Leucosceptosides A and B: Two Phenyl-Ethanoid Glycosides with Important Occurrence and Biological Activities

In this review paper, the occurrence in the plant kingdom, the chemophenetic value and the biological activities associated with two specific phenyl-ethanoid glycosides, i.e., leucosceptoside A and leucosceptoside B, were reported. This is the first work ever conducted on such a subject. Analysis of the literature data clearly led to three important conclusions: leucosceptoside A is much more common in plants than leucosceptoside B; leucosceptoside A exerts more biological activities than leucosceptoside B even if nothing can be generally concluded about which one is actually the most potent; neither of these compounds can be used as a chemophenetic marker. These three aspects and more are discussed in more depth in this work.


Introduction
Leucosceptoside A and leucosceptoside B are two natural compounds belonging to the class of phenyl-ethanoid glycosides which have gained increasing attention in recent years due to their important and effective biological activities [1].
Phenyl-ethanoid glycosides are biosynthetically generated merging two different processes, the shikimic acid pathway, which produces the β-hydroxy-tyrosol part of phenylethanoid glycosides, and the cinnamate pathway, which produces its caffeic acid part after a series of intermediate steps [2].
The base compound of phenyl-ethanoid glycosides is called verbascoside, acetoside or acteoside, which is structurally characterized by a central glucose residue linked to one β-hydroxy-tyrosol and one rhamnose residue through ether bonds, and to one caffeic acid through an ester bond.Leucosceptoside A differs from verbascoside for the substitution with a methyl group in the caffeic acid moiety.Indeed, leucosceptoside B differs from verbascoside for the substitution with one methyl group each in the caffeic acid and βhydroxy-tyrosol moieties as well as for the substitution with one β-D-apiose residue in the position 6 of the glucose moiety [3] (Figure 1).
In the literature, there are some review papers on phenyl-ethanoid glycosides in general, exploring mainly their occurrence, structure and biological activities [1,2,4]; however, no review paper has ever focused its complete attention on leucosceptoside A and leucosceptoside B, which have often been actually neglected regarding several of their aspects in the past reviews.In addition, some of these reviews are now outdated and do not cover the chemophenetics of these compounds or even of the phenyl-ethanoid glycosides in general.These represent the main reasons why this review paper was written.In this, the specific occurrence of leucosceptoside A and leucosceptoside B in the plant kingdom as well as their relative biological activities were reported with major details.In addition, chemophenetic conclusions on these compounds were drawn and a strict comparison on the biological activities of these two compounds in more senses was also performed, both for the first time.This review paper is based on all the published papers until now, as recovered from Scopus, Reaxys, Google Scholar and PubMed.Only works regarding plants were considered, thus, excluding cell cultures.In addition, only works without any kind of procedure possibly producing alterations and artifacts in the phytochemical pattern were cited.Lastly, papers not written in English were not considered.In the literature, there are some review papers on phenyl-ethanoid glycosides in general, exploring mainly their occurrence, structure and biological activities [1,2,4]; however, no review paper has ever focused its complete attention on leucosceptoside A and leucosceptoside B, which have often been actually neglected regarding several of their aspects in the past reviews.In addition, some of these reviews are now outdated and do not cover the chemophenetics of these compounds or even of the phenyl-ethanoid glycosides in general.These represent the main reasons why this review paper was written.In this, the specific occurrence of leucosceptoside A and leucosceptoside B in the plant kingdom as well as their relative biological activities were reported with major details.In addition, chemophenetic conclusions on these compounds were drawn and a strict comparison on the biological activities of these two compounds in more senses was also performed, both for the first time.This review paper is based on all the published papers until now, as recovered from Scopus, Reaxys, Google Scholar and PubMed.Only works regarding plants were considered, thus, excluding cell cultures.In addition, only works without any kind of procedure possibly producing alterations and artifacts in the phytochemical pattern were cited.Lastly, papers not written in English were not considered.

Occurrence in the Plant Kingdom
In the following Tables, the occurrences of leucosceptoside A (Table 1) and leucosceptoside B (Table 2) in the plant kingdom are reported and divided according to the family of the plant they have been isolated from.These tables are sub-divided according to the plant species and report data on the collection area of the plant cited, the studied organs and the methodologies of isolation and identification for these compounds.In the collection area columns, if not differently specified, the studied population or populations are intended to be collected from the wild.

