ABSTRACT
ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.
Subject(s)
Drug Design , Guanosine/analogs & derivatives , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Pyrimidinones/administration & dosage , Pyrimidinones/chemical synthesis , Toll-Like Receptor 7/agonists , Administration, Oral , Antiviral Agents/pharmacology , Guanosine/pharmacology , Humans , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokineticsABSTRACT
A unified synthesis of several quinone sesquiterpenes is described herein. Essential to this strategy is a novel radical addition reaction that permits the attachment of a fully substituted bicyclic core 16 to a variably substituted quinone 10. The addition product 15 can be further functionalized, giving access to natural products with a high degree of oxygenation at the quinone unit. The quinone addition reaction is characterized by excellent chemoselectivity, taking place only at conjugated and unsubstituted double bonds, and regioselectivity, being strongly influenced by the resonance effect of heteroatoms located on the quinone ring. These features were successfully applied to the synthesis of avarol (1), avarone (2), methoxyavarones (4, 5), ilimaquinone (6), and smenospongidine (7), thereby demonstating the synthetic value of this new method.
Subject(s)
Quinones/chemical synthesis , Sesquiterpenes/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Cyclohexenes , Substrate SpecificityABSTRACT
[reaction: see text] A stereoselective synthesis of (-)-ilimaquinone (4) is presented. The synthetic strategy is based on a novel radical decarboxylation and quinone addition methodology that produces quinone 7 from reaction of thiohydroxamic acid derivative 8 with benzoquinone (9). Final functionalization of 7 to ilimaquinone (4) is achieved by exploring the electronic effects of the residual thiopyridyl group.
