Four bisbenzyltetrahydroisoquinoline alkaloids (-)-medelline, (+)-antioquine, (+)-aromoline, and (+)-obamegine were isolated from the fruits of Xylopia columbiana. These compounds, the previously isolated alkaloids (+)-thaligrisine and (+)-isotetrandrine, as well as their O-acetylated derivatives were assayed on submitochondrial particles from beef heart as inhibitors of the mammalian respiratory chain. The results revealed that these alkaloids act as selective inhibitors of mitochondrial complex I in a 0.15 - 4.71 microM range. O-Acetylation, which increases their lipophilicity, considerably increased the inhibitory potency.

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.

To study the relevance of the terminal α,β-unsaturated γ-methyl-γ-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 β-hydroxy γ-methyl γ-lactone acetogenins, laherradurin (3) and itrabin (4), are more potent complex I inhibitors than any other known compounds.

A new monotetrahydrofuran acetogenin, araticin (I), was isolated from the MeOH extract of Annona spinescens, in addition to the known compound almunequin (2). The structure of 1 was elucidated by spectroscopic methods including LSI-MS/MS technique, and confirmed by a chemical transformation. The cytotoxic activity of the new compound 1 is reported and discussed.

A new bistetrahydrofuran acetogenin, salzmanin (1), was isolated from the MeOH extract of Annona salzmanii, in addition to the known compounds, squamocin, almunequin, bullatalicin, and annonacin. The structure of 1 was elucidated by spectroscopic methods, including LSIMS-MS technique, and confirmed by a chemical transformation. The cytotoxic activity of 1 and squamocin was investigated.

On a preliminary screening, substantial leishmanicidal activity was observed for the petroleum ether and alkaloidal extracts of the stem bark of Unonopsis buchtienii, the alkaloids and sterols isolated from these were studied. Of the alkaloids, liriodenine exhibited the highest activity against Leishmania major and L donovani (IC100 = 3.12 micrograms/mL). On the other hand, O-methylmoschatoline and the petroleum ether extract without alkaloids showed an interesting in vitro activity against Trypanosoma brucei with an IC100 of 6.25 micrograms/mL. The highest cytotoxic activities were found with the petroleum ether extracts without alkaloids and with all alkaloids isolated (IC50 < 9 micrograms/mL for Vero cell line).

(+)-Amino-muricatacin, a non natural aza-analogue of the bioactive annonaceous acetogenin muricatacin was prepared with >99 % d.e. and 68 % e.e., by addition of N-Boc-tertbutyldimethylsilyloxypyrrole (TBSOP) on achiral tridecanal in the presence of (R)-1,1′-Bi-2-naphtol (Binol), followed by hydrogenation and N-Boc removal protecting group.

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The seeds of Annona glauca have yielded four Annonaceous acetogenins. Two of them, glaucabellin and glaucaflorin, whose chemical structure was deduced by spectral and chemical methods, are new.

Chatenaytrienins-1,-2 and -3, muridienins-3 and -4 and muricadienin were characterized by tandem mass spectrometry (MS/MS) in a mixture of natural precursors of annonaceous acetogenins from Annona muricata. Chatenaytrienin-1, -2, -3 and -4 were then isolated from A. nutans and fully characterized by spectroscopic methods (NMR, MS) and by chemical and enzymatic oxidative processes. Isolation of these trienes confirmed the postulated biosynthetic pathway leading to the acetogenins.

Three new bistetrahydrofuran acetogenins, carolins A-C (1-3), were isolated from the MeOH extract of Annona spinescens in addition to the known compound, squamocin (4). The structures of 1, 2, and 3 were elucidated by spectroscopic methods including LSIMS/MS technique and confirmed by a chemical transformation, The cytotoxic activity of the new compounds 1-3 is reported and discussed in comparison with 4 and the previously isolated spinencin (5).

Phytochemical investigation of roots of Annona muricata led to the identification of seven mono-tetrahydrofuran (mono-THF) acetogenins. Six new acetogenins having the unusual cis-configuration of the THF ring, cis-solamin (1), cis-panatellin (2), cis-uvariamicin IV (3), cis-uvariamicin I (4), cis-reticulatacin (5), and cis-reticulatacin-10-one (6) were identified, in addition to a known compound, solamin.

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Structural elucidation of absolute configurations of the stereogenic centers of acetogenins of Annonaceae was performed using the modified Mosher's method. Thus, by replacing MTPA (methoxytrifluoromethylphenylacetic acid) by 2-NMA (naphthylmethoxyacetic acid), we were able to determine the absolute configuration of the stereogenic centers of rolliniastatin-2 by simple analysis of the 1H NMR spectra recorded at 400 MHz. Indeed, by comparing the differences of chemical shifts between the MTPA esters with those obtained with 2-NMA esters, we showed that we could take advantage of the long-range anisotropic effect of the naphthyl ring for the elucidation of the unsymmetrical systems.

The dichloromethane extract of seeds of Annona glauca (Annonaceae) was active against three strains of Leishmania species. Nine known acetogenins were isolated and identified and then evaluated in vitro against Leishmania species and the bloodstream forms of Trypanosoma cruzi. Annonacin A and goniotha-lamicin showed activity against Leishmania, and glaucanisin, squamocin, annonacin A and annonacin against Trypanosoma cruzi reducing the parasites by 78%, 67%, 71% and 85%, respectively, (C) 1998 John Wiley & Sons, Ltd.

TMSOF 2-[(trimethylsilyl)oxy]furan has been used in an enantioselective aldol reaction far the first time. Indeed, addition of TMSOF to achiral aldehydes, in the presence (R)-1,1'-bi-2-naphthol (Binol), gave the corresponding butenolides with moderate diastereomeric ratios (dr = 60%) and ee's between 60 and 90%. Application of this reaction to the total synthesis of annonaceous muricatacin in only two steps (in regards to the numerous multistep syntheses published so far) illustrated the efficiency of this strategy.