Occurrence in the Plant Kingdom
In the following Tables, the occurrences of leucosceptoside A (Table 1) and leucosceptoside B (Table 2) in the plant kingdom are reported and divided according to the family of the plant they have been isolated from.These tables are sub-divided according to the plant species and report data on the collection area of the plant cited, the studied organs and the methodologies of isolation and identification for these compounds.In the collection area columns, if not differently specified, the studied population or populations are intended to be collected from the wild.Caryopteris incana (Thunb.ex Houtt.)Miq.

Clerodendrum bungei
Steud.Leucosceptoside A proved to be quite common in the plant kingdom.In fact, it has been evidenced in eleven families.In particular, its lowest occurrence was observed in Asteraceae, Malvaceae and Oleaceae with one report each.In contrast, the highest occurrence has been noticed in the Lamiaceae family with 69 reports even though these were singular reports in most cases.Nevertheless, it is important to underline that not all the genera in the Lamiaceae family have shown the presence of this compound.Within the Lamiaceae family, this compound has been found particularly in the Phlomis L. genus with 15 reports whereas it is quite rare in Betonica L., Schnabelia Hand.-Mazz.and Volkameria L. genera with only one report of its presence each.Henceforth, further phytochemical studies on species belonging to these genera are necessary in order to verify if this compound is really part of their phytochemical components or if its presence was only accidental.All the other seven families see a moderate occurrence of leucosceptoside A. For what concerns the collection areas of the studied species, no significatively restricted zone for the occurrence of this compound has been observed since its presence has been found in species collected from four continents, i.e., America, Europe, Africa and Asia.Nothing can be stated at the moment about the Oceanian situation since no work on it has been found.As for the studied organs, leucosceptoside A has shown no particular preference for a specific accumulation site having been individuated in leaves, aerial parts, tubers, roots and the whole plant even if it seems this compound prefers aerial organs.A few procedures have been used to extract this compound mainly associated with maceration processes in their different forms.Indeed, several techniques have been used for its isolation and identification, including high performing liquid chromatography relative techniques, liquid chromatography relative techniques, thin-layer chromatography relative techniques, infrared, ultraviolet and nuclear magnetic resonance spectroscopies and mass spectrometry.
In the end, it is extremely relevant to highlight that Table 1 clearly indicates how leucosceptoside A cannot be used as a chemophenetic marker at any level since it has shown no specificity and also because the families where it was found are taxonomically very distant from each other.
With respect to leucosceptoside A, leucosceptoside B proved to be less common in the plant kingdom.In fact, it has been evidenced only in six families.Its lowest occurrence was observed in the Bignoniaceae, Orobanchaceae, Plantaginaceae and Verbenaceae families with one report each, whereas the highest occurrence has been noticed in the Lamiaceae family again with seventeen reports.There is a certain parallelism between the results found for leucosceptoside A and those found for leucosceptoside B for what concerns the collection areas of the studied species, the studied organs and the methodologies adopted for their isolation and identification.Indeed, there are some important differences for what concerns the families, genera and species where their presence has been reported.In particular, leucosceptoside B has not been reported in the Acanthaceae, Compositae, Linderniaceae, Malvaceae and Oleaceae families.In addition, for what concerns the Bignoniaceae, Scrophulariaceae and Verbenaceae families, leucosceptoside B has been found in completely different species, if not genera themselves, than leucosceptoside A. For what concerns the Lamiaceae family, the reported genera and species are not generally the same as for leucosceptoside A. In particular, leucosceptoside B has not been found in the Betonica L., Caryopteris Bunge, Clerodendrum L., Galeopsis L., Lagopsis Bunge, Leonurus L., Salvia L., Scutellaria L., Sideritis L. and Volkameria L. genera.This situation prompts the need to perform more phytochemical analyses on the species for its further research, also because several singular reports have been found in the literature with the same conclusions as drawn before.
Leucosceptoside B cannot also be used as a chemophenetic marker at any level for the same reasons as presented before, even if it presents a lower occurrence than leucosceptoside A.

