Amination Products of Inula britannica Lactones and Their Antitumor Activity

Abstract

The reactions with amines of the sesquiterpene lactones britanin and inuchinenolide C isolated from Inula britannica were studied. Migration of the acetyl group during the addition reaction was observed and depended on the nature of the amine and solvent. Compounds with antitumor activity were found among the new amine derivatives.The genus Inula (Asteraceae) comprises about 100 plants, many of which are widely used in folk medicine owing to a variety of biological activities [1] including anti-inflammatory, antitumor, and bactericidal [2]. Plants of this genus contain a large number of physiologically active compounds, e.g., sesquiterpene lactones, among which compounds with valuable biological properties were observed [3].The sesquiterpene lactone britanin (1) is frequently encountered in plants of the genus Inula and was isolated from I. caspica Blume, I. britannica L., and I. aspera Poir.[4]. Its pseudoguaianolide structure was first described over 50 years ago [5]. An x-ray crystal structure analysis [6] established the R-configuration for the 2-acetoxy group. ** We also obtained a significant quantity of a britanin isomer during its isolation by the previously described method [7]. This was inuchinenolide C (2), which was first isolated from I. britannica var. chinensis and differed in the position of the acetyl group [8]. Despite the similar structures, 1 and 2 were easily differentiated by the positions of the resonances for the 4-and 6-protons in the PMR spectrum.Chemical modifications of 1 that affected the five-and seven-membered rings included acylation and deacetylation [9] and oxidation [9, 10]. However, 1 and 2 also include a highly reactive electrophilic center as an exomethylene in the lactone ring that is susceptible to attack by nucleophiles. The reaction of 1 with methylmercaptoacetate (S-nucleophile) is known to occur at the lactone ring and to produce addition products at the C-11 and C-13 atoms in a 3:1 ratio [11]. Examples of the addition of N-nucleophiles to britanin isolated from I. caspica are known. According to some researchers [12][13][14], the reaction with secondary (diethylamine and morpholine) and primary (ethanolamine) amines in addition to bifunctional ethylenediamine occurred stereospecifically. However, the physicochemical properties of the products were not characterized in those studies. Furthermore, these reactions with 2 have not been reported. Recently, compounds with various biological activities, including antitumor activity, were observed among sesquiterpene lactone amine derivatives [15]. This is responsible for the heightened interest in such compounds.We studied the reaction of 1 with several primary aliphatic and secondary amines, including heterocyclic ones, in order to prepare new amine derivatives. The reaction proceeded readily in a polar protic (MeOH) or nonpolar aprotic (CH 2 Cl 2 ) solvent at room or slightly elevated temperature. The structures of the reaction products depended on the reaction conditions and the nature of the amine (basicity and nucleophil...

Aniline-containing derivatives of parthenolide: Synthesis and anti-chronic lymphocytic leukaemia activity

“…The 1,4-conjugate addition of primary and secondary aniline derivative to various Michael acceptor motifs has been widely reported [ [43] , [44] , [45] , [46] , [47] , [48] , [49] ], including related natural product derived lactones [ 38 , 41 , 43 , 44 , 50 ] that have been shown to be amenable to Lewis or Brønsted acid catalysed conjugate addition of anilines. In order to extend the scope of such aniline derivative additions to parthenolide ( 1 ) a series of model, precedent-informed, reactions were investigated.…”

Protective Effects of the Natural Sesquiterpene Lactones Against Damage Induced by Glutamate and Peroxide in SK-N-MC Cells

“…1). Из наземной части девясила британского (I. britannica) были выделены лактоны с гвайановым скелетоминнучиненолид С (L20) и британин (L25) [8]. Эвдесманолиды -изоалантолактон (L01) и его изомер по положению двойной связи алантолактон (L02) выделены как основные компоненты корней девясила высокого (I. helenium).…”

Britanin Exhibits Potential Inhibitory Activity on Human Prostate Cancer Cell Lines Through PI3K/Akt/NF-κB Signaling Pathways

“…1) is a bioactive sesquiterpene lactone isolated from the aerial portions of Inula lineariifolia (Genus: Inula; Family: Asteraceae) [6]. Previous pharmacological studies of britanin primarily established its antioxidant, anti-inflammation, and cerebroprotective effects [7][8][9][10][11]. However, few studies have been conducted in the anticancer field.…”