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
The identification of biologically active target compounds and their binding proteins is important in mechanism-of-action studies for drug development. Additionally, the newly discovered binding proteins provide unforeseen ideas for novel drug discovery and for subsequent structural transformation to improve target specificity. Based on the lead and final candidate compounds related to the type 5 phosphodiesterase (PDE5) inhibitor E4021, we designed chemical probes and identified their target proteins by the affinity chromatography approach. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3), currently reported as a cancer stem cell target, was clearly isolated as a binding protein of the lead 'immature' inhibitor probe against PDE5. In the early derivatization to the closely related structure, Compound 5 (ER-001135935) was found to significantly inhibit ALDH1A3 activity. The discovery process of a novel ALDH1A3-selective inhibitor with affinity-based binder identification is described, and the impact of this identification method on novel drug discovery is discussed.
Assuntos
Aldeído Oxirredutases , Inibidores de Fosfodiesterase , Aldeído Oxirredutases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Descoberta de DrogasRESUMO
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
Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23-O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14-C35 and halichondrin C14-C38 building blocks have been synthesized from the corresponding C27-C35 and C27-C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling.
Assuntos
Éteres Cíclicos/síntese química , Catálise , Ciclização , Éteres Cíclicos/química , Espectroscopia de Ressonância Magnética , EstereoisomerismoRESUMO
An operationally simple and efficient workup method for tetrabutylammonium fluoride (TBAF)-mediated t-butyldimethylsilyl (TBS) deprotection has been developed. The procedure includes addition of a sulfonic acid resin and calcium carbonate, followed by filtration and evaporation. This method eliminates the tedious aqueous-phase extraction process to remove excess TBAF and materials derived from TBAF, thereby making the protocol highly amenable to multiple TBS deprotections. Its efficiency and usefulness were demonstrated by using the transformation of 1a to 3a in the halichondrin synthesis. [reaction: see text].
Assuntos
Éteres Cíclicos/síntese química , Compostos de Amônio Quaternário/química , Carbonato de Cálcio , Filtração , Indicadores e Reagentes , Resinas de Troca Iônica , Macrolídeos , Espectroscopia de Ressonância Magnética , Ácidos Sulfônicos/químicaRESUMO
A highly effective procedure is reported to synthesize 1,2-aminoalcohols by regio- and chemo-selective ammonolysis of monosubstituted epoxides. Additive- and concentration-effects were studied, revealing that: (1) methanesulfonic acid is most effective among the additives tested and (2) formation of bis-adducts is practically eliminated at [C] = 40 mM. The optimum condition thus identified was successfully applied to the final step of the synthesis of potent anti-tumor compound E7389.
RESUMO
Total synthesis of (-)-strychnine is described. Notable features of our synthesis include (1) palladium-catalyzed coupling of the indole and vinyl epoxide moieties, (2) synthesis of the nine-membered cyclic amine derivative from the diol precursor in a one-pot procedure, and (3) transannular cyclization of the nine-membered cyclic amine.
Assuntos
Estricnina/síntese química , Venenos/síntese química , Venenos/química , Estereoisomerismo , Estricnina/químicaRESUMO
A convergent total synthesis of leustroducsin B (1), which is known to exhibit a variety of biological activities, was successfully carried out. Notable features of our synthesis include construction of the C8 stereocenter by lipase-mediated desymmetrization of meso-diol 4 (90.2% ee) and preparation of the C9-C11 anti-diol moiety by the addition of alkynylzinc reagent 20 to the aldehyde 19. Furthermore, a new diol protecting group, p-silyloxybenzylidene, was developed for the deprotection from densely functionalized substrates under weakly acidic conditions. The protecting group was easily removed in a two-step procedure ((HF)3.Et3N; AcOH-THF-H2O).