RESUMO
The design, synthesis and evaluation of transition metal containing combinatorial libraries has received much attention in the past few years. As a result, a variety of synthetic techniques have been developed, and rapid assays for metal ion binding have yielded new ligand classes displaying high affinity and selectivity. Research in catalysis has centered around lead optimization using much smaller parallel libraries because of the lack of a truly efficient reaction screening method. Materials science applications have also focused on spatially addressed libraries and have employed a variety of techniques to identify compounds with desired physical properties. Nonetheless, high-throughput characterization and reaction product detection methods must still be developed in order to realize the full potential of combinatorial chemistry for the discovery of novel metal-containing compounds.
Assuntos
Catálise , Química Orgânica/métodos , Metais , Oligopeptídeos/química , Biblioteca de Peptídeos , Sítios de Ligação , Desenho de Fármacos , Ligantes , Oligopeptídeos/síntese químicaRESUMO
Small molecule natural products have aided in the discovery and characterization of many proteins critical to the progression and maintenance of the cell cycle. Identification of the direct target of a natural product gives scientists a tool to control a specific aspect of the cell cycle, thus facilitating the study of the cell-cycle machinery.
Assuntos
Produtos Biológicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Produtos Biológicos/química , Produtos Biológicos/fisiologia , Ciclo Celular/fisiologia , Dano ao DNA , Estrutura Molecular , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
The natural product FR901464 (1) was isolated by the Fujisawa Pharmaceutical Co. and shown to have intriguing biological properties including impressive antitumor activity. In this paper we describe the first total synthesis of 1 in full detail. A chiral building block synthetic strategy was used to assemble the target: optically active components were generated using asymmetric catalytic reactions, and these fragments were coupled together at a late stage in a convergent synthesis. In particular, a versatile, asymmetric hetero-Diels-Alder (HDA) reaction was developed in the context of this synthesis and used with great effectiveness for the preparation of the two densely functionalized pyran rings. The flexible nature of the synthetic route also allowed us to prepare a series of analogues of 1. These compounds were used to prove the relative stereochemistry of the natural product as well as to probe the importance of certain structural features of FR901464 with regard to biological activity.