Prodrugs for colon-restricted delivery: Design, synthesis, and in vivo evaluation of colony stimulating factor 1 receptor (CSF1R) inhibitors.

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.

Total synthesis of (±)-γ-lycorane via the electrocyclic ring closure of a divinylpyrroline.

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.

A strategy for the total synthesis of dragmacidin E. Construction of the core ring system.

[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.

Total syntheses of (+/-)-cis-trikentrin A and (+/-)-cis-trikentrin B via electrocyclic ring closures of 2,3-divinylpyrrolines.

[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.