Leucosceptoside A
Leucosceptoside A has shown several interesting pharmacological activities.In the following lines, these activities are explored and detailed one-by-one.

Antioxidant and Radical Scavenging Activity
Leucosceptoside A proved to be a good antioxidant compound.Several studies against DPPH.+ confirm this with quite similar efficacy values.In particular, Ersöz et al. [58] obtained an IC 50 value of 76.0 µM, which is lower than ascorbic acid used as a positive control (IC 50 = 112 µM).Harput et al. [7] observed an IC 50 value of 18.43 µg/mL, which is higher than quercetin but comparable (IC 50 = 4.3 µg/mL), whereas Ono et al. [154] obtained an EC 50 value of 25.7 µM, which is very similar to that for α-tocopherol (EC 50 = 25.9 µM).Huang et al. [150] obtained an IC 50 value of 72.14 µM, which is lower than vitamin C (IC 50 = 81.83µM).Lan et al. [117] obtained an EC 50 value of 11.26 µM, which is slightly better than the positive control, ascorbic acid (EC 50 value of 12.29 µM).Indeed, Calis et al. [60] obtained an IC 50 value of 125.4 µM, which is quite higher than that of dl-α-tocopherol, used as a positive control (IC 50 = 75.5 µM).Delazar et al. [61] obtained an RC 50 of 0.0148 mg/mL, which is higher than trolox and quercetin, used as positive controls (RC 50 values of 0.00307 and 0.0000278 mg/mL), instead.Lastly, Shen et al. [13] obtained an IC 50 value of 53.32 µM, which was found to be higher than that of BHT, but no value of this latter was given.
On the other hand, Charami et al. [86] expressed the results as percentages of inhibition, which were 88.3% and 89.0% after 20 and 60 min, respectively, at the concentration of 0.1 mM, whereas the positive control acetyl salicylic, at the same concentration and times, showed a percentage of inhibition of 80.6%.Additionally, Harput et al. [54] expressed their results as percentages of inhibition and compared their results with three positive controls.In particular, the value for leucosceptoside A was 41.8% at the concentration of 200 µM, which is near to ascorbic acid and BHA (percentages of inhibition equal to 39.9 and 35.6%, respectively) but worse than chlorogenic acid (percentage of inhibition equal to 68.6%).

Radical Scavenging
Leucosceptoside A was observed to be a modest radical scavenging compound.In particular, Wang et al. [112] studied the scavenging properties of this compound with respect to superoxide anion and obtained a SC 50 of 0.294 mM, which is higher than all the other phenyl-ethanoid glycosides studied in this work.The best one was verbascoside, which presents an SC 50 value of 0.063 mM.In addition, Wang et al. [112] also studied the antioxidant potential of this compound through a luminol-enhanced chemiluminescence assay against N-formyl-methionyl-leucyl-phenylalanine in stimulated human polymorphonuclear neutrophils.The results showed that this compound is a weak inhibitor of hydroxyl radicals with a percentage of inhibition of 27.8% at the concentration of 0.55 mM and a modest iron reductor with a percentage of 17.86% at the concentration of 1.57 mM.The former value represents the lowest percentage of inhibition among all the phenyl-ethanoid glycosides considered in this study, whereas the latter value is the second worst.Verbascoside was the most active as an inhibitor of the hydroxyl radical with a percentage of 55.7% at the concentration of 0.55 mM, whereas pedicularioside M was the most active as an iron reductor with a percentage of 23.57% at the concentration of 1.73 mM.Heilmann et al. [185] also studied the radical scavenging effects of this compound in N-formyl-methionyl-leucyl-phenylalanine-stimulated human polymorphonuclear neutrophils through a luminol-enhanced chemiluminescence assay.The obtained IC 50 value was 0.18 µM, which is higher but not too far from that of quercetin used as a positive control (IC 50 value = 0.5 µM).Nevertheless, most of the other phenyl-ethanoid glycosides studied in this work showed better results than leucosceptoside A and, in particular, echinacoside was the best one with an IC 50 value of 0.03 µM.

