Secondary Metabolites of Ponderosa Lemon (Citrus pyriformis) and their Antioxidant, Anti-Inflammatory, and Cytotoxic Activities

Abstract

Column chromatography of the dichloromethane fraction from an aqueous methanolic extract of fruit peel of Citrus pyriformis Hassk. (Rutaceae) resulted in the isolation of seven compounds including one coumarin (citropten), two limonoids (limonin and deacetylnomilin), and four sterols (stigmasterol, ergosterol, sitosteryl-3-β-D-glucoside, and sitosteryl-6-O-acyl-3-β-D-glucoside). From the ethyl acetate fraction naringin, hesperidin, and neohesperidin were isolated. The dichloromethane extract of the defatted seeds contained three additional compounds, nomilin, ichangin, and cholesterol. The isolated compounds were identifi ed by MS (EI, CI, and ESI), 1 H, 13C, and 2D-NMR spectral data. The limonoids were determined qualitatively by LC-ESI/MS resulting in the identifi cation of 11 limonoid aglycones. The total methanolic extract of the peel and the petroleum ether, dichloromethane, and ethyl acetate fractions were screened for their antioxidant and anti-infl ammatory activities. The ethyl acetate fraction exhibited a signifi cant scavenging activity for DPPH · free radicals (IC 50

The Chemistry and Pharmacology of Citrus Limonoids

“…No surprise, then, if the two CLs present similar activities and potencies of action [3,47,51,58,77]. Paralleling what has been observed for 1 and its glucoside 11, the glucoside of 4 (12) sharply reduced cancer cell viability as compared to aglycone [58] thus corroborating the hypothesis that glucosides may be better active apoptosis-inducing agents [132].…”

“…Citrus limonoids (CLs) are a crowded family of polycyclic secondary metabolites found mostly in seeds [1], fruits [2], and peel [3][4][5][6][7] tissues of citrus fruits, including lemons, limes, oranges (both sour and sweet), pumellos, grapefruits, bergamots, and mandarins [5]. CLs are regarded as highly oxygenated triterprenoids as they contain relatively high numbers of oxygen atoms (7)(8)(9)(10)(11) in their structures.…”

“…Generally, 1 and its derivatives were more active than the corresponding deoxygenated congeners, thus underlying the relevant contribution of the oxirene moiety to analgesic and anti-inflammatory activities. Whether this contribution stems from epoxyde reactivity towards protein nucleophilic side chains [3] however remains to be demonstrated. Incidentally, these findings are in agreement with the above general observation on LRI, Fsp 3 , and the number of chirality centers as reliable predictors of drug developability.…”

“…Furthermore, while micromolar concentrations of both 1 and 11 arrested cell growth, biochemical and morphological data showed that 11 induced a more rapid cell death. Incidentally, the higher resistance of Caco-2 cells may be related to high expression of the ABC transporter P-gp [3,51], an efflux pump that impedes cytoplasmic accumulation of lipophilic compounds. (1); and deoxylimonin (10) endowed with analgesic and anti-inflammatory properties [45].…”

“…For the sake of graphical clarity, we adopted the descriptor LE (ligand efficiency) corresponding to the product LEI × 1.37 (LE = ∆G • /HA = −2.303 RT/HA ≈ 1.37 potency/HA). An ideal lead compound should have LE >~0.3 kcal per mole per HA [102].Fraction sp 3 (Fsp 3 = number of sp 3 hybridized carbons/total carbon count). Lovering [108] suggested this descriptor as a measure of complexity since he noted that drug candidates nearest to clinical use generally present high Fsp 3 and chirality centers.…”