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Biomedical subjects

A Cavé

Publications and source records attributed to A Cavé.

At least 19 recordsLinked to original sources
PubMed2001

Structure of rat parvalbumin with deleted AB domain: implications for the evolution of EF hand calcium-binding proteins and possible physiological relevance.

Among the EF-hand Ca(2+)-binding proteins, parvalbumin (PV) and calbindin D9k (CaB) have the function of Ca(2+) buffers. They evolved from an ancestor protein through two phylogenetic pathways, keeping one pair of EF-hands. They differ by the extra helix-loop-helix (AB domain) found in PV and by the linker between the binding sites. To investigate whether the deletion of AB in PV restores a CaB-like structure, we prepared and solved the structure of the truncated rat PV (PVratDelta37) by X-ray and NMR. PVratDelta37 keeps the PV fold, but is more compact, having a well-structured linker, which differs remarkably from CaB. PvratDelta37 has no stable apo-form, has lower affinity for Ca(2+) than full-length PV, and does not bind Mg(2+), in contrast to CaB. Structural differences of the hydrophobic core are partially responsible for lowering the calcium-binding affinity of the truncated protein. It can be concluded that the AB domain, like the linker of CaB, plays a role in structural stabilization. The AB domain of PV protects the hydrophobic core, and is required to maintain high affinity for divalent cation binding. Therefore, the AB domain possibly modulates PV buffer function.

Amino Acid Sequence↗
PubMed2001

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.

Animals↗
PubMed1999

Antiprotozoal activity of aporphine alkaloids isolated from Unonopsis buchtienii (Annonaceae).

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).

Alkaloids↗
PubMed1999

A new bistetrahydrofuran acetogenin from the roots of Annona salzmanii.

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.

4-Butyrolactone↗
PubMed1998

15N NMR relaxation studies of calcium-loaded parvalbumin show tight dynamics compared to those of other EF-hand proteins.

Dynamics of the rat alpha-parvalbumin calcium-loaded form have been determined by measurement of 15N nuclear relaxation using proton-detected heteronuclear NMR spectroscopy. The relaxation data were analyzed using spectral density functions and the Lipari-Szabo formalism. The major dynamic features for the rat alpha-parvalbumin calcium-loaded form are (1) the extreme rigidity of the helix-loop-helix EF-hand motifs and the linker segment connecting them, (2) the N and C termini of the protein being restricted in their mobility, (3) a conformational exchange occurring at the kink of helix D, and (4) the residue at relative position 2 in the Ca2+-binding sites having an enhanced mobility. Comparison of the Ca2+-binding EF-hand domains of alpha-parvalbumin-Ca2+, calbindin-Ca2+, and calmodulin-Ca2+ shows that parvalbumin is probably the most rigid of the EF-hand proteins. It also illustrates the dynamical properties which are conserved in the EF-hand domains from different members of this superfamily: (1) a tendency toward higher mobility of NH vectors at relative position 2 in the Ca2+-binding loop, (2) a restricted mobility for the other residues in the binding loop, and (3) an overall rigidity for the helices of EF-hand motifs. The differences in mobility between parvalbumin and the two EF-hand proteins occur mainly at the linker connecting the pair of EF hands and also at the C terminus of the last helix. In parvalbumin-Ca2+, these two regions are characterized by a pronounced rigidity compared to the corresponding more mobile regions in calbindin-Ca2+ and calmodulin-Ca2+.

Amides↗
PubMed1998

Three new bistetrahydrofuran acetogenins from the seeds of Annona spinescens.

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).

4-Butyrolactone↗
PubMed1997

Experimental treatment of cutaneous leishmaniasis with argentilactone isolated from Annona haematantha.

From the hexanic extract of roots of Annona haematantha an alpha,beta-unsaturated delta-lactone was isolated and identified as argentilactone. This compound exhibited in vitro activity against various strains of Leishmania ssp. at 10 micrograms/ml. BALB/c mice infected with Leishmania amazonensis were treated four weeks after infection with argentilactone by oral or subcutaneous routes for 14 days at 25 mg/kg daily. The reference drug, N-methylglucamine antimonate, was administered by subcutaneous injections at 100 mg/kg for 14 days. In these conditions, argentilactone showed the same efficacy as the reference drug, reducing by 96% the parasite loads in the lesion and by 50% the parasite burden in spleen.

Animals↗
PubMed1996

Assignment of 13C resonances and analysis of relaxation properties and internal dynamics of pike parvalbumin by 13C-NMR at natural abundance.

Pike parvalbumin is an 11.5-kDa globular protein which binds Ca2+ through EF-hand structural motifs. Nearly complete assignment of the protonated 13C resonances has been achieved by means of heteronuclear two-dimensional experiments. The study shows that 13Ca chemical shifts can be very sensitive to localised conformational aspects. To characterise internal dynamics of pike parvalbumin, longitudinal-relaxation and transverse-relaxation rates and 1H-13C NOEs were measured for alpha-carbons at natural abundance by means of two-dimensional NMR spectroscopy. Relaxation data were obtained at a spectrometer frequency of 600 MHz for 69 residues with an even spread along the parvalbumin polypeptide chain. A double approach that included Lipari-Szabo analysis and direct mapping of spectral densities was used to interpret relaxation data in terms of internal dynamics. The former analysis provides valuable information about the overall rotational correlation time and S2 order parameters, while the mapping approach characterises the relative contributions of different motional frequencies. The results suggest that Ca(2+)-loaded pike parvalbumin has a rigid structure, even in the functional regions, i.e., the Ca(2+)-binding loops. The patterns of density-function values are more sensitive to the secondary structure than those of S2. Moreover, depending on the sampling frequency, these patterns reveal different aspects of structure-specific motions.