Anti-Inflammatory Activity
Leucosceptoside A shows moderate anti-inflammatory activities with respect to NO production.In particular, Han et al. [151] obtained an IC 50 value of 9.0 µM in the Raw 264.7 cell line, whereas the positive control aminoguanidine had an IC 50 value of 10.7 µM.Vien et al. [14] obtained a different result in LPS-stimulated BV2 microglial cells using the Griess assay, with an IC 50 value of 61.1 µM, which is much higher than the positive control butein (IC 50 = 4.5 µM).In contrast, Ochi et al. [147] obtained a moderate percentage of inhibition of 40% in cell culture supernatants of LPS-stimulated RAW264.7 macrophages at the concentration of 100 µM, whereas the positive control L-NMMA presents an inhibition value of 55% at the same concentration.

Enzyme Inhibitory Activity
Leucosceptoside A has been also studied for its potential inhibitory effects on some enzymes, i.e., α-glucosidase, acetylcholinesterase, protein kinase C alpha and tyrosinase.
Concerning α-glucosidase, this compound has shown contrasting results.In fact, Liu et al. [27] obtained an IC 50 value of 0.7 mM, which is much lower than acarbose used as a positive control (IC 50 = 14.4 mM).Indeed, Thu et al. [146] obtained an IC 50 value of 273.0 µM, which is a little higher than that of acarbose (IC 50 = 204.2µM).
Leucosceptoside A also possesses between moderate and modest acetylcholinesterase inhibitory effects.In fact, Kang et al. [33] obtained an IC 50 value of 423.7 µg/mL, which is much higher than Captopril ® used as a positive control (IC 50 value of 20 nM).In addition, Saidi et al. [186] obtained an IC 50 value of 72.85 µM, which is also much higher than that of the positive control used in this study, i.e., galantamine (IC 50 value of 4.14 µM).Indeed, Li et al. [187], using the Scheffe's test, obtained an IC 50 value of 3.86 mM, which is comparable to that of Captopril ® used again as a positive control (IC 50 value of 2.11 nM).
This compound is also a modest protein kinase C alpha inhibitor with an IC 50 value of 19.0 µM.This value is good in number but, in the same study, other phenyl-ethanoid glycosides were found to be more active, such as forsythoside and verbascoside, showing IC 50 values of 4.6 and 9.3 µM, respectively [131].
In addition, this compound shows only modest tyrosinase inhibitory activities, with a percentage of inhibition of 21.65% at the concentration of 0.051 mM.Kojic acid, used as a positive control, has a percentage of inhibition of 53.87% at the concentration of 0.047 mM [188].A similar result was obtained by Saidi et al. [186], who observed a percentage of inhibition of 39.5% at the concentration of 100 µM, whereas the positive control hydroquinone has a percentage of inhibition of 72.0% at the same concentration.
Lastly, this compound has shown no effect on the hyaluronidase enzyme inhibition test and collagenase enzyme inhibition test at the concentration of 100 µg/mL [138].

Hepatoprotective Activity
At 100 µM, leucosceptoside A exerts strong hepatoprotective properties in pretreatment as obtained by studying the viability of HepG2 cells after CCl 4 intoxication, by means of an MTT assay and flow cytometry, with values of cell number and cell viability both above 80%, thus, implying a restoration of cell survival.These values are extremely good in numbers, but no standard compound was tested for comparison.The mechanism of action occurs through the inhibition of NF-kB activation since it was observed that pretreatment with this compound can inhibit CCl 4 -induced lipid peroxidation in HepG2 cells by 177.73% and attenuate the decrease in SOD by 76.58%; furthermore, pre-incubation of the same cells with this compound can prevent ROS production by 183.56% [13].

Neuroprotective Activity
Leucosceptoside A, in pretreatment, exerts good neuroprotective effects against the 1-methyl-4-phenylpyridinium ion (MPP + )-induced cell death in mesencephalic neurons of rats.MPP + is the ion produced after the biotransformation of the neurotoxin 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine by the monoamine oxidase B, and it is well known to cause Parkinson's disease in rats and non-human primates.By means of an MTT assay, it was observed that leucosceptoside A, at the concentration of 4 µM, reduces cell death by 7%, whereas at the concentration of 16 µM, it increases cell growth by 3.7%.These values are extraordinary, however, in the same study, a more efficient compound was found, i.e., pedicularioside A. In fact, at the concentration of 4 µM, this latter compound shows a reduction value of cell death by 3.4% and, at the concentration of 16 µM, it increases cell growth by 21.4% [189].

