RESUMO
Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field.
Assuntos
Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismoRESUMO
Allylboron reagents are popular in synthesis owing to their versatility and the predictable stereochemical outcomes of their reactions with carbonyl compounds. Herein, we describe the synthesis of (Z,Z)-hexadienyl bis-boronate 1, a configurationally stable, crystalline, and easy to handle compound, which represents a class of bis-allylic boron reagents with heretofore untapped synthetic potential. In combination with a chiral phosphoric acid catalyst, the reagent can be employed for the enantioselective allyl transfer reaction to a variety of one-pot transformations, enabling swift access to functionalized 1,n-diols. The inâ situ conversion of the reagent into the corresponding bis-borinic ester allows for the direct and diastereoselective two-fold allyl transfer to aldehydes. This affords C2 - or Ci -symmetric stereotetrads containing a 1,4-diol moiety for natural product synthesis. The usefulness of our method was demonstrated with a short synthesis of the lignan (±)-neo-olivil.