Jesús T. Vázquez

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.

Conformational study of the hydroxymethyl group in α-D-mannose derivatives

Abstract A study of the dependence of the hydroxymethyl group in α- d -mannose derivatives on the aglycon and its absolute configuration was performed by means of circular dichroism (CD) and NMR data. Depending mainly on the aglycon present, the gg or the gt rotamer was the most populated, the tg rotamer having a small population. In addition, the study showed a correlation between the rotational populations and the aglycon, the population of the gt rotamer increasing as the p K a of the bonded alcohol (aglycon) increased. Furthermore, the results revealed a strong dependence on the absolute configuration of the aglycon and point to the stereoelectronic exo -anomeric effect being responsible for these rotational dependencies besides nonbonding interactions.

Ferric chloride: An excellent reagent for the removal of benzyl ethers in the presence of p-bromobenzoate esters

Abstract Anhydrous FeCl 3 in dry CH 2 Cl 2 removed benzyl ethers from carbohydrates containing p -bromobenzoate esters, without hydrogenolysis of the bromine atoms. In addition, debenzylations of β-glycopyranosides occurred with simultaneous anomerization or retention of the anomeric configuration.

Withanolides from Withania aristata and their cytotoxic activity

Seven new withanolides (1-7), along with three known ones (8-10), were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 2D NMR experiments and spectrometric techniques, and the absolute configuration of 1 and 2 was established by CD analysis. In the search for new cytotoxic compounds from Withania species, the isolated compounds 1-9, along with two derivatives, were assayed for their cytotoxicity against HeLa, MCF-7 and A-549 human tumor cell lines. Derivative (4S,20R,22R)-27-acetoxy-4-p-bromobenzoyloxy-1-oxo-witha-2,5,16,24-tetraenolide (13) showed cytotoxicity against all the cell lines assayed with IC(50) values ranging from 2.8 to 3.6microM, and (4S,20R,22R)-4,27-diacetoxy-4-hydroxy-1-oxo-witha-2,5,16,24-tetraenolide (12) exhibited an IC(50) value of 5.4microM on the MCF-7 cell line.

Diterpenes from Laennecia sophiifolia

From the aerial parts of Laennecia sophiifolia (Kunth) G.L. Nesom, a neo-clerodane and an acyclic furano diterpene were isolated, along with four known compounds, 2beta-hydroxyhardwickiic acid, hawtriwaic acid, apigenin, and beta-sitosterol. Their structures were established as 12-epi-bacchotricuneatin A and (2E,6E)-9-(3-furyl)-6-methyl-2-(4-methylpent-3-enyl)-nona-2,6-dienoic acid, by analysis of spectral evidence. The absolute structure of 12-epi-bacchotricuneatin A was determined by a circular dichroism spectral comparison with that of bacchotricuneatin A.

ROTATIONAL POPULATION DEPENDENCES OF THE HYDROXYMETHYL GROUP IN ALKYL GLUCOPYRANOSIDES : ANOMERS COMPARISON

A CD and 1H NMR study of the rotamer population around the C5–C6 bond of alkyl α-d-glucopyranosides proved it to be dependent on the aglycon and its absolute configuration, showing a similar, but not identical, behavior to that of their β-anomers. Thus, the population of the gt rotamer increased as the pKa of the aglycon increased, whereas the population of the tg and gg rotamers decreased, mainly that of the tg rotamer. The results showed the existence of a clear correlation between the stereoelectronic exo-anomeric effect and the rotamer distributions, the endo-anomeric effect not being directly involved. In addition, the 1H NMR chemical shift differences (δD–δROH) of the alkyl α-d-glucopyranosides are characteristic of the absolute configuration of the aglycon, as occurred with the β-anomers. Therefore, the absolute configuration of secondary chiral alcohols or the aglyconic moiety of natural glycosides can be determined independently of the anomeric configuration, a single enantiomer being sufficient. Chirality 9:626–637, 1997.

Addition of chiral enolates to N-alkyl-3-acylpyridinium salts. Total synthesis of (+)-16-epivinoxine and (−)-vinoxine

Abstract Chiral enolates of indolylacetyl derivatives 6a–f undergo addition to pyridinium salt 7 with complete trans-selectivity and varied diastereofacial selectivities to give, after acid-induced cyclization of the intermediate 1,4-dihydropyridines, the vinoxine-related tetracycles 8a–f. Starting from (S)-prolinol indolylacetamide 6e, subsequent elaboration of the ethylidene substituent from tetracycle 8e and removal of the chiral auxiliary has resulted in a straightforward synthesis of (+)-16-epivinoxine and (−)-vinoxine.

Circular dichroic studies of 2-amino-2-deoxy-galactopyranosides - conformations of the 2-(N-acetyl-p-bromobenzamido) group

Abstract The CD spectra of methyl 2-amino-2-deoxy-D-galactopyranoside mono- N -acylates (acetyl or p -bromobenzoyl) resemble those of the corresponding O -acylates and can be accounted for by the additivity rule. However, the CD of pyranosides containing the N -acetyl- p -bromobenzamido imide group (NAcBz) are far more complex than those of mono- N -acylates and their O -counterparts, and furthermore, the solvent- and temperature-dependent changes differ for the α- and β-anomers. These differences can be accounted for by the different conformations of the 2-NAcBz group.

Stereochemical studies of cyclonoyl systems

Abstract The kinetically controlled electrophilic additions to (Z,Z)-1-hydroxy-cyclonona-2,6-diene and to (Z)-threo-1-hydroxy-2,3-epoxy-6-cyclononene are studied. The stereoselectivity of these reactios can be explained by the conformational preferences of the cyclononyl systems, which are revealed by the CD exciton chirality methodology and molecular mechanics calculations. An absolute configurational study is also included.

Sesquiterpene esters fromMaytenus disticha

Abstract Four new sesquiterpenes, 9β-benzoyloxy-1α,6β-diacetoxy-15-hydroxy-dihydro-β-agarofuran, 9β-benzoyloxy-1α,6β, 15-triacetoxy-8α-hydroxydihydro-β-agarofuran, 9β-benzoyloxy-1α,6β,8α,15-tetracetoxydihydro-β-agarofuran and 1α, 9β-dibenzoyloxy-6β,8β-diacetoxy-4β-hydroxydihydro-β-agarofuran were isolated from Maytenus disticha . Their structures were determined by spectroscopic studies, chemical correlations and selective hydrolysis. The absolute configuration of the last compound mentioned above was determined by CD.