p,p-Dihydroxydihydrostilbenophanes related to antimitotic combretastatins. Conformational analysis and its relationship to tubulin inhibition.

The structures of a new family of macrocyclic analogues of combretastatins B combining oxygenated substituents on the phenyl rings and indole rings are described. The effects of the stereochemistry, of the length of the spacer linking both aryl groups, and of the decoration of the macrocycles on the kinematics of the system have been studied by means of NMR studies at several temperatures and in different solvents combined with theoretical studies including Monte Carlo conformational searches and molecular dynamics simulations at different temperatures. The new indole macrocycles provide a more rigid view of this kind of macrocycles than that previously held. The tubulin polymerization activity of this new class of macrocycles has been assayed and analyzed.

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 and conformational analysis of macrocyclic dihydroxystilbenes linked between the para-para positions.

A new family of diphenylethanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. The two phenyl rings are linked between the para-phenolic positions through a 3-oxapentamethylene or hexamethylene chain. The key macrocyclization step was achieved in moderate yields by using an intramolecular McMurry pinacol coupling of linked aromatic dialdehydes, except for the nitro-substituted compounds. The relative stereochemistry of the isomeric pinacols was determined by a combination of spectroscopic, chemical derivatization, and molecular-modeling approaches. The NMR spectra of these compounds (with a polyoxygenated crownophane skeleton) indicate severe conformational restrictions relative to their parent combretastatins; the rotation of the phenyl rings is hampered by interactions of their substituents and the linker and the conformational restrictions imposed by the substituted bridge.

Water-soluble titanocene complexes with sulfur-containing amino acids: synthesis, spectroscopic, electrochemical and Ti(IV)-transferrin interaction studies.

Three new water soluble titanocene-amino acid complexes have been synthesized via the reaction of Cp(2)TiCl(2) and two equivalents of amino acid (L) in methanol, affording [Cp(2)TiL(2)]Cl(2), L = L-cysteine (2), D-penicillamine (3) and L-methionine (4). These complexes have been characterized by (1)H, IR and UV-Vis spectroscopies, elemental analysis and cyclic voltammetry. Kinetic studies of ligand hydrolysis have been monitored at low pH using UV-Vis and (1)H NMR spectroscopies to assess their stability in aqueous solution. At low pH, amino acid ligands are lost one order of magnitude faster than cyclopentadienyl. However, at physiological pH, in Tris buffer solution, the complexes decompose rapidly to form an insoluble titanium compound. The affinity of these complexes to apo-transferrin was also investigated to elucidate how the ancillary amino acid ligands affect the titanium intake by apo-transferrin.