Amino Acid Sequence↗
PubMed1996

Coriadienin, the first annonaceous acetogenin with two double bonds isolated from Annona coriaceae.

A new Annonaceous acetogenin, coriadienin (1), has been isolated from the roots of Annona coriacea Mart. (Annonaceae). This structure is the first reported acetogenin containing two double bonds. Compound 1 showed potent cytotoxicity against VERO and KB cell lines. Compound 1 appears to play an important role in the biosynthetic pathway of mono- and bis-THF acetogenins, and it is proposed as a biogenetic precursor of coriacin. A known cytotoxic acetogenin, gigantetronenin, was also isolated from this plant.

Animals↗
PubMed1996

New prenylated quinones from Peperomia galioides.

Two new prenylated quinones, piperogalone (1) and galopiperone (2), and a new prenylated dihydroquinone, hydropiperone (3), were isolated from Peperomia galioides H.B.K (Piperaceae). Hydropiperone exhibited potent antiparasitic activity against three species of Leishmania.

Animals↗
PubMed1996

Pessoine and spinosine, two catecholic berbines from Annona spinescens.

The trunk bark and roots of Annona spinescens have been investigated for their alkaloid content. Two new berbine alkaloids, pessoine (1) and spinosine (2), have been isolated from the bark, and their structures were elucidated by spectroscopic methods. Eight known isoquinoline alkaloids were also obtained. The trypanocidal and antileishmanial activities of these isolated compounds have been investigated.

Animals↗
PubMed1995

Piperogalin, a new prenylated diphenol from Peperomia galioides.

A petroleum ether extract of Peperomia galoides showed significant in vitro activity against three Leishmania species and Trypanosoma cruzi. Three major prenylated diphenols, including two known compounds, grifolic acid [1], and grifolin [2], and the new substance piperogalin [3], have been isolated. Structures were established on the basis of spectral analysis including 2D nmr spectroscopy.

Animals↗
PubMed1995

Relaxant activity of three aporphine alkaloids from Annona cherimolia on isolated aorta of rat.

In the present study we tested the relaxant effect of three aporphine alkaloids--roemerine, anonaine and dehydroroemerine--isolated from the roots of Annona cherimolia, on isolated strips of rat thoracic aorta. All compounds completely relaxed KCl- and noradrenaline-induced contractions with different potencies depending on their structural characteristics. The experiments, carried out in Ca(2+)-free medium using two different agonists (noradrenaline and caffeine) which mobilize calcium intracellularly by different mechanisms of action, showed that the alkaloids made no contribution to intracellular calcium processes. The present study provides evidence that the relaxant effects produced by aporphine alkaloids may be due to the blockade of calcium movements across the cell membrane, mainly through voltage-operated channels, and to the disruption of alpha 1-adrenoceptors connected to receptor-operated channels.

Alkaloids↗
PubMed1994

New aporphine alkaloids from guatteria foliosa.

Four new alkaloids were obtained from Guatteria foliosa, namely, the noraporphines (-)-3-methoxyputerine [1] and (+)-norguattevaline [2], the more highly oxidized (+)-3-methoxyguattescidine [3], and the oxoaporphine 3-methoxyoxoputerine [4]. Among several other known alkaloids also found in this same plant, (-)-3-hydroxynornuciferine, (-)-isoguattouregidine, and argentinine exhibited significant activity against Trypanosoma cruzi.

Animals↗
PubMed1994

Antileishmanial activity of a tetralone isolated from Ampelocera edentula, a Bolivian plant used as a treatment for cutaneous leishmaniasis.

The stem bark of Ampelocera edentula Kuhlm. (Ulmaceae) is used by the Chimanes Indians from Bolivia for the treatment of cutaneous leishmaniasis caused by the protozoan Leishmania braziliensis. A chloroform extract of the stem barks was found to be active against extracellular forms of Leishmania ssp. and Trypanosoma cruzi at 50 micrograms/ml. Bioassay-guided fractionation of this extract allowed us to isolate one active compound. Its structure was elucidated by spectral and chemical studies as 4-hydroxy-1-tetralone. BALB/c mice infected with L. amazonensis (PH8) or L. venezuelensis were treated one day after the parasitic infection with 4-hydroxy-1-tetralone (25 mg/kg/day) or with reference drug, Glucantime (56 mg Sbv/kg/day) for 14 days. Lesion development was the criteria used to evaluate the disease severity. 4-Hydroxy-1-tetralone was slightly less effective than the reference drug against L. amazonensis or L. venezuelensis. Single treatment near the site of infection, 14 days after infection with L. amazonensis, with 4-hydroxy-1-tetralone (50 mg/kg) was more effective than Glucantime (112 mg/kg). This study is, to our knowledge, the first to show the activity of a tetralone for the experimental treatment of New World cutaneous leishmaniasis.

Animals↗
PubMed1994

Cytotoxic and antiparasitic activity from Annona senegalensis seeds.

Several extracts of Annona senegalensis (Annonaceae) seeds were tested for antiparasitic activity against Leishmania major, Leishmania donovani, Trypanosoma brucei brucei, and for cytotoxic activity against KB and VERO cell lines. Fractionation of seeds extracts was mainly guided by means of a biocidal assay against Artemia salina nauplii. The biological activities resulted from extract-isolated acetogenins.

Animals↗