Synthesis of photolabile .DELTA.lac-acetogenin for photoaffinity labeling of mitochondrial complex I

Abstract

Dlac-Acetogenins are a novel type of inhibitor acting at the terminal electron transfer step of mitochondrial NADH-ubiquinone oxidoreductase (complex I). To identify the binding site of Dlacacetogenins by photoaffinity labeling, we synthesized a photolabile Dlac-acetogenin that possesses a biotin probe to enable the detection and the isolation of the labeled peptide without the use of a radioisotope. The photolabile Dlac-acetogenin synthesized in this study elicited potent inhibition of bovine heart mitochondrial complex I at the nanomolar level.

Medicinal Chemistry of Annonaceous Acetogenins: Design, Synthesis, and Biological Evaluation of Novel Analogues

“…Surprisingly, Miyoshi et al . discovered that the analogues that possessed two alkyl tails without a γ-lactone in bis-THF acetogenins showed potent inhibitory activity against mitochondrial complex I ( Scheme 22 ) [ 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. A representative synthetic pathway is given by the preparation of 320 .…”

Historic Perspectives on Annonaceous Acetogenins from the Chemical Bench to Preclinical Trials

“…They also synthesised a photolabile Δlac-AGE (24) connected to a biotin probe to trace the labelled peptide without the use of a radioisotope. This photolabile Δlac-AGE (24) elicited potent inhibition of bovine heart mitochondrial complex I at nanomolar levels [88]. Ichimaru et al further synthesised a series of Δlac-AGEs, in which the stereochemistry around the hydroxylated tetrahydrofuran (THF) ring moiety was systematically modified, and examined their inhibitory effects on complex I.…”

Stereoselective Formal Synthesis of Herbarumin III via Prins Cyclization

“…4a Protection of the secondary alcohol as the methoxymethyl ether 7 was performed with methoxymethyl chloride in dichloromethane in the presence of N,N-diisopropylethylamine. 6 Treatment of tosylate 7 with sodium iodide in refluxing acetone gave the corresponding iodo compound 8. Elimination of HI 7 from 8 using sodium hydride in N,N-dimethylformamide produced enolic exocyclic alkene 9, which on column chromatography revealed rearranged product 10.…”