Cytoprotective Activity
Leucosceptoside A exhibits promising cytoprotective effects against t-BHP-induced toxicity in HepG2 cells with an IC 50 value of 21.1 µM.This value is lower than silymarin used as a positive control (IC 50 = 37.1 µM) [23].

Anticomplementary Activity
Leucosceptoside A exerts good anticomplementary effects with a CH 50 value of 0.23 mM, which is slightly higher than that of the standard compound heparin (CH 50 = 0.06 mM) [119].

Anti-HIV Activity
Leucosceptoside A has shown strong HIV-1 integrase inhibitory effects with an IC 50 value of 29.4 µM.This value is better than curcumin (IC 50 = 54.3 µM) and comparable to L-chicoric acid (IC 50 = 21.0 µM) used as positive controls [32].

Cytotoxic Activity
According to Argyropoulou et al. [46], leucosceptoside A exerts very modest cytotoxic effects on HeLa (human epithelial carcinoma), MCF7 (breast metastatic adenocarcinoma) and HC7-116 (colon cancer) cell lines with IC 50 values of 200, 189.08 and 182.33 µg/mL, respectively.The standard compound doxorubicin presents IC 50 values of 0.175, 0.235 and 0.096 µg/mL, respectively, whereas the other standard compound actinomycin D presents IC 50 values of 0.013, 0.022 and 0.019µg/mL, respectively.On the contrary, it showed no effect against melanoma.Saidi et al. [186] also tested the cytotoxic effects of this compound on HeLa cell lines obtaining an IC 50 = 80.87 µM as well as a positive result on the A549 (adenocarcinomic human alveolar basal epithelial cells) cancer cell line obtaining an IC 50 = 99.00µM.All these values are much higher than the standard compounds used, i.e., doxorubicin for the former cancer cell line (IC 50 = 0.36 µM) and ellipticine for the latter cancer cell line (IC 50 = 0.31 µM).Abe et al. [159] obtained promising results on Hela (GI 50 = 42 µM) and also against the B16F10 (murine melanoma) cell line with a GI 50 value equal to 28 µM and against the MK-1 (gastric carcinoma with liver metastasis) cell line with a GI 50 value equal to 33 µM.All these values are good in numbers, but some other phenyl-ethanoid glycosides studied in this work present better results in full or in part.In particular, iso-verbascoside was the most potent against B16F10 and MK-1 with GI 50 values of 10 and 32 µM, respectively, whereas arenarioside was the most potent against HeLa with a GI 50 value of 34 µM.Unlike the previous works, Saracoglu et al. [49] did not observe any effect on HeLa cells for this compound and this contrast all depends on the methodology adopted.Saracoglu et al. [49] did not observe any effect against dRLh-88 (rat hepatoma), P-388-d1 (mouse lymphoid neoplasma) and S-180 (sarcoma) cancer cell lines, too.

Inhibitory Activities
Leucosceptoside A exhibits good inhibitory effects against ADP + NADPH-induced lipid peroxidation in rat liver microsomes with an IC 50 value of 1.69 µM, which is very promising.Yet, other phenyl-ethanoid glycosides studied in this work showed better results.In particular, iso-verbascoside was the most potent with an IC 50 value of 0.38 µM [132].
This compound also exhibits inhibitory effects on the protonation of thymine radical anion induced by pulse radiolysis, which causes severe damages in cells with a reaction rate constant of electronic transfer equal to 1.54 × 10 9 dm 3 mol −1 s −1 .This value is very good in number, but without a direct comparison with any compound [190].

Antimicrobial Activities
Leucosceptoside A exerts poor antimicrobial effects against Staphylococcus aureus ATCC29213 and Enterococcus faecalis ATCC29212 with MIC values of 1000 µg/mL [60].These values are extremely high and are generally considered to be inactive.

Leucosceptoside B
Leucosceptoside B has also shown some interesting pharmacological activities, even if less numerous than leucosceptoside A. In the following lines, these activities are explored and detailed one-by-one.

