ABSTRACT
Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.
Subject(s)
Antiviral Agents/pharmacology , Hepatitis B, Chronic/drug therapy , Pteridines/pharmacology , Toll-Like Receptor 7/agonists , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Dogs , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Microsomes, Liver/metabolism , Models, Molecular , Protein Conformation , Pteridines/chemistry , Pteridines/metabolism , Pteridines/pharmacokinetics , Rats , Structure-Activity Relationship , Substrate Specificity , Toll-Like Receptor 7/chemistry , Toll-Like Receptor 7/metabolismABSTRACT
An overview of the chemistry and biology of the diterpene natural products known as the furanocembranoids, pseudopteranes, and gersolanes is provided; 85 references are cited.
Subject(s)
Biological Products/chemistry , Biological Products/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , Marine Biology , Molecular Mimicry , Molecular StructureABSTRACT
The asymmetric total synthesis of (-)-bipinnatin J and its conversion into (+)-intricarene through a transannular 1,3-dipolar cycloaddition is described. In addition, the conversion of (-)-bipinnatin J into (+)-rubifolide and (+)-isoepilophodione B is reported. Biosynthetic relationships among furanocembranoids and the possible role of 1,3-dipolar cycloadditions in biosynthesis are discussed. [reaction: see text]
Subject(s)
Diterpenes/chemical synthesis , Triterpenes/chemical synthesis , Cyclization , Diterpenes/chemistry , Magnetic Resonance Spectroscopy , Oxidation-Reduction , StereoisomerismABSTRACT
[reaction: see text] A nine-step, stereoselective synthesis of bipinnatin J is described, which features a ruthenium-catalyzed Alder-ene reaction, a Stille cross coupling, and an intramolecular Nozaki-Hiyama-Kishi allylation as key steps. The biosynthetic relationship between bipinnatin J and complex polycyclic diterpenes isolated from gorgonian corals is discussed.
Subject(s)
Diterpenes/chemical synthesis , Animals , Anthozoa/chemistry , Catalysis , Diterpenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
[reaction: see text] Synthesis of the northern hemisphere (C1-C16) of bryostatin 1, a potent anticancer agent, has been accomplished in 14 steps and 11% overall yield via desymmetrization by ketalization/ring-closing metathesis. A 2,9-dioxabicyclo[3.3.1]nonane template facilitated stereoselective A-ring functionalization, while an efficient hetero-Diels-Alder reaction was used to elaborate the B-ring.
Subject(s)
Acetals/chemistry , Antineoplastic Agents/chemical synthesis , Macrolides/chemical synthesis , Alkanes/chemistry , Bridged Bicyclo Compounds/chemistry , Bryostatins , Cyclization , Molecular StructureABSTRACT
An efficient synthesis of Hale and co-workers' C17-C27 bryostatin southern hemisphere intermediate has been accomplished in six steps and 33% overall yield from (R)-2-(benzyloxy)propanal. The synthesis features a one-pot DIBALH/HWE ester homologation as well as a novel acetonide rearrangement/glycal formation cascade.