Electrosynthesis of Stable Betulin‐Derived Nitrile Oxides and their Application in Synthesis of Cytostatic Lupane‐Type Triterpenoid‐Isoxazole Conjugates

Abstract

AbstractNovel lupane‐type triterpenoid‐isoxazole conjugates were designed by direct placing of isoxazole linker at C(17) of triterpenoid. The suggested synthetic sequence demonstrates successful combination of electro‐organic synthesis and conventional approaches. TEMPO‐mediated electrooxidation of betulin to betulinal was developed and optimized at boron‐doped diamond anodes with potassium acetate as inexpensive supporting electrolyte. Betulinal‐derived oxime was further selectively electro‐oxidized at a graphite anode to nitrile oxide, which proved to be stable and isolable species. The same reaction sequence was performed with 3β‐lupane‐3,28‐diol. Nitrile oxides were characterized by 15N NMR and X‐ray crystallography. The isolable nitrile oxides allowed creation of isoxazole library by 1,3‐dipolar cycloaddition reactions with various alkynes. Some of the title conjugates exhibit cytostatic properties against breast cancer cell line MCF7, glioblastoma multiform cell line U‐87 MG and lung carcinoma cell line A549 with growth inhibition (GI50) concentrations up to 11 μm, while being harmless to immortalized human fibroblasts hTERT (GI50 >100 μm).