Synthesis, Cyclization, and Cytotoxic Activity of 2,3-Secolupane Triterpenoids With an Ethylketone Fragment

Abstract

3-Ethyl substituted triterpenoids with a fragmented and 5-membered A ring were synthesized from the lupane ketoxime via the Beckmann reaction and intramolecular oxonitrile cyclization, respectively. Transformations of the triterpenic isopropylidene fragment with the formation of C(30) and C(20) modified derivatives were performed by either allylic C(30) oxidation or ozonolytic cleavage of the C(20)-C(29) double bond. Antitumor activity of the synthesized compounds was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,3-diphenyl-tetrazolium bromide test against 7 human cancer cell lines. Methyl 1-cyano-3-ethyl-3-oxo-2,3-seco-2-norlup-20(29)-en-30-al-28-oate (4), methyl 3-[1-bromoethyl]-1-cyano-3-oxo-2,3-seco-2-norlup-20(29)-en-30-al-28-oate (6), and methyl 1-cyano-3-ethyl-2-norlup-1(3),20(29)-dien-30-al-28-oate (9) were selected as compounds with highest cytotoxicity (IC50 1.38-15.91 μM).

Stereoselective Epoxidation of Triterpenic Allylic Alcohols and Cytotoxicity Evaluation of Synthesized Compounds

“…The structures of compounds 3 , 7 – 9 with the assignment of the absolute configuration of a new C3 asymmetric carbon center were finally confirmed by the X-ray crystallography technique of alcohols 3 , 7 , 8 ( Figure 1 a,c,d). Thus, the β-orientation of the 3-hydroxy group of compounds 3 , 7 – 9 agrees with the previously obtained data when, during the reductive alkylation of 3-oxotriterpenoids, the Grignard reagent ensured attack exclusively on the α-side to afford an α-oriented 3-alkyl/aryl substituent, due to the complexation of the Grignard reagent with the solvent THF and steric loading of axially oriented angular methyl groups at С4 and С10 atoms [ 33 , 34 , 35 , 36 ].…”

“…Ring A plays an important role in realizing anticancer, antiviral, anti-inflammatory, antibacterial, antifungal, and antiparasitic activities by pentacyclic triterpenoids [ 1 , 2 , 3 , 4 , 5 , 6 , 16 , 32 , 33 , 34 , 35 , 36 ]. At the same time, the modification of ring A with the 1,2-oxirane fragment most often improves the antibacterial, antifungal, and anticancer properties of triterpenoids [ 17 , 46 , 47 ].…”