Antioxidant Activity
Leucosceptoside B proved to be an antioxidant compound.Several studies, according to different assays, confirm this with opposite efficacy values.
According to the DPPH.+ assay, this compound exerts between moderate and modest effects.In fact, Niu et al. [166] obtained an IC 50 value of 31.16 µM, which is higher than ascorbic acid used as a positive control (IC 50 = 7.81 µM).In addition, Georgiev et al. [182] obtained an IC 50 value of 96 µg/mL, which is high with respect to the other phenyl-ethanoid glycosides studied in this work.In particular, this compound was found to be the weakest, whereas the most potent was forsythoside B with an IC 50 value of 21 µg/mL.Indeed, Lan et al. [117] obtained an EC 50 value of 13.05 µM, which is comparable to that of ascorbic acid (EC 50 value of 12.29 µM).Lastly, Calis et al. [60] obtained an IC 50 value of 61.3 µM, which is lower than that of dl-α-tocopherol used as a positive control (IC 50 = 75.5 µM); yet there was one phenyl-ethanoid glycosides (myricoside) that is even more potent than this (IC 50 = 46.8µM).

Radical Scavenging Activity
Through a luminol-enhanced chemiluminescence assay with formyl-methionyl-leucylphenylalanine in stimulated human polymorphonuclear neutrophils, Heilmann et al. [185] reported the radical scavenging activities of this compound with an IC 50 value of 0.17 µM, which is higher but not too far from that of quercetin used as a positive control (IC 50 value = 0.5 µM).
Indeed, Georgiev et al. [182] also studied the ORAC, HORAC, FRAP and superoxide anion activities of this compound obtaining different results.In particular, good effects were observed for the first one with a value of 16264.7 ORACFL/g, which is higher than chlorogenic acid used as a standard compound (9172.8ORACFL/g), and for the second one with a value of 3885.1 HORACFL/g, which is higher than chlorogenic acid used as a standard compound (3584.5 ORACFL/g).Conversely, poor effects were observed for the third assay with a value of absorbance of 0.602 at 700 nm, which is much lower than chlorogenic acid used as a reference compound (3.547), whereas moderate effects were observed for the last assay with an IC 50 value of approximately 45 µg/mL, which is much higher with respect to the other phenyl-ethanoid glycosides studied in this work, and in particular, of verbascoside, which was the best one (IC 50 = 4.2 µg/mL).

Anti-Inflammatory Activity
Leucosceptoside B exerts good inhibitory effects on cobra venom factor-induced alternative pathway activation in mouse sera with a percentage of inhibition of 40% and on COX-2 production with a percentage of inhibition near 30%.The positive control, indomethacin, presents a percentage of inhibition near 70%.In addition, it shows moderate inhibitory effects on NO production and IL-10 production as well as good inhibitory effects on COX-1, even if in the study, the values were not clearly expressed.Furthermore, all these values are higher than indomethacin [183].

Enzyme Inhibitory Activity
Georgiev et al. [182] studied the acetylcholinesterase and butyrylcholinesterase inhibitory activities of leucosceptoside B. In both cases, the activity is dose-dependent; however, in the former, the percentage of inhibition is almost 50% at the concentration of 100 µg/mL, whereas in the latter, the percentage of inhibition is a little above 10% at the concentration of 100 µg/mL.These values are much lower than the positive control galanthamine, which presents percentages of inhibition of 98.97 and 89.95%, respectively, at the same concentrations.
Indeed, Cespedes et al. [191] obtained a different result for the acetylcholinesterase inhibitory effects of this compound with an IC 50 value of 20.1 µg/mL, whereas galanthamine has an IC 50 value of 13.2 µg/mL.
Cespedes et al. [191] did not observe any butyrylcholinesterase inhibitory activity for leucosceptoside B.

Neuroprotective Activity
Leucosceptoside B, in pretreatment, is also able to exert strong neuroprotective effects against the 1-methyl-4-phenylpyridinium ion (MPP + )-induced cell death in mesencephalic neurons at the concentration of 40 µg/mL.The potency was measured as optical density with a value of 1.06.However, buddleoside A, another phenyl-ethanoid glycoside, was found to be much more potent with a value of 1.62 [149].

