RESUMO
A potent dictyostatin-discodermolide hybrid was designed and synthesised; it showed enhanced cell growth inhibitory activity relative to discodermolide in four human cancer cell lines including the Taxol-resistant NCI/ADR-Res cell line.
Assuntos
Alcanos/síntese química , Alcanos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Macrolídeos/síntese química , Macrolídeos/farmacologia , Pironas/síntese química , Pironas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Paclitaxel/farmacologiaAssuntos
Antimitóticos/química , Macrolídeos/química , Poríferos/química , Animais , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Macrolídeos/farmacologia , Mitose/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oceanos e MaresRESUMO
A combined biochemical, structural, and cell biology characterization of dictyostatin is described, which enables an improved understanding of the structural determinants responsible for the high-affinity binding of this anticancer agent to the taxane site in microtubules (MTs). The study reveals that this macrolide is highly optimized for MT binding and that only a few of the structural modifications featured in a library of synthetic analogues resulted in small gains in binding affinity. The high efficiency of the dictyostatin chemotype in overcoming various kinds of clinically relevant resistance mechanisms highlights its potential for therapeutic development for the treatment of drug-resistant tumors. A structural explanation is advanced to account for the synergy observed between dictyostatin and taxanes on the basis of their differential effects on the MT lattice. The X-ray crystal structure of a tubulin-dictyostatin complex and additional molecular modeling have allowed the rationalization of the structure-activity relationships for a set of synthetic dictyostatin analogues, including the highly active hybrid 12 with discodermolide. Altogether, the work reported here is anticipated to facilitate the improved design and synthesis of more efficacious dictyostatin analogues and hybrids with other MT-stabilizing agents.
RESUMO
The design, synthesis, and biological evaluation of a series of hybrids and analogues of the microtubule-stabilizing anticancer agents dictyostatin, discodermolide, and taxol is described. A 22-membered macrolide scaffold was prepared by adapting earlier synthetic routes directed towards dictyostatin and discodermolide, taking advantage of the distinctive structural and stereochemical similarities between these two polyketide-derived marine natural products. Initial endeavors towards accessing novel discodermolide/dictyostatin hybrids led to the adoption of a late-stage diversification strategy and the construction of a small library of methyl-ether derivatives, along with the first triple hybrids bearing the side-chain of taxol or taxotere attached through an ester linkage. Biological assays of the anti-proliferative activity of these compounds in a series of human cancer cell lines, including the taxol-resistant NCI/ADR-Res cell line, allowed the proposal of various structure-activity relationships. This led to the identification of a potent macrocyclic discodermolide/dictyostatin hybrid 12 and its C9 methoxy derivative 38, accessible by an efficient total synthesis and with a similar biological profile to dictyostatin.
Assuntos
Alcanos/química , Antimitóticos/química , Antineoplásicos/química , Carbamatos/química , Lactonas/química , Macrolídeos/química , Paclitaxel/análogos & derivados , Pironas/química , Alcanos/síntese química , Alcanos/farmacologia , Antimitóticos/síntese química , Antimitóticos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/síntese química , Lactonas/farmacologia , Macrolídeos/síntese química , Macrolídeos/farmacologia , Neoplasias/tratamento farmacológico , Paclitaxel/síntese química , Paclitaxel/farmacologia , Pironas/síntese química , Pironas/farmacologiaRESUMO
A hybrid library of the marine natural products dictyostatin and discodermolide, incorporating the taxol or taxotere side chains, were synthesised; preliminary biological evaluation in the PANC-1 cancer cell line revealed significant antiproliferative activity, demonstrating that a macrolide scaffold is an effective surrogate for the baccatin core of taxol.