RESUMO
Macrocyclic compounds represent a structural class with exceptional potential for biological activity; however, they have historically been underrepresented in screening collections and synthetic libraries. In this article we report the development of a highly step-efficient strategy for the diversity-oriented synthesis of complex macrocyclic architectures, using a modular approach based on the two-directional synthesis of bifunctional linear precursors and their subsequent combination in a two-directional macrocyclisation process. In this proof of principle study, the synthesis of 14 such compounds was achieved. Cheminformatic analysis of the compounds produced suggests that they reside in biologically relevant regions of chemical space and the compounds were screened for activity against two cancer cell lines.
Assuntos
Antineoplásicos/farmacologia , Compostos Macrocíclicos/farmacologia , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ciclização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Maleimidas/síntese química , Maleimidas/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Starting from commercially available ( S)-glycidol, and via a common intermediate, the total synthesis of (-)-histrionicotoxin 285A and (-)-perhydrohistrionicotoxin has been achieved. Key to this synthesis was the efficient construction of a six-membered, chiral, cyclic nitrone.
Assuntos
Venenos de Anfíbios/síntese química , Alcadienos/química , Alcaloides/síntese química , Alcaloides/química , Venenos de Anfíbios/química , EstereoisomerismoRESUMO
The sequential intramolecular conjugate addition of the oxime 13 followed by intramolecular dipolar cycloaddition of the intermediate nitrone 14 affords a mixture of the isoxazolidines 15, 16 and 17. The tricyclic 6,5,5-adduct 15 is believed to be the product of kinetic control and can be equilibrated with the epimeric tricyclic 6,5,5-isoxazolidine 17 through a beta-elimination/conjugate addition process. Conditions have been developed for the two-step conversion of the ketone 12 under thermodynamic control into the racemic tricyclic 6,6,5-adduct 16 which is the core precursor of all the known histrionicotoxin alkaloids.