Inhibitory Activities
Leucosceptoside B has shown no human lactate dehydrogenase inhibitory activity [172].

Antimicrobial Activity
Leucosceptoside B has shown very poor antimicrobial effects against Staphylococcus aureus ATCC29213 and Enterococcus faecalis ATCC29212 with MIC values of 1000 µg/mL [60].Again, these values are extremely high and are generally considered to be inactive.
In addition, it has proven to be inactive against Escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC27853 [60].

Comparing the Biological Results of Leucosceptosides A and B
Tables 3 and 4 below summarize the biological activities and efficacy values of leucosceptoside A and leucosceptoside B, respectively.Value not reported [183] Enzyme inhibitory Acetylcholinesterase inhibition % = about 50% (at the concentration of 100 µg/mL) [182] IC 50 = 20.1 µg/mL [191] Butyrylcholinesterase Inhibition % = a little above 10% (at the concentration of 100 µg/mL) [182] No activity [191] Neuroprotective According to the data as reported in Sections 3.1 and 3.2 and Tables 3 and 4, leucosceptoside A proved to be a more important biological compound than leucosceptoside B based on the number of biological assays performed on them.In fact, leucosceptoside A has been tested for more numerous biological assays than leucosceptoside B (10 vs. 5).In particular, leucosceptoside A was also tested for its hepatoprotective, cytoprotective, cytotoxic, anticomplementary and anti-HIV activities with respect to leucosceptoside B. This minor number of assays performed on leucosceptoside B may be explained not only by its minor occurrence in the plant kingdom but also for the fact that this compound is much more difficult to isolate in pure form since its co-elution with more polar compounds than phenyl-ethanoid glycosides is extremely common.On the contrary, given the literature data results, it is not so easy to ascertain which compound is generally the most efficient.This is due to the fact that leucosceptoside A and leucosceptoside B were directly compared only in two cases.The first case regards the radical scavenging effects of these compounds in formyl-methionyl-leucyl-phenylalanine-stimulated human polymorphonuclear neutrophils through a luminol-enhanced chemiluminescence assay and showed that leucosceptoside A and leucosceptoside B basically have the same efficacy (IC 50 values of 0.18 µM vs. 0.17 µM) [185].The second case regards the DPPH.+ radical scavenging assay and showed that leucosceptoside A is slightly better than leucosceptoside B (EC 50 values of 11.26 µM vs. 13.05µM) [117].One further indirect comparison of the efficacy values of these two compounds can be made also according to the DPPH.+ radical scavenging assay; however, the relative studies led to extremely contrasting results.In fact, the IC 50 values found for leucosceptoside A were 76.0 µM [58], 18.43 µM [7], 72.14 µM [150], 125.4 µM [60] and 53.32 µM [13], whereas the IC 50 values found for leucosceptoside B were 31.16µM [166], 96.0 µM [182] and 61.3 µM [60].These discrepancies are due to several intrinsic methodological factors and are also dependent on the fact that leucosceptosides A and B were not studied together in these works.In this context, these results do not really allow to make any general conclusion on which of these compounds is the most potent.Indeed, for what concerns the rest of the biological activities, no comparison can be made since the two compounds were not studied together, different protocols were used, and the values were expressed in different unities of efficacy.These last aspects are certainly something to keep in consideration for future research in order to improve this situation.

Conclusions
This review article clearly shows how leucosceptoside A and leucosceptoside B are important compounds with regards to some aspects.In fact, they have been found in different species belonging to several families and, even though they do not possess chemophenetic significance on their own, they are also endowed with several interesting pharmacological activities including antioxidant, anti-inflammatory, enzyme inhibitory and neuroprotective.However, searching for these phytochemical components of plants is still quite limited due to the several factors.This review article also aimed to be a stimulus to amplify studies on both phytochemistry and pharmacology since there is still a lot to be discovered.

Figure 1 .
Figure 1.Structures of leucosceptoside A and leucosceptoside B.

Table 1 .
Occurrence of leucosceptoside A in the plant kingdom.

Table 1 .
Occurrence of leucosceptoside A in the plant kingdom.

