Synthesis of 3beta,7alpha-Dihydroxy-Δ5-cholenoic Acid Derivatives: ‘Atypical’ Bile Acid Metabolites and Useful Biomarkers to Detect 3delta-HSDH Deficiency

Inborn errors responsible for impaired bile acid (BA) biosynthesis and metabolism are demonstrated to be potential cause of severe gastrointestinal diseases including neonatal cholestasis, neurological disorders, as well as lipids and fat-soluble vitamins malabsorption. If not diagnosed and treated, progressive liver and intestinal disorders may develop leading, in some circumstances, to serious morbidity or mortality. These defects which derive from the failed action of key enzymes, block the production of 'normal' BAs whereas favour the accumulation of 'atypical' BAs and intermediary metabolites. In this framework, the presence and/or the variation of the concentration related to specific BAs and their metabolic intermediates in plasma, serum, bile or urine are considered important biomarkers for diagnostic purposes. Based on these premises, the need to identify and confirm the biochemical diagnosis of these defects has required the use of sophisticated analytical techniques, sensitive and validated analytical protocols, as well as the development of efficient synthetic methods for the preparation of suitable reference standard compounds. As a continuation of our interest in the field of BAs, herein we report the synthesis of 3beta,7alpha-dihydroxy-5-cholen-24-oic acid derivatives, which represent the signature metabolites of the 3beta-hydroxy-C27-steroid oxidoreductase (3delta-HSDH) deficiency. According to the published literature, clinical manifestations of this metabolic disorder include jaundice, elevated serum glutamyl transpeptidase, fat-soluble vitamine malabsorption and conjugated bilirubinemia.