43080-09-7Relevant articles and documents
Structural analysis of the dual-function thioesterase SAV606 unravels the mechanism of Michael addition of glycine to an α,β-unsaturated thioester
Chisuga, Taichi,Miyanaga, Akimasa,Kudo, Fumitaka,Eguchi, Tadashi
, p. 10926 - 10937 (2017)
Thioesterases catalyze hydrolysis of acyl thioesters to release carboxylic acid or macrocyclization to produce the corresponding macrocycle in the biosynthesis of fatty acids, polyketides, or nonribosomal peptides. Recently, we reported that the thioesterase CmiS1 from Streptomyces sp. MJ635-86F5 catalyzes the Michael addition of glycine to an α,β-unsaturated fatty acyl thioester followed by thioester hydrolysis in the biosynthesis of the macrolactam antibiotic cremimycin. However, the molecular mechanisms of CmiS1-catalyzed reactions are unclear. Here, we report on the functional and structural characterization of the CmiS1 homolog SAV606 from Streptomyces avermitilis MA-4680. In vitro analysis indicated that SAV606 catalyzes the Michael addition of glycine to crotonic acid thioester and subsequent hydrolysis yielding (R)-N-carboxymethyl-3-aminobutyric acid. We also determined the crystal structures of SAV606 both in ligand-free form at 2.4 ? resolution and in complex with (R)-N-car-boxymethyl-3-aminobutyric acid at 2.0 ? resolution. We found that SAV606 adopts an α/β hotdog fold and has an active site at the dimeric interface. Examining the complexed structure, we noted that the substrate-binding loop comprising Tyr-53–Asn-61 recognizes the glycine moiety of (R)-N-carboxymethyl-3-aminobutyric acid. Moreover, we found that SAV606 does not contain an acidic residue at the active site, which is distinct from canonical hotdog thioesterases. Site-directed mutagenesis experiments revealed that His-59 plays a crucial role in both the Michael addition and hydrolysis via a water molecule. These results allow us to propose the reaction mechanism of the SAV606-catalyzed Michael addition and thioester hydrolysis and provide new insight into the multiple functions of a thioesterase family enzyme.
Convergent synthesis of (R)-silodosin via decarboxylative cross-coupling
Baran, Phil S.,Chen, Tie-Gen,Delbrayelle, Dominique,Echeverria, Pierre-Georges,Jentzer, Olivier,Mele, Lucas,Vantourout, Julien C.
supporting information, (2021/08/06)
A new approach to Silodosin capitalizing on a radical retrosynthetic strategy to dissect the molecule into two halves is reported. Using a reductive decarboxylative cross-coupling, a simple indoline can be coupled to a chiral pool-derived fragment to arrive at the target in only seven steps (LLS). This route avoids the use of resolution strategies or asymmetric hydrogenation that requires a subsequent Curtius rearrangement to install a key amino functionality.
Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors
Honda, Eiji,Ishichi, Yuji,Kimura, Eiji,Yoshikawa, Masato,Kanzaki, Naoyuki,Nakagawa, Hideyuki,Terao, Yasuko,Suzuki, Atsuko,Kawai, Takayuki,Arakawa, Yuuichi,Ohta, Hiroyuki,Terauchi, Jun
, p. 3898 - 3902 (2014/09/17)
A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.
