Ernesto Estornell

Acetogenins from Annonaceae: recent progress in isolation, synthesis and mechanisms of action

The aim of the present review is to summarise the knowledge about newly isolated acetogenins (ACGs) in the last six years. It will also report the total syntheses that have allowed either the confirmation or the revision of some structures, together with the biological activities and mechanism of action of such interesting natural products. In fact, of the 417 isolated compounds reviewed, over 176 have been added during the period from 1998 to 2004.

Acetogenins from annonaceae, inhibitors of mitochondrial complex I

One-hundred and twenty-eight different linear, epoxy, mono-tetrahydrofuran, bis-tetrahydrofuran or tri-tetrahydrofuran acetogenins have been isolated from the Annonaceae. These new secondary metabolites are potent cytotoxic inhibitors of the mitochondrial NADH:ubiquinone oxidoreductase (complex I of the respiratory chain).

SPECIFIC INTERACTIONS OF MONOTETRAHYDROFURANIC ANNONACEOUS ACETOGENINS AS INHIBITORS OF MITOCHONDRIAL COMPLEX I

Annonaceous acetogenins (ACG) are a wide group of cytotoxic compounds isolated from plants of the Annonaceae family. Some of them are promising candidates to be a future new generation of antitumor drugs due to the ability to inhibit the NADH:ubiquinone oxidoreductase of the respiratory chain (mitochondrial complex I), main gate of the energy production in the cell. ACG are currently being tested on standard antitumor trials although little is known about the structure activity relationship at the molecular level. On recent studies, the relevance of several parts of the molecule for the inhibitory potency has been evaluated. Due to the great diversity of skeletons included in this family of natural products, previous studies on the presence and distribution of oxygenated groups along the alkyl chain only covered the compounds with different bis-tetrahydrofuranic (bis-THF) relative configurations. Therefore, we have investigated the inhibitory action of all the mono-tetrahydrofuranic (mono-THF) acetogenins available, which differ in the oxygenated arrangements along the molecule. Our results show that the hydroxyl and carbonyl groups, placed in the aliphatic chain that links the initial gamma-lactone moiety with the dihydroxylated tetrahydrofuranic ring system, significantly contribute for modulating the inhibitory potency of the ACG through specific effects.

Rollimembrin, a novel acetogenin inhibitor of mammalian mitochondrial complex I

Abstract Rollimembrin (3), is a new adjacent bis-tetrahydrofuranic acetogenin with a scarce relative configuration, threo/cis/threo/cis/erythro, isolated from Rollinia membranacea seeds. The mechanism of cytotoxic activity, determined by NADH-oxidase experiments, establish that rollimembrin (3) is the most potent inhibitor of mammalian mitochondrial complex I.

Circumdatin H, a new inhibitor of mitochondrial NADH oxidase, from Aspergillus ochraceus

Circumdatin H (1), a new alkaloid from the culture broth of Aspergillus ochraceus, has been isolated, together with a known circumdatin, circumdatin E (2) and other known compounds: flavacol (3) and stephacidin A (4). The structure of 1 was established on the basis of chemical and spectral evidence. All of these alkaloids showed biological activity as inhibitors of the mammalian mitochondrial respiratory chain.

γ-Lactone-functionalized antitumoral acetogenins are the most potent inhibitors of mitochondrial complex I

To study the relevance of the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety of the antitumoral acetogenins of Annonaceae for potent mitochondrial complex I inhibition, we have prepared a series of semisynthetic acetogenins with modifications only in this part of the molecule, from the natural rolliniastatin-1 (1) and cherimolin-1 (2). Some of the hydroxylated derivatives (1b, 1d and 1e) in addition to two infrequent natural beta-hydroxy gamma-methyl gamma-lactone acetogenins, laherradurin (3) and itrabin (4), are more potent complex I inhibitors than any other known compounds.

In vitro antitumor SAR of threo/cis/threo/cis/erythro bis-THF acetogenins: correlations with their inhibition of mitochondrial Complex I.

