Acetogenins from annonaceae, inhibitors of mitochondrial complex I

Zafra‐Polo, M. Carmen; González, M. C.; Estornell, Ernesto; Şahpaz, Sevser; Cortés, Diego

doi:10.1016/0031-9422(95)00836-5

Cited by 157 publications

(113 citation statements)

References 104 publications

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“…Moreover, Falsone et al (1982) have isolated a biologically active diterpene, which inhibits the NADH oxidase system of the mammalian mitochondrial respiratory chain. Research on inhibitors of the respiratory chain has revealed the existence of compounds with a high potential for basic biomedical research as possible antitumour agents (Degli Esposti et al 1994, Zafra-Polo et al 1996. Indeed, the bis-tetrahydrofuran acetogenin membrarollin isolated from R. membranacea, appears to be a very potent inhibitor of the NADH oxidase activity (Degli Esposti et al 1994, Zafra-Polo et al 1996.…”

Section: Resultsmentioning

confidence: 99%

“…Research on inhibitors of the respiratory chain has revealed the existence of compounds with a high potential for basic biomedical research as possible antitumour agents (Degli Esposti et al 1994, Zafra-Polo et al 1996. Indeed, the bis-tetrahydrofuran acetogenin membrarollin isolated from R. membranacea, appears to be a very potent inhibitor of the NADH oxidase activity (Degli Esposti et al 1994, Zafra-Polo et al 1996. For this reason, the cytotoxic activity of the species R. membranacea has served here as a positive control (Betancur-Galvis et al 1999) in experiments aimed at finding the antitumour potential of our extracts.…”

Section: Resultsmentioning

confidence: 99%

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Cytotoxic and Antiviral Activities of Colombian Medicinal Plant Extracts of the Euphorbia genus

Betancur‐Galvis

Morales²,

Forero

et al. 2002

Mem. Inst. Oswaldo Cruz

145

104

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Several species of the genus Euphorbia (Euphorbiaceae) have been tested for their efficiency as antiviral and antitumour agents, partly based on information concerning plants that have traditionally been used as medication to treat various human diseases (Bernal & Correa 1990, Unander et al. 1995. In fact, pronounced antiviral activity has been reported in several species of the genus Euphorbia, against polio, coxsackie, and rhinoviruses (Vlietinck et al. 1986, 1995, Ninomiya et al. 1990, Unander et al. 1995. Additionally, antitumour activity against sarcoma 180 ascites, leukemia in mice, and cytotoxic activity against certain cancer cell lines has also been observed (Itokawa et al. 1989, Wu et al. 1991, Fatope et al. 1996.There seems to be increasing possibility of finding biological activity among plants with recorded medicinal uses rather than from plants randomly selected (Unander et al. 1995, Cordell 1995. Furthermore, selection of plants gives better criteria for screening programs especially in its initial phases, compared to the screening of compounds isolated and/or purified from natural products (Kusumoto et al. 1995, Cordell 1995, Baker et al. 1995.Finally, the strategy for research and in vitro evaluation of biological activity of natural products, has changed in the past few years. One of the recent developments is the highly automated bioassay screening method based on colorimetric assays, that quantify the proliferation of cell cultures (Mosmann 1983, Denizot & Lang 1986). These techniques, considered rapid and inexpensive for the evaluation of antitumour (Carmichael et al. 1987, Rubinstein et al. 1990) and antiviral activity (Weislow et al. 1989) of a large number of natural products, have also permitted the isolation and purification of biologically active principles (Cordell 1995, Baker et al. 1995.The objective of our work was to evaluate, using colorimetric assays, the in vitro antiherpetic and cytotoxic activity of some Euphorbia species that are known in Colombia, to have traditional medical uses against skin infections such as ulcers, warts, cancers, tumors, and possibly diseases of viral origin (Garcia-Barriga 1974, Perez 1975, Vasquez 1982, Bernal & Correa 1990, Piñeros et al. 1992. MATERIALS AND METHODSPlant collection -The species were collected in different municipalities of the Department of Antioquia and deposited in the herbarium of the University of Antioquia, Medellín, Colombia. E. cotinifolia, was collected in Girardota, at a mean altitude of 350 m; a voucher specimen was deposited under the number HUA 115472. E. cestrifolia was collected in Guarne, at a mean altitude of 2,000 m; a voucher specimen was deposited under the number HUA 95065. E. tirucalli, E. arenaria, and E. pulcherrima were collected in Medellín, at a mean altitude of 450 m; voucher specimens were deposited under the numbers RC11383, HUA 55275, RC11384, respectively. The species E. heterophyla, E. cyatophora, E. graminea, E. cf. cotinifolia and Euphorbia sp. were collected in San Jerónimo, at a mean altitude of...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cytotoxic and Antiviral Activities of Colombian Medicinal Plant Extracts of the Euphorbia genus

Betancur‐Galvis

Morales²,

Forero

et al. 2002

Mem. Inst. Oswaldo Cruz

145

104

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“…The structural features of ∆lac-acetogenins are highly unique compared to those of ordinary complex I inhibitors and rather resemble amphiphilic phospholipid or detergent molecules. Interestingly, the ∆lac-acetogenin carrying two n-undecanyl groups (compound 1 in Figure 1) elicited very potent inhibition with bovine heart mitochondrial complex I despite the lack of an R, -unsaturated γ-lactone ring, which is one of the common structural features of a large number of natural acetogenins (1)(2)(3). Double-inhibitor titration of steady-state complex I activity showed that the inhibition of compound 1 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical (8).…”

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confidence: 99%

Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I

et al. 2004

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We have synthesized ∆lac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an R, -unsaturated γ-lactone ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of ∆lac-acetogenins in more detail, we carried out wide structural modifications of original ∆lac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF rings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original ∆lac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that ∆lac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.

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“…Although many research results mentioned the mechanisms of AGEs, for instance, the inhibitory action of mitochondria complex I (NADH : ubiquinone oxidoreductase) [145], induction of programmed cell death by the expression of the pro-apoptotic proteins Bax, Bad, caspase-3 [74] and the structure-activity relationships of either natural, semisynthesised or synthesised compounds, the diverse bioactivities of the various types of AGEs still seem difficult to explain. Some researchers notice the chemophysical features of various AGEs and more direct evidence was provided as a new structure-activity relationship for AGEs.…”

Section: Ages As Cation Ionophoresmentioning

confidence: 99%

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

Liaw¹,

Wu²,

Chang³

et al. 2010

Planta Med

112

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Studies on the Annonaceous acetogenins began after the first cytotoxic acetogenin, uvaricin, was isolated in 1982. This attractive finding made many medicinal and natural product chemists direct their efforts on the isolation and identification of these classes of compounds. As more Annonaceous acetogenins were isolated, more information about them was uncovered. From their structural identification to the total synthesis of natural product analogues and from cell-based screening and molecular-based targeting to animal testing, the mechanisms of action of the Annonaceous acetogenins became clearer. The purpose of this review is to give an account of recent studies on this class of compounds and their analogues, which will aid us not only in clarifying how the Annonaceous acetogenins act but also in establishing principles for the further development of this class of compounds

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Acetogenins from annonaceae, inhibitors of mitochondrial complex I

Cited by 157 publications

References 104 publications

Cytotoxic and Antiviral Activities of Colombian Medicinal Plant Extracts of the Euphorbia genus

Cytotoxic and Antiviral Activities of Colombian Medicinal Plant Extracts of the Euphorbia genus

Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I

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

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