Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

Abstract

Verticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities. Also measured were the abilities of several of the analogues to inhibit respiration as judged by a shift to glycolysis, and to inhibit the growth of several mammalian cell lines. The nature of the pyrone ring was shown to be important to potency of inhibition, as was the length and nature of substituents in the side chain of the analogues.

Exploring Fungal Polyketide C-Methylation through Combinatorial Domain Swaps

“…A second set of reactions was also carried out, analogous to those above, but the ACP and CMeT were cognate and paired 1) and variously methylated derivatives 3−5 were obtained using published procedures 16,17 or from commercial sources. These were further elaborated to tetraketides 6, 7, 10, 12−15 as detailed in the Supporting Information.…”

Efficient prediction of reaction paths through molecular graph and reaction network analysis

“…It has been widely utilized in total synthesis and biosynthesis. 86 – 90 We applied our method to this reaction to test whether or not it is able to find the accepted reaction mechanism. The input parameters and prediction results are summarized in Table 1 .…”

Enantio- and Periselective Nitroalkene Diels-Alder Reactions Catalyzed by Helical-Chiral Hydrogen Bond Donor Catalysts

“…The synthesis of various diketones 13 from commercially available materials 11 and 12 is well documented by Burnell and co workers [39,40], and thus we began with the alkenation step. Considering the ease of operation and the preparation of ylide, we tested the Wittig reaction first [41]. Unfortunately, the methylenation of diketone 15 by this protocol resulted in no desired product (Table 3, entry 1), presumably because it is sterically congested.…”