at a carbon chain length of 12–14 Å. Oxidant-induced reduction of cytochrome b established that some quinolones are inhibitors of the Qp rather than the Qn site

Inhibition of photosystem II electron transport by acyl derivatives of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid)

AbstractIn the course of the synthesis of γ-pyrones, well-known inhibitors of photosystem II electron transport, it turned out that the starting material, acyl derivatives of 2,2-dimethyl-1,3-dioxane-5,6-dione (Meldrum's acid) are potent inhibitors of photosystem II electron transport. Thus, in a simple one-step synthesis from commercial available substances, highly potent photosystem II inhibitors are generated. The biological activity of the acyl derivatives is in a parabolic fashion dependent from the length of the alkyl side chain

Heterocyclic ortho-quinones, a novel type of Photosystem II inhibitors

AbstractMembers of the new chemical class of 7-substituted 6-bromo-benzo[4,5]imidazo[1,2α]pyridin-8,9-diones were found to be excellent inhibitors at the QB site of the photosystem II D1 reaction center protein. The best inhibitors with pI50-values of >7 are: dimethyl-propyl, 7.05; i-pentyl, 7.36; t. butyl, 7.47; and i-propyl, 7.51. Displacement experiments with [14C]atrazine revealed that the 8,9-diones behave non-competitively in respect of Photosystem II herbicides and, hence, have to be considered as a new type of Photosystem II inhibitors. This notion is further corroborated by their inhibitory activity in D1 mutants of Chlamydomonas reinhardtii

Mapping of two tyrosine residues involved in the quinone- (QB) binding site of the D-1 reaction center polypeptide of photosystem II

AbstractThe property of the D-1 subunit of photosystem II in binding herbicides in its quinone-binding niche has provided important approaches to study its structure and function. In the D-1 protein, amino acid residues Tyr-254 and Tyr-237 are labeled by an [14C]azido-urea derivative, as identified by protein sequencing of proteolytic fragments. Whereas Tyr-254 is in a parallel α-helix already indicated to contribute to the herbicide-binding site, Tyr-237 is in a hydrophilic sequence that is partly accessible from the matrix space of the chloroplasts. This area has been implicated to contain a cleavage site for a protease involved in the rapid turnover of the D-1 polypeptide. The photoaffinity labeling results show that some of the amino acids in this cleavage site are actually part of the quinone-binding niche. It allows a refined and extended prediction of the three-dimensional folding of the reaction center of photosystem II