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

Abstract

Novel 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).

Isoxazole/Isoxazoline Skeleton in the Structural Modification of Natural Products: A Review

“…Compound 21d ( Figure 14 ) was found on cells of breast cancer MCF7 (12.49 ± 1.18 µM) and lung cancer A549 (13.15 ± 1.56 µM). The constitutive relationship indicated that compounds with hydrophilic substituents on the isoxazole ring had stronger cytotoxic activity [ 47 ].…”

Semisynthetic Derivatives of Pentacyclic Triterpenes Bearing Heterocyclic Moieties with Therapeutic Potential

“…The SAR study proved that the substituents attached to the isoxazole ring significantly influenced the overall cytotoxic effects; as an example, the saponin-like derivatives containing glucose substituents grafted on the isoxazole fragment induced cytotoxic effects against A549 and MCF7 cell lines, but no activity was recorded in the HepG2 cells. The most promising results were reported for derivatives bearing small hydrophilic substituents on the isoxazole ring, such as hydroxymethyl (Bet 9–10), 2-hydroxypropan-2-yl (Bet 11), (2-hydroxyethoxy)methyl (Bet 12), carboxyl (Bet 13), and (acetylthio)methyl (Bet-14), for which IC 50 values within the micromolar range were calculated; moreover, the selected compounds proved to be harmless against healthy human fibroblasts [ 32 ].…”

Electrochemical Synthesis of Pyrazolines and Pyrazoles via [3+2] Dipolar Cycloaddition

“…In general, the presented approach is analogous to the synthesis of isoxazoles, and isoxazolines from aldoximes [29] . The synthesis of nitriles, isoxazolines and isoxazoles can be achieved by electrolysis via nitrile oxides as key intermediates [30–34] . These reactions have been investigated since the late 1980s when Shono et al.…”