RESUMO
E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologiaRESUMO
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Éteres Cíclicos/síntese química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Macrolídeos/síntese química , Moduladores de Tubulina/síntese química , Actinas/genética , Actinas/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cetuximab/farmacologia , Descoberta de Drogas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Éteres Cíclicos/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Análise de Sobrevida , Moduladores de Tubulina/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The first successful effort to replicate the beginning of the Taxol oxidase phase in the laboratory is reported, culminating in the total synthesis of taxuyunnanine D, itself a natural product. Through a combination of computational modeling, reagent screening, and oxidation sequence analysis, the first three of eight C-H oxidations (at the allylic sites corresponding to C-5, C-10, and C-13) required to reach Taxol from taxadiene were accomplished. This work lays a foundation for an eventual total synthesis of Taxol capable of delivering not only the natural product but also analogs inaccessible via bioengineering.