Annonaceous acetogenins (ACG) are a large family of natural products that have been described as the most potent in vitro inhibitors of the mitochondrial respiratory chain Complex I. During the last two decades a large number of related structures have been discovered, increasing the number of members of this family. The large diversity of structural moieties and the general trends observed for inhibiting both growth of tumor cell lines and mitochondrial respiratory chain activity have resulted in the classification of these compounds into several structural groups according to their potency. Among them, the adjacent bis-tetrahydrofuranic acetogenins (bis-THF ACG) with a threo/cis/threo/cis/erythro relative configuration, have been described as the most potent subgroup, the prototypical member of which, rolliniastatin-1, was originally isolated from Rollinia membaranacea seeds. In this report we describe the different structure-activity relationships (SAR) observed for some natural ACG and semisynthetic derivatives as growth inhibitors of human tumor breast, lung, liver, and colon cell lines. All the compounds assayed showed potencies in the micromolar range. Trends observed in the cytotoxicity assay have been compared with previous data reported for these compounds as inhibitors of mitochondrial respiratory chain.

3-acetylaltholactone and related styryl-lactones, mitochondrial respiratory chain inhibitors.

A novel furano-pyrone, 3-acetylaltholactone, and two other known styryl-lactones, altholactone and 5-acetoxyisogoniothalamin oxide, have been isolated from Goniothalamus arvensis (Annonaceae) stem bark. We report here the isolation and structural elucidation of these compounds with furane-pyrone and styryl-pyrone skeletons, postulating also for the first time their mechanism of cytotoxicity based on inhibition on mammalian mitochondrial respiratory chain.

Effects of vitamin A deficiency on mitochondrial function in rat liver and heart.

The aim of this study was to investigate comparative effects of vitamin A deficiency on respiratory activity and structural integrity in liver and heart mitochondria. Male rats were fed a liquid control diet (control rats) or a liquid vitamin A-deficient diet (vitamin A-deficient rats) for 50 days. One group of vitamin-A deficient rats was refed a control diet for 15 days (vitamin A-recovered rats). To assess the respiratory function of mitochondria the contents of coenzyme Q (ubiquinone, CoQ), cytochrome c and the activities of the whole electron transport chain and of each of its respiratory complexes were evaluated. Chronic vitamin A deficiency promoted a significant increase in the endogenous coenzyme Q content in liver and heart mitochondria when compared with control values. Vitamin A deficiency induced a decrease in the activity of complex I (NADH-CoQ reductase) and complex II (succinate-CoQ reductase) and in the levels of complex I and cytochrome c in heart mitochondria. However, NADH and succinate oxidation rates were maintained at the control levels due to an increase in the CoQ content in accordance with the kinetic behaviour of CoQ as an homogeneous pool. On the contrary, the high CoQ content did not affect the electron-transfer rate in liver mitochondria, whose integrity was preserved from the deleterious effects of the vitamin A deficiency. Ultrastructural assessment of liver and heart showed that vitamin A deficiency did not induce appreciable alterations in the morphology of their mitochondria. After refeeding the control diet, serum retinol, liver and heart CoQ content and the activity of complex I and complex II in heart mitochondria returned to normality. However, the activities of both whole electron transfer chain and complex I in liver were increased over the control values. The interrelationships between physiological antioxidants in biological membranes and the beneficial effects of their administration in mitochondrial diseases are discussed.

Semisynthesis of new tetrahydrofuranic alkyl ester and furano-pyrone derivatives as inhibitors of the mitochondrial complex I

Abstract Methoxymethylation of altholactone ( 1 ) led to the corresponding O -methoxymethyl derivative ( 3 ) in addition to the unexpected 6,7-dihydro-7-methoxy analogue ( 4 ), and two original tetrahydrofuranic (THF) alkyl esters ( 5 , 6 ). Moreover, when we accomplished a new method for the preparation of the furano-pyrone goniofupyrone ( 7 ) through 7-hydroxylation of 1 in acid medium, a minor compound ( 8 ) with an identical skeleton to that of compounds 5 and 6 was identified. Careful examination of the published spectral data of the reported styryl-lactones with an heptolide skeleton reveals that those structures possess also a THF alkyl ester skeleton. The revision of those structures was confirmed by chemical correlation. All altholactone derivatives assayed proved to be specific inhibitors of the mitochondrial complex I.