Rafael Peláez

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.

Diarylmethyloxime and hydrazone derivatives with 5-indolyl moieties as potent inhibitors of tubulin polymerization.

We describe the synthesis and biological evaluation of a series of diarylmethyloxime and diarylmethylhydrazone analogues that contain an indole ring and different modifications on the nitrogen of the bridge. Several compounds showed potent tubulin polymerization inhibitory action as well as cytotoxic activity against cancer cell lines. The N-methyl-5-indolyl substituted analogues are more potent than ethyl substituted ones. The most potent inhibitors of tubulin polymerization are the diarylketones and the diaryloximes. The cytotoxicity against several cancer cell lines is lower for the oximes than for the ketones. Other substitutions on the imine nitrogen greatly reduce the tubulin inhibitory and/or cytotoxic potencies.

Exploring the effect of 2,3,4-trimethoxy-phenyl moiety as a component of indolephenstatins

A new family of phenstatin analogues has been synthesized and assayed. This family simultaneously incorporates modifications of the A-ring (replacement of the 3,4,5-trimethoxyphenyl by the 2,3,4-trimethoxyphenyl arrangement), B-ring (N-alkyl-5-indolyl) and conversion of the Oxygen keto group into a substituted nitrogen (oximes, hydrazones, and their acetylderivatives). The conjunction of all this changes greatly diminishes the antimitotic and antiproliferative activities, but the maintenance of the keto bridge produces a potent analogue with the unusual 2,3,4-trimethoxyphenyl moiety.

Naphthylphenstatins as tubulin ligands : Synthesis and biological evaluation

A new family of naphthalenic analogues of phenstatins with modifications on the ketone-bridge has been synthesised. The synthesised compounds have been assayed for tubulin polymerisation inhibitory activity as well as for cytotoxic activity against cancer cell lines. The naphthalene has been confirmed as a good surrogate for the isovanillin moiety (3-hydroxy-4-methoxyphenyl) of phenstatin, when combined with the 3,4,5-trimethoxyphenyl ring, but not when combines with the 2,3,4-trimethoxyphenyl ring. Binding models for the synthesised compounds have been generated and analysed in terms of a pharmacophore proposed for colchicine site ligands. The ketone is the optimal bridge substitution but E-acetyloximes or acetylhydrazones are also tolerated. Significant differences with indole substituted phenstatins are observed and discussed.

Heterolignanolides. Furo- and thieno-analogues of podophyllotoxin and thuriferic acid

Abstract The conjugate addition–alkylation to 5H-furan-2-one followed by cyclization and controlled epimerizations have been applied to the synthesis of new furo- and thieno-lignan analogues. Podophyllotoxin and thuriferic acid heteroanalogues have been obtained by this methodology, as representative members of these families.

Total Synthesis of (+)-seco-C-Oleanane via Stepwise Controlled Radical Cascade Cyclization

An asymmetric concise total synthesis of the (+)-seco-C-oleanane 1 was accomplished. The successful route to this natural product involves as the key step a stepwise regio- and stereocontrolled catalytic radical polyene cascade cyclization from preoleanatetraene oxide (16), a process mediated by Cp(2)TiCl. The use of this single-electron-transfer complex permits mild cyclization conditions without using unnecessary prefunctionalizations and stops the process at the bicyclic level. Theoretical data revealed high activation energy for the third ring closure, which would account for the control of the cyclization. This process also led to natural (-)-achilleol B, camelliol A, and (+)-seco-β-amyrin as minor compounds.

Exploring the size adaptability of the B ring binding zone of the colchicine site of tubulin with para-nitrogen substituted isocombretastatins

We have synthesized and assayed dimethylaminophenyl, pyrrolidin-1-ylphenyl and carbazole containing phenstatins and isocombretastatins as analogues of the highly potent indoleisocombretastatins with extended or reduced ring sizes. This is an attempt to explore beyond the structural constraints of the X-ray crystal structures the zone of the colchicine site where the tropolone ring of colchicine binds to tubulin (zone 1). The isocombretastatins display up to 30 fold increased water solubility when compared with combretastatin A-4, potent inhibition of tubulin polymerization, and nanomolar cytotoxicities against several human cancer cell lines irrespective of the size of the B ring. On the other hand, substitutions ortho to the nitrogen cause an important reduction in potency. We have also shown that representative compounds inhibit autophagy. These results show that zone 1 can adapt to systems of different size as far as they stay in a common plane, but does not tolerate substituents protruding above or below it. These results can help in the understanding of the binding modes of structures with similar systems and in the design of new colchicine site ligands.

Application of Chemoinformatic Tools for the Analysis of Virtual Screening Studies of Tubulin Inhibitors

Virtual screening (VS) experiments were applied to rank more than 700000 candidate lead-like virtual molecules in order of likelihood of binding to the colchicine site of tubulin, which is an important antitumor target. The best ranked compounds were clustered and classified by means of “ad hoc” semiautomatic chemoinformatic tools. The results obtained in this way were compared with those achieved by visual inspection protocols and the best were selected for synthesis and screening stages.

New para–para Stilbenophanes: Synthesis by McMurry Coupling, Conformational Analysis and Inhibition of Tubulin Polymerisation

The synthesis of a new family of methoxy-substituted [2.7]- and [2.8]paracyclophanes linked by 3-oxapentamethylene-1,5-dioxy and hexamethylene-1,6-dioxy bridges has been carried out by using the McMurry methodology. Related indole compounds were also synthesised. Olefin-to-diol ratios depended on the bridge length, the structure of the aromatic ring and the reaction conditions. Macrocyclisation, the methoxy substituents and the presence of a rigid indole moiety restricted the conformational equilibria, as observed by NMR spectroscopy and according to theoretical calculations. The synthesised compounds display micromolar tubulin polymerisation inhibitory activity. The conformational implications on the tubulin polymerisation inhibitory activity derived from the macrocyclisation when compared with combretastatins, closely related stilbenes, are also discussed.

Synthesis of imidazo[4,5-d]oxazolo[3,4-a]pyridines. New heterocyclic analogues of lignans.

The preparation of new analogues of lignans carrying an imidazole ring has been achieved. Starting from L‐histidinol, cis and trans stereoisomers have been obtained. The synthesized products lack the cytotoxicity displayed by related podophyllotoxins and azatoxin.