ABSTRACT
The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect-measured as reduction in macrophages in the colon-was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets.
Subject(s)
Colitis/immunology , Cyclodextrins/chemistry , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Colitis/chemically induced , Colitis/drug therapy , Colon/chemistry , Dextran Sulfate/adverse effects , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Macrophages/drug effects , Macrophages/metabolism , Mice , Models, Molecular , Molecular Structure , Prodrugs/chemistry , Prodrugs/pharmacokineticsABSTRACT
A concise total synthesis of (±)-γ-lycorane is described. The key step in the synthesis is the 6π-electrocyclic ring closure of a divinylpyrroline to give a tetrahydroindole, which is subsequently hydrogenated to give the all-cis indolizidine core.
ABSTRACT
[reaction: see text] The construction of the dragmacidin core ring system by a route that features the application of a new indole annelation reaction sequence is described.
Subject(s)
Indole Alkaloids/chemistry , Indole Alkaloids/chemical synthesis , Catalysis , Molecular StructureABSTRACT
[Structure: see text] A convergent and versatile strategy for the diastereoselective syntheses of (+/-)-cis-trikentrin A and B in 10 and 12 steps, respectively, from commercially available N-BOC-2-pyrrolidinone is described. The key step in each of the total syntheses is the construction of the central benzene ring via a facile 6pi-electrocyclic ring closure of an appropriately substituted 2,3-divinylpyrroline, in turn, readily available by a Stille coupling reaction.
