title: Synthesis of B- and C-ring-modified lithocholic acid analogues as potential sialyltransferase inhibitors.
abstract: In order to identify structural features of lithocholic acid (LCA) critical for inhibition of the enzyme sialyltransferase (ST) novel analogues with modifications of the skeleton (7-9, 16-18 and 20) were designed and synthesized. Methyl 3α-acetoxy-7-oxo-cholanate (1), methyl 3α-acetoxy-12-oxo-cholanate (2) and methyl 3α,7α-diacetoxy-12-oxo-cholanate (3) were subjected to Baeyer-Villiger oxidation to provide homolactones (7-9) or to the Beckmann rearrangement of the corresponding oximes to give homolactams (16-18). Both reactions proceed regio- and stereoselectively. Ring B homolog of lithocholic acid (20) was efficiently synthesized. Among these compounds, 7, 9 and 16 were found to have the significant activity, with IC50 values ⩽3μM against α-2,6-(N)-ST selectively, which are 5-fold lower than that of Lith-O-Asp. Given the reality that LCA and its analogue, Lith-O-Asp, have been revealed to improve inhibitory efficacy of ST and to have a wide range of antimetastatic activities in different human cancer cells, the up-to-date findings have noteworthy pharmacological significance as they open a promising path to the improvement of a prospective molecular targeted application of modified LCA analogues as agents for the treatment of cancer metastasis.
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Hajjaj H M
authors.initials: HH
authors.lastname: Abdu-Allah
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Tzu Ting
authors.initials: TT
authors.lastname: Chang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. Electronic address: wenshan@gate.sinica.edu.tw.
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D012799:Sialyltransferases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008095:Lithocholic Acid; D012799:Sialyltransferases
keywords: Homolactam; Homolactone; Lithocholic acid; Oxidation; Rearrangement; Sialyltransferase inhibitors