Synthesis and evaluation of colletoic acid core derivatives

Mechanistic Insight on the Mode of Action of Colletoic Acid

“…Subsequently, C-4, C-8, C-9, and C-10 centers of CA were evaluated (Figure 2C). Epoxide 13a was synthesized from the CA core in gram quantity as previously reported, 20 which was subjected to a two-step reaction sequence involving Swern oxidation [(COCl) 2 , DMSO, and Et 3 N] of the primary hydroxyl group, followed by Pinnick oxidation (NaClO 2 , t-BuOH, 2-methyl-2-butene) to afford compound 13f. Alternatively, compound 13a was directly submitted to TBSCl in the presence of imidazole and sequential treatment with thionyl chloride and pyridine at 0 °C to afford the exocyclic olefin system.…”

“…To test that hypothesis, co-crystallization and ligand-soaking strategies of CA with a construct of 11β-HSD1 containing the coding sequence for the catalytic domain (residues 24–292), a single point mutation (C272S), and a C-terminal truncation (residues 264–292) were conducted. These amino acid perturbations of the protein construct are remote from the ligand- and cofactor-binding sites (the catalytic pocket) and should have minimal effects on the ligand–protein interaction, as previously described. , After several attempts, CA was soaked into preformed 11β-HSD1 crystals resulting in a 2.6 Å resolution structure of the 11β-HSD1-CA crystal complex (Table S3), with a root-mean-square deviation of 0.008 Å for aligned Cα atoms and describes the binding mode of CA to the enzyme for the first time. A global cartoon of the tetramer of 11β-HSD1 with CA bound near the cofactor NADP+ is shown in Figure , highlighting the narrow but flexible cavity of the ligand entrance.…”

“…A convergent and enantioselective total synthesis of CA and its first-generation analogues were previously described by our group. 20 However, the exact mode of action of CA and its potential activity in functional cellular assays remained unknown. Thus, the main objective of our study was to elucidate the mode of action of CA and to develop new potential chemical tools to study GC signaling in adipocyte biology.…”

“…Previous studies have demonstrated that CA is a potent 11β-HSD1 inhibitor with no observable 11β-HSD2 inhibition. , CA is a member of the acorane natural products family, featuring a synthetically challenging all-carbon spirocenter. A convergent and enantioselective total synthesis of CA and its first-generation analogues were previously described by our group . However, the exact mode of action of CA and its potential activity in functional cellular assays remained unknown.…”

Synthesis of Spirocyclohexadienones through Radical Cascade Reactions Featuring 3-Fold Carbon–Carbon Bond Formation

“…Sodium borohydride reduction of 5aa selectively occurred at the more exposed double bond of the cyclohexadienone system, and its increased conformational flexibility led to the formation of the hemiacetal substructure in the tricyclic product 16 . Compounds similar to 16 , which are structurally related to (+)-colletoic acid ( 17 ), have recently been evaluated as 11β-hydroxysteroid dehydrogenase type 1 inhibitors …”