Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

Abstract

A practical and high-yielding Schmidt reaction for the synthesis of fused tetrazoles from bile acid precursors was developed. Mild reaction conditions using TMSN3 instead of hydrazoic acid as an azide source produced good yields of the desired tetrazoles. These conditions could be applied to other steroidal precursors. Additionally, an improved methodology for the synthesis of different ketone and enone precursors from cholic acid, deoxycholic acid, and chenodeoxycholic acid was established. Newly obtained tetrazole derivatives were characterized by NMR and X-ray diffraction spectroscopy. In a number of cases, preliminary antiproliferative tests of new compounds showed strong and selective activity towards certain tumor cell lines.

X-ray structure of human aldo–keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis

“…In the present study, a series of bile acid derivatives ( 1–8 ) with a tetrazole group fused to either the B- or C-ring of the steroidal core were tested for their ability to inhibit the reduction of 9,10-phenanthrenequinone (PQ), a general AKR1C substrate, by human AKR1C3. 28 Initial screening of the effect of 1–8 on AKR1C3 enzymatic activity was conducted using a standard assay, by monitoring NADPH consumption during the reaction using fluorescence spectroscopy (excitation 340 nm, emission 460 nm) (Fig. 1 and Table 1).…”

“…Compounds 1-8 were characterized by 1 H and 13 C NMR spectroscopy, IR spectroscopy and HRMS, and their chemical synthesis and full characterization have been published. 28 Compound 1.…”

“…Recently, the synthesis and chemical characterization of a series of bile acid fused tetrazoles with anticancer properties was described by members of our group. 28 Tetrazole modifications can change the bioactivity of the parent compounds by changing the hydrogen bonding potential and introducing a carboxylic acid bioisostere. 29 Thus, the aim of the present study was to test the potential of this series of bile acid fused tetrazoles as AKR1C3 inhibitors using enzymatic assays in vitro .…”

A Convenient Synthesis of Novel Isoxazolidine and Isoxazole Isoquinolinones Fused Hybrids

“…It is known [ 44 , 45 ] that this type of tetrazole by-product may be derived via an alternative pathway of the Schmidt reaction, where the initially formed nitrilium ion is quenched by hydrazoic acid when the latter is present at high concentrations. To exclude the possibility of tetrazole ring formation via a post-amidation reaction, we left pure lactam 9a to react under our Schmidt protocol conditions, but the latter remained intact.…”

Screening the binding affinity of bile acid derivatives for the glucocorticoid receptor ligand-binding domain

“…Details of the synthesis of the tetrazole compounds used in the present study have been published by our group. 35 Dienones 25 and 26 were obtained by the following procedures: when compound 27 (Scheme 3) was refluxed in methanolic potassium hydroxide solution, elimination and hydrolysis occurred to afford 25 at a yield of 90 % (78 % reported by Leppik et. al.…”