RESUMEN
The preparation of two new fluorescent derivatives of paclitaxel in which the fluorophore is bonded to paclitaxel at the C-10 position is reported. Both analogues, 10-deacetyl-10-(m-aminobenzoyl)paclitaxel (1, BTax) and 10-deacetyl-10-[7-(diethylamino) coumarin-3-carbonyl]paclitaxel (2, CTax) retain good activity as promoters of in vitro tubulin assembly. Microtubule binding enhances the emission intensity of both probes.
Asunto(s)
Colorantes Fluorescentes/química , Microtúbulos/metabolismo , Paclitaxel/química , Taxoides , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/metabolismo , Paclitaxel/análogos & derivados , Paclitaxel/metabolismo , Espectrometría de Fluorescencia , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
The synthesis of 16a'-homo-leurosidine was achieved through enantioselective generation of a ring D'-seco-precursor 33 (without requirement of a chiral auxiliary). Its cyclization provided the N(b')-quaternary salt 35 with a configuration corresponding to the atropisomeric form 8a rather than 8b of the target product. On debenzylation, the amine 8a was obtained and found not to isomerize thermally to the anticipated atropisomer 8b (in contrast to its lower homologue, with its formation of natural leurosidine). However, on protonation, a 1:1 mixture of atropisomers of 16a'-homo-leurosidine was obtained. A synthesis of 16a'-homo-vinblastine provided two atropisomers 5a and 5b for the free base at equilibrium (1:2.3 at room temperature in CDCl(3)), with a shift to the major conformer 5b with increasing solvent acidity or decreasing temperature. The synthesis was achieved through a stereoselective inversion of the tertiary hydroxyl function in the enantioselectively generated C-20' progenitor 39.
Asunto(s)
Alcaloides/síntesis química , Antineoplásicos Fitogénicos/síntesis química , Vinblastina/síntesis química , Alcaloides de la Vinca , Alcaloides/química , Alcaloides/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ratones , Conformación Molecular , Células Tumorales Cultivadas , Vinblastina/análogos & derivados , Vinblastina/química , Vinblastina/farmacologíaRESUMEN
[reaction: see text] This work describes the synthesis of two novel macrocyclic taxoid constructs by ring-closing olefin metathesis (RCM) and their biological evaluation. Computational studies examine conformational profiles of 1 and 2 for their fit to the beta-tubulin binding site determined by electron crystallography. The results support the hypothesis that paclitaxel binds to microtubules in a "T" conformation.
