Pharmacophore-Directed Retrosynthesis Applied to Ophiobolin A: Simplified Bicyclic Derivatives Displaying Anticancer Activity
Yongfeng Tao, Keighley Reisenauer, Marco Masi, Antonio Evidente, Joseph H. Taube, Daniel Romo
Abstract
Pharmacophore-directed retrosynthesis applied to ophiobolin A led to bicyclic derivatives that were synthesized and display anticancer activity. Key features of the ultimate defensive synthetic strategy include a Michael addition/facially selective protonation sequence to set the critical C6 stereocenter and a ring-closing metathesis to form the cyclooctene. Cytotoxicity assays toward a breast cancer cell line (MDA-MB-231) confirm the anticipated importance of structural complexity for selectivity (vs MCF10A cells) while C3 variations modulate stability.
Topics & Concepts
PharmacophoreChemistryStereocenterBicyclic moleculeMetathesisRetrosynthetic analysisStereochemistrySalt metathesis reactionCytotoxicityRing-closing metathesisCancer cell linesCombinatorial chemistryCancer cellCancerTotal synthesisBiochemistryOrganic chemistryBiologyEnantioselective synthesisIn vitroGeneticsPolymerizationPolymerCatalysisSynthetic Organic Chemistry MethodsMarine Sponges and Natural ProductsMicrobial Natural Products and Biosynthesis