Manuel Medarde

A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues

Concepcion P. Melero*, Manuel Medarde and Arturo San FelicianoDepartamento de Quimica Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, 37007Salamanca, SpainTel.: +34 923 29 45 28, Fax: +34 923 29 45 15, E-mail: medarde@gugu.usal.es*Author to whom correspondence should be addressed.Received: 14 November 1999 / Accepted: 9 December 1999 / Published: 21 January 2000Abstract: A short review on cardiotonic steroids and their analogues is presented. The natu-ral, semisynthetic and synthetic derivatives, as well as their mechanism of action and struc-ture-activity relationships are shown, with a special reference to aminoguanidine deriva-tives.Keywords: Digitalis glycosides analogues, structure-activity relationships, inotropic activ-ity, Na+,K+-ATPase, aminoguanidine analogues.

Sesquiterpenoids and phenolics of pulicaria paludosa

Abstract Thirteen sesquiterpenoids of the skeletal types caryophyllane, cadinane, oplopane, eudesmane, allo-aromadendrane and 4-epi-guaiane, were isolated from Pulicaria paludosa. Their structures were established mainly by NMR techniques and chemical transformations. Four of them are new natural products. Three flavonoids and some simple phenolic derivatives were also isolated.

Synthesis and pharmacological activity of diarylindole derivatives. Cytotoxic agents based on combretastatins

Taking into account the structure of Combretastatins, we have synthesized and assayed for cytotoxic activity of new indole derivatives. Two aryl groups are maintained in the cis orientation required for activity by means of an indole moiety built up on less active ketoderivatives used as starting materials.

Terpenoids from leaves of Juniperus thurifera

Abstract Nineteen diterpenoids of the labdane, pimarane and abietane skeletons and four known sesquiterpenoids were isolated from Juniperus thurifera leaves. Thirteen of these diterpenoids are described for the first time as natural products. Their structures were elucidated principally by NMR techniques and chemical transformations.

Asteriscanolide: a sesquiterpene lactone with a new natural skeleton

Abstract A sesquiterpene lactone was isolated from the hexane extract of Asteriscus aquaticus . Its constitution and stereochemistry were determined by spectroscopic techniques, principally two-dimensional NMR correlations (COSY, HCCORR, RELAY) and with the interpretation of certain chemical transformations. The results were confirmed by X-ray diffraction and the name asteriscane is proposed for the new natural skeleton.

Review ArticleNaphthalene Combretastatin Analogues: Synthesis, Cytotoxicity and Antitubulin Activity

Synthesis and evaluation of new combretastatin analogues with varied modifications on the bridge and the aromatic rings, have shown that the 2-naphthyl moiety is a good surrogate for the 3-hydroxy-4-methoxyphenyl (B-ring) of combretastatin A-4. Other bicyclic systems, such as 6(7)-quinolyl and 5-indolyl, can replace the B-ring, but they produce less potent analogues in the cytotoxicity and tubulin polymerization inhibition assays. Other modifications are detrimentral for the potency of the studied analogues. The 2-naphthyl combretastatin 53 and the related 6-quinolyl combretastatin 106 analogues are the most potent among the derivatives of this type, whereas 92 and 95 are the most potent among the naphthalene derivatives with a heterocycle in the bridge. Previous and new results in this family of combretastatin analogues are discussed.

Isocombretastatins A: 1,1-diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds.

Isocombretastatins A are 1,1-diarylethene isomers of combretastatins A. We have synthesized the isomers of combretastatin A-4, deoxycombretastatin A-4, 3-amino-deoxycombretastatin A-4 (AVE-8063), naphthylcombretastatin and the N-methyl- and N-ethyl-5-indolyl analogues of combretastatin A-4. Analogues with a 2,3,4-trimethoxyphenyl ring instead of the 3,4,5-trimethoxyphenyl ring have also been prepared. The isocombretastatins A strongly inhibit tubulin polymerization and are potent cytotoxic compounds, some of them with IC(50)s in the nanomolar range. This new family of tubulin inhibitors shows higher or comparable potency when compared to phenstatin or combretastatin analogues. These results suggest that one carbon bridges with a geminal diaryl substitution can successfully replace the two carbon bridge of combretastatins and that the carbonyl group of phenstatins is not essential for high potency.

Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3‑Substituted Indolephenstatins and Indoleisocombretastatins

Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring.

Lignans from Juniperus thurifera

Abstract The isolation and identification of two new natural lignans, (-)epi-podorhizol and deoxypicropodophyllotoxin, and 12 known lignans from a hexane extract of Juniperus thurifera is described.

Novel chelates of Pd(II) dithiocarbamates. Spectroscopic studies and thermal behaviour

Abstract Complexes of Pd(II) with dithiocarbamate derived from α-amino acid (glycine, DL -alanine, DL -valine, L -valine and DL -leucine) have been synthesized. The complexes have been characterized by chemical analysis, infrared, electronic, 1 H and 13 C NMR and X-ray photoelectron spectroscopies, magnetic susceptibilities measurements, mass spectrometry and TG and DSC analysis. The stoichiometry of these complexes is Pd:L = 1:2 and coordination around the metallic cation seems to be distorted square planar, close to D 2 h . Coordination takes place through the sulphur atoms of the ligands and the carboxylic group is in a free, acidic form. Both sulphur atoms are chemically equivalent, according to the XPS results. 1 H and 13 C NMR spectra for the DL - and L -valine derivatives indicate that different complexes DD , DL and DL do not have any spectroscopic difference due to the large distance between the chiral centers. Thermal decomposition of the complexes takes place through a multi-step process, the first step being a decarboxylation, followed by a complex pyrolysis that leads to palladium oxide. The thermal stability of these complexes decreases in the order Pd(dtc- DL - val) 2 > Pd(dtc- DL -ala) 2 > Pd(dtc-gly) 2 > Pd(dtc- DL - leu) 2 . The mass spectrometric data indicate that the [S 2 CNHCH 2 COO] + ion is formed in all cases, with the final formation of [S 2 C] + for the ligands. For the complexes, however, the species [S-C-ala] + , [S-C-val] + and [S-C-leu] + are formed.