TAILIEUCHUNG - Báo cáo khoa học: Specific targeting of a DNA-alkylating reagent to mitochondria Synthesis and characterization of [4-((11aS)-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-on-8-oxy)butyl]-triphenylphosphonium iodide

The selective manipulation of the expression and replica-tion of mitochondrial DNA (mtDNA) within mammalian cells has proven difficult. In progressing towards this goal we synthesized a novel mitochondria-targeted DNA-alkylating reagent. The active alkylating moiety [(11aS)-8-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c] [1,4]benzodiazepin-5-one (DC-81)], irreversibly alkylates guanine bases in DNA (with a preference for AGA tri-plets), preventing its expression and replication. | Eur. J. Biochem. 270 2827-2836 2003 FEBS 2003 doi Specific targeting of a DNA-alkylating reagent to mitochondria Synthesis and characterization of 4- 11aS -7-methoxy-1 2 3 11a-tetrahydro-5Mpyrrolo 2 1-c 1 4 benzodiazepin-5-on-8-oxy butyl -triphenylphosphonium iodide Andrew M. James1 Frances H. Blaikie2 Robin A. J. Smith2 Robert N. Lightowlers3 Paul M. Smith3 and Michael P. Murphy1 1MRC-Dunn Human Nutrition Unit Wellcome Trust-MRC Building Cambridge UK 2Department of Chemistry University of Otago Dunedin New Zealand 3Department of Neurology Medical School University of Newcastle upon Tyne UK The selective manipulation of the expression and replication of mitochondrial DNA mtDNA within mammalian cells has proven difficult. In progressing towards this goal we synthesized a novel mitochondria-targeted DNA-alkylating reagent. The active alkylating moiety 11aS -8-hydroxy-7-methoxy-1 2 3 11a-tetrahydro-5H-pyrrolo 2 1-c 1 4 benzodiazepin-5-one DC-81 irreversibly alkylates guanine bases in DNA with a preference for AGA triplets preventing its expression and replication. To target this compound to mitochondria it was covalently coupled to the lipophilic triphenylphosphonium TPP cation to form a derivative referred to as mitoDC-81. Incorporation of this lipophilic cation led to the rapid uptake of mitoDC-81 by mitochondria driven by the large membrane potential across the inner membrane. This com pound efficiently alkylated isolated supercoiled relaxed-circular or linear plasmid DNA and isolated mtDNA. However mitoDC-81 did not alkylate mtDNA within isolated mitochondria or cells even though it accessed the mitochondrial matrix at concentrations up to 100-fold higher than those required to alkylate isolated DNA. This surprising finding suggests that mtDNA within intact mitochondria may not be accessible to this class of alkylating reagent. This inability to alkylate mtDNA in situ has significant implications for the design of therapies for .

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