Epoxy-Acetogenins and other Polyketide Epoxy Derivatives as Inhibitors of the Mitochondrial Respiratory Chain Complex I

Abstract

Annonaceous acetogenins (ACG), an extensive group of cytotoxic natural products, are antitumor agents whose main mode of action is inhibition of the mammalian mitochondrial complex I. Herein we describe the importance of the different chemical groups along the alkyl chain for optimal inhibitory potency, discussing the structurally relevant factors present in these compounds. For this purpose, a series of epoxide derivatives from α-linolenic acid were prepared and their activity compared with that of epoxy-acetogenins and tetrahydrofuranic (THF) acetogenins isolated from Rollinia membranacea.

Annonaceae - Rollinia membranacea - epoxy-acetogenins - tripoxyrollin - diepomuricanin A - membrarollin - α-linolenic acid derivatives - inhibitors of mitochondrial complex I

References

• 1 Cavé  A,, Figadère  B,, Laurens  A,, Cortes  D.. Acetogenins from Annonaceae.  Prog. Chem. Org. Nat. Prod.. 1997;;  70 81-288
• 2 Zafra-Polo  M C,, Figadère  B,, Gallardo  T,, Tormo  J R,, Cortes  D.. Natural acetogenins from Annonaceae, synthesis and mechanisms of action.  Phytochemistry. 1998;;  48 1087-117
• 3 Alali  F Q,, Liu  X X,, McLaughlin  J L.. Annonaceous acetogenins: Recent progress.  J. Nat. Prod.. 1999;;  62 504-40
• 4 Londershausen  M,, Leicht  W,, Lieb  F,, Moeschler  H,, Weiss  H.. Molecular mode of action of annonins.  Pestic. Sci.. 1991;;  33 427-38
• 5 Degli Esposti  M,, Ghelli  A,, Ratta  M,, Cortes  D,, Estornell  E.. Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (complex I).  Biochem. J.. 1994;;  301 161-7
• 6 Miyoshi  H,, Ohshima  M,, Shimada  H,, Akagi  T,, Iwamura  H,, McLaughlin  J L.. Essential structural factor of Annonaceous acetogenins as potent inhibitors of mitochondrial complex I.  Biochim. Biophys. Acta. 1998;;  1365 443-52
• 7 Gromek  D,, Figadère  B,, Hocquemiller  R,, Cavé  A,, Cortes  D.. Corepoxylone, a possible precursor of mono-tetrahydrofuran γ-lactone acetogenins: Biomimetic synthesis of corossolone.  Tetrahedron. 1993;;  49 5247-52
• 8 Sahpaz  S,, Figadère  B,, Sáez  J,, Hocquemiller  R,, Cavé  A,, Cortes  D.. Tripoxyrollin, a new epoxy acetogenin from the seeds of Rollinia membranacea. .  Nat. Prod. Lett.. 1993;;  2 301-8
• 9 Sahpaz  S,, Hocquemiller  R,, Cavé  A,, Sáez  J,, Cortes  D.. Diepoxyrollin and diepomuricanin B: Two new diepoxyacetogenins from Rollinia membranacea seeds.  J. Nat. Prod.. 1997;;  60 199-201
• 10 González  M C,, Lavaud  C,, Gallardo  T,, Zafra-Polo  M C,, Cortes  D.. New method for the determination of the absolute stereochemistry in antitumoral Annonaceous acetogenins.  Tetrahedron . 1998;;  54 6079-88
• 11 Fato  R,, Estornell  E,, Di Bernardo  S,, Pallotti  F,, Parenti-Castelli  G,, Lenaz  G.. Steady-state kinetics of the reduction of coenzyme Q analogs by complex I (NADH : ubiquinone oxidoreductase) in bovine heart mitochondria and submitochondrial particles.  Biochemistry. 1996;;  35 2705-16
• 12 Estornell  E,, Fato  R,, Pallotti  F,, Lenaz  G.. Assay conditions for the mitochondrial NADH : coenzyme Q oxidoreductase.  FEBS Lett.. 1993;;  332 127-31
• 13 Hoye  T R,, Suhadolnik  J C.. Stereocontrolled synthesis of 2,5-linked bistetrahydrofurans via the triepoxide cascade reaction.  Tetrahedron. 1986;;  42 2855-62
• 14 Lenaz  G.. Quinone specificity of complex I.  Biochim. Biophys. Acta. 1998;;  1364 207-21
• 15 Degli Esposti  M.. Inhibitors of NADH-ubiquinone reductase: An overview.  Biochim. Biophys. Acta. 1998;;  1364 222-35
• 16 Tormo  J R,, González  M C,, Cortes  D,, Estornell  E.. Kinetic characterization of mitochondrial complex I inhibitors using Annonaceous acetogenins.  Arch. Biochem. Biophys.. 1999;;  369 119-26
• 17 Shimada  H,, Grutzner  J B,, Kozlowski  J F,, McLaughlin  J L.. Membrane conformations and their relation to cytotoxicity of asimicin and its analogues.  Biochemistry. 1998;;  37 854-66