Table 1 .
Cont.HPLC-UV: reversed-phase high pressure liquid chromatography coupled to ultraviolet detector; rp-MPLC: reversed-phase medium pressure liquid chromatography; rp-VLC: reversed-phase vacuum liquid chromatography; SE: solvent extraction; SER: solvent extraction under reflux; SPE = solvent extraction via percolation; sp-HPLC-PDA: semipreparative high pressure liquid chromatography coupled to photodiode array detector; sp-HPLC-UV: semipreparative high pressure liquid chromatography coupled to ultraviolet D : optical rotation; ASE = accelerated solvent extraction; CC: column chromatography; DCCC: droplet counter current chromatograph; DP: defatting procedure; ESP: procedure to eliminate sugars; FCC: flash column chromatography; FP = fraction purification; GLC: gas liquid chromatography; HP = homogenization procedure; HPLC-DAD: high pressure liquid chromatography coupled to diode array detector; HPLC-DAD-MS: high pressure liquid chromatography coupled to diode array detector and mass spectrometry; HPLC-DAD-MS n : high pressure liquid chromatography coupled to tandem mass spectrometry; HPLC-MS: high pressure low pressure liquid chromatography coupled to ultraviolet detector; MAE = microwave-assisted extraction; MPLC: medium pressure liquid chromatography; MS: mass spectrometry; NMR: nuclear magnetic resonance spectroscopy; n.a.= not accessible; n.r.= not reported; PE = percolation procedure; p-HPLC: preparative high pressure liquid chromatography; p-HPLC-RID: preparative high pressure liquid chromatography coupled to a refractive index detector; p-HPLC-UV: preparative high pressure liquid chromatography coupled to ultraviolet detector; p-LPLC-UV: preparative low pressure liquid chromatography coupled to ultraviolet detector; p-rp-HPLC-UV: preparative reversed-phase high pressure liquid chromatography coupled to ultraviolet detector; PP: partition procedure; p-TLC: preparative thin-layer chromatography; rp-CC: reversed-phase column chromatography; rp-HPLC-DAD-MS: reversed-phase high pressure liquid chromatography coupled to diode array detector and mass spectrometry; rp-

Table 2 .
Occurrence of leucosceptoside B in the plant kingdom.

Table 2 .
Cont. : optical rotation; CC: column chromatography; DP: defatting procedure; HPLC-DAD: high pressure liquid chromatography coupled to diode array detector; HPLC-DAD-MS: high pressure liquid chromatography coupled to diode array detector and mass spectrometry; HPLC-MS: high pressure liquid chromatography coupled to mass spectrometry; HPLC-PAD: high pressure liquid chromatography coupled to pulsed amperometry detector; HPLC-PAD-MS: high pressure liquid chromatography coupled to pulsed amperometry detector and mass spectrometry; HPLC-UV: high pressure liquid chromatography coupled to ultraviolet detector; HPLC-UV- D MS: high pressure liquid chromatography coupled to ultraviolet detector and mass spectrometry; HSE: hot solvent extraction; HSCCC = high-performance countercurrent chromatography; IR: infrared spectroscopy; LC-MS: liquid chromatography coupled to mass spectrometry; LC-UV: liquid chromatography coupled to ultraviolet detector; LPLC-UV: preparative low pressure liquid chromatography coupled to ultraviolet detector; MPLC: medium pressure liquid chromatography; NMR: nuclear magnetic resonance spectroscopy; MS: mass spectrometry; p-HPLC-UV: preparative high pressure liquid chromatography coupled to ultraviolet detector; PP: partition procedure; rp-CC: reversed-phase column chromatography; rp-HPLC-UV: reversed-phase high pressure liquid chromatography coupled to ultraviolet detector; rp-MPLC: reversed-phase medium pressure liquid chromatography; SE: solvent extraction; SER: solvent extraction under reflux; sp-HPLC-UV: semipreparative high pressure liquid chromatography coupled to ultraviolet detector; sp-rp-HPLC-UV: semipreparative reversed-phase high pressure liquid chromatography coupled to ultraviolet detector; TLC: thin-layer chromatography; UV: ultraviolet spectroscopy; VLC: vacuum liquid chromatography.

Table 3 .
Summary of the biological activities and efficacy values of leucosceptoside A.

Table 4 .
Summary of the biological activities and efficacy values of leucosceptoside B.