Gamma-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.

Semisynthesis of antitumoral acetogenins: SAR of functionalized alkyl-chain bis-tetrahydrofuranic acetogenins, specific inhibitors of mitochondrial complex I.

The acetogenins of Annonaceae are known by their potent cytotoxic activity. In fact, they are promising candidates as a new future generation of antitumoral drugs to fight against the current chemiotherapic resistant tumors. The main target enzyme of these compounds is complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial respiratory chain, a key enzymatic complex of energy metabolism. In an attempt to characterize the relevant structural factor of the acetogenins that determines the inhibitory potency against this enzyme, we have prepared a series of bis-tetrahydrofuranic acetogenins with different functional groups along the alkyl chain. They comprise several oxo, hydroxylimino, mesylated, triazido, and acetylated derivatives from the head series compounds rolliniastatin-1, guanacone, and squamocin. Our results suggest a double binding point of acetogenins to the enzyme involving the alpha,alpha'-dihydroxylated tetrahydrofuranic system as well as the alkyl chain that links the terminal alpha, beta-unsaturated-gamma-methyl-gamma-lactone. The former mimics and competes with the ubiquinone substrate. The latter modulates the inhibitory potency following a complex outline in which multiple structural factors probably contribute to an appropriate conformation of the compound to penetrate inside complex I.

Epoxy-acetogenins and other polyketide epoxy derivatives as inhibitors of the mitochondrial respiratory chain complex I.

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 alpha-linolenic acid were prepared and their activity compared with that of epoxy-acetogenins and tetrahydrofuranic (THF) acetogenins isolated from Rollinia membranacea.

Polyalthidin: new prenylated benzopyran inhibitor of the mammalian mitochondrial respiratory chain.

Polyalthidin (3), a new benzopyran derivative, was isolated from the stem bark of Polyalthia cerasoides. Its structure was established on the basis of chemical and spectral evidence. Polyalthidin has showed potent biological activity as an inhibitor of the mammalian mitochondrial respiratory chain.

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).

Annosenegalin and annogalene: two cytotoxic mono-tetrahydrofuran acetogenins from Annona senegalensis and Annona cherimolia.

Two new cytotoxic mono-tetrahydrofuran acetongenins, annosenegalin and annogalene, have been isolated from the cytotoxic methanolic extract of Annona senegalensis and A. cherimolia seeds. Their structures were established on the basis of 1D and 2D NMR spectroscopic techniques. Annosenegalin belongs to the rare type of C37 mono-tetrahydrofuran acetogenins, and annogalene is an olefinic acetogenin.

Effects on rat uterine and aorta strip smooth muscle of Thymus leptophyllus extract.

The diethylether extract from Thymus leptophyllus was found to be more active on uterine smooth muscle than on aorta strips. Rat uterus experiments with and without extracellular calcium, yielded similar IC50 values. A nonspecific mechanism for the relaxant activity can therefore be postulated. In rat aorta and in the presence of extracellular calcium the extract inhibited the contractile response induced by K+ depolarizing solution and had a less inhibitory effect on noradrenaline (NA) contraction. In a Ca(2+)-free solution the extract strongly reduced the Ca(2+)-release induced by NA, but it did not affect the transient contraction caused by caffeine (CAF).

Influence of the absolute configuration on the vascular effects of tetrandrine and isotetrandrine in rat aorta.

The relaxant action of (1S, 1'S) tetrandrine and its isomer (1R, 1'S) isotetrandrine were examined in rat aortic strips, in presence or absence of extracellular calcium. Both alkaloids relax, concentration dependently, the contractile response elicited by depolarizing solution (KCl 80 mM) or noradrenaline (1 microM). Tetrandrine, however, showed a selectivity of action towards the KCl-induced contraction while isotetrandrine did not. In Ca(2+)-free solution, both alkaloids inhibited the contraction induced by noradrenaline, but they did not affect the transient contraction due to caffeine then this effect is not attributable to direct inhibition of the smooth muscle contractile elements. The refilling of intracellular calcium stores sensitive to noradrenaline or caffeine was significantly inhibited by both alkaloids.

Comparative study of the rat uterine smooth muscle relaxant activity of three bisbenzyltetrahydroisoquinolines with tetrandrine.

The relaxant activity of three bisbenzyltetrahydroisoquinolines--obaberine, popisonine and lindoldhamine--was examined in rat isolated uterus and their inhibitory potencies were compared with that of tetrandrine. All alkaloids tested relaxed KCl-depolarized rat uterus and totally or partially inhibited oxytocin-induced rhythmic contractions. The degree of methylation of the free phenolic hydroxy groups and the loss of one diarylether bridge influence the potency of relaxant action of these alkaloids. Only alkaloids with absolute configuration 1R,1'S or 1R1'R acted intracellularly, promoting relaxation of contractile responses induced by oxytocin or vanadate in a Ca(2+)-free medium.

Selective chiral inhibition of Ca2+ entry promoted by bisbenzyltetrahydroisoquinolines in rat uterus.

The effects of diltiazem and six bisbenzyltetrahydroisoquinoline alkaloids (antioquine, 7-O-methylantioquine, dimethylantioquine, monterine, granjine and cordobimine) were studied in rat isolated uterus in order to clarify the mechanisms of their relaxant actions. All the compounds tested completely relaxed KCl-induced contractions and totally or partially inhibited oxytocin-induced rhythmic contractions. Only alkaloids with absolute configurations (1R,1'S or 1R,1'R) acted intracellularly, promoting relaxation of contractile responses induced by oxytocin in a Ca(2+)-free medium, as does papaverine. Alkaloids of the antioquine series (1S,1'R) selectively inhibited Ca2+ entry. The great rigidity of these structures and their stereoselective action make these alkaloids useful in studies of the conformational features of the Ca2+ channel.

Antioquine: a new bisbenzylisoquinoleine alkaloid with calcium antagonist activity.

The objective of this work was to examine the smooth muscle relaxing properties of antioquine, compared to papaverine, in isolated rat uterus. The results obtained show that both antioquine and papaverine are capable of relaxing sustained contractions induced by Ca2+ in K-depolarizing solution as well as the spontaneous activity of rat uterus. Antioquine (0.1 mM, 0.5 mM and 1 mM) also induces a displacement to the right of the dose-response curves to Ca2+, and the antagonism was not competitive. Papaverine produced a decrease in the frequency and amplitude of contractile responses induced by oxytocin, and these inhibitory effects were observed regardless of whether papaverine was added before or after the induced contractions. On the other hand, antioquine only modified the frequency of contractile responses to oxytocin or desynchronized cumulative dose-response curves to oxytocin when the uterus was preincubated with this alkaloid before addition of the agonist. These experiments suggest that the relaxant effects produced by antioquine may be due to the blockade of calcium movements across the cell membrane, mainly through voltage-operated channels, whereas papaverine affects Ca2+-entry both through VOCs and through ROCs.