RESUMO
A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.
Assuntos
Glicosídeos/síntese química , Glicosídeos/química , Conformação Molecular , Piranos/química , EstereoisomerismoRESUMO
A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/química , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos de Epóxi/síntese química , Compostos de Epóxi/metabolismo , Macrolídeos/síntese química , Macrolídeos/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/química , Splicing de RNA/efeitos dos fármacos , Ribonucleoproteína Nuclear Pequena U2/antagonistas & inibidores , Ribonucleoproteína Nuclear Pequena U2/química , Antineoplásicos/química , Sítios de Ligação , Compostos de Epóxi/química , Humanos , Macrolídeos/química , Fatores de Processamento de RNARESUMO
A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery.