ABSTRACT
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.
Subject(s)
Glycosides/chemical synthesis , Glycosides/chemistry , Molecular Conformation , Pyrans/chemistry , StereoisomerismABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor/chemistry , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Epoxy Compounds/chemical synthesis , Epoxy Compounds/metabolism , Macrolides/chemical synthesis , Macrolides/metabolism , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/chemistry , RNA Splicing/drug effects , Ribonucleoprotein, U2 Small Nuclear/antagonists & inhibitors , Ribonucleoprotein, U2 Small Nuclear/chemistry , Antineoplastic Agents/chemistry , Binding Sites , Epoxy Compounds/chemistry , Humans , Macrolides/chemistry , RNA Splicing FactorsABSTRACT
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.