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Review
. 2016 Nov 13;21(11):1530.
doi: 10.3390/molecules21111530.

The Chemistry and Pharmacology of Citrus Limonoids

Roberta Gualdani  1 , Maria Maddalena Cavalluzzi  2 , Giovanni Lentini  3 , Solomon Habtemariam  4
Affiliations
Review

The Chemistry and Pharmacology of Citrus Limonoids

Roberta Gualdani et al. Molecules. .

Abstract

Citrus limonoids (CLs) are a group of highly oxygenated terpenoid secondary metabolites found mostly in the seeds, fruits and peel tissues of citrus fruits such as lemons, limes, oranges, pumellos, grapefruits, bergamots, and mandarins. Represented by limonin, the aglycones and glycosides of CLs have shown to display numerous pharmacological activities including anticancer, antimicrobial, antioxidant, antidiabetic and insecticidal among others. In this review, the chemistry and pharmacology of CLs are systematically scrutinised through the use of medicinal chemistry tools and structure-activity relationship approach. Synthetic derivatives and other structurally-related limonoids from other sources are include in the analysis. With the focus on literature in the past decade, the chemical classification of CLs, their physico-chemical properties as drugs, their biosynthesis and enzymatic modifications, possible ways of enhancing their biological activities through structural modifications, their ligand efficiency metrics and systematic graphical radar plot analysis to assess their developability as drugs are among those discussed in detail.

Keywords: anticancer; antidiabetic; antiinflammatory; antimicrobial; antioxidant; citrus limonoids; developability; insecticidal; lead compound; ligand efficiency metrics; structure-activity relationships; tetranortriterpenoids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of citrus limonoids (CLs) of the limonin (1) biosynthetic group (aglycones and corresponding β-d-glucosides) studied in the stated period (2005–2016).
Figure 1
Figure 1
Structures of citrus limonoids (CLs) of the limonin (1) biosynthetic group (aglycones and corresponding β-d-glucosides) studied in the stated period (2005–2016).
Figure 2
Figure 2
Structures of reference compounds for citrus limonoids (CLs).
Figure 3
Figure 3
Precursors of citrus limonoids and proposed biogenetic relationships between congeners of the limonin (1) group.
Figure 4
Figure 4
Structures of limonoic acid (31) and limondiol (32).
Figure 5
Figure 5
Radar plot of ligand efficiency metrics as a graphical tool to assess developability of limonin (1) as a drug. Sub-optimal property space corresponds to the inner red hexagon showing sides marked with “zero”. Ideally, good lead compounds would be represented by areas wider than this inner hexagon. This spider plot indicates the properties of 1 that need improvement. Legend: Fsp3: fraction sp3; LRI: heterocycles/carbocycles ratio; PEI: potency efficiency index; LE: ligand efficiency; LLE: lipophilic ligand efficiency; LELP: ligand efficiency dependent lipophilicity; see text for details.
Figure 6
Figure 6
Semisynthetic analogs of limonin (1); and nomilin (2) endowed with anti-aromatase (33–36) [46]; and anti-biofilm (33–35) [63] properties.
Figure 7
Figure 7
Water-soluble analogs of limonin (1); and deoxylimonin (10) endowed with analgesic and anti-inflammatory properties [45].
Figure 8
Figure 8
Radar plot of ligand efficiency metrics as a graphical tool to assess developability of limonin (1, purple area) and nomilin (2, blue-green area) as drugs. Sub-optimal property space corresponds to the inner hexagon showing red sides marked with “zero”. Ideally, good lead compounds would be represented by areas wider than this inner hexagon. This spider plot indicates that 1 should be preferred to 2 as a lead compound. Legend: Fsp3: fraction sp3; LRI: heterocycles/carbocycles ratio; PEI: potency efficiency index; LE: ligand efficiency; LLE: lipophilic ligand efficiency; LELP: ligand efficiency dependent lipophilicity; see text for details.
Figure 9
Figure 9
Radar plot of ligand efficiency metrics (LEM) as a graphical tool to assess developability of limonin (1, blue area) and obacunone (3, yellow area) as anticancer agents. Sub-optimal property space corresponds to the inner hexagon showing red sides marked with “zero”. Ideally, good lead compounds would be represented by areas wider than this inner hexagon. This spider plot indicates that 1 should be preferred to 3 as a lead compound. Legend: Fsp3: fraction sp3; LRI: heterocycles/carbocycles ratio; PEI: potency efficiency index; LE: ligand efficiency; LLE: lipophilic ligand efficiency; LELP: ligand efficiency dependent lipophilicity; see text for details.
Figure 10
Figure 10
Structures of obacunone oxime (39) and two of its ester derivatives (40,41) endowed with high larvicidal activity [80].
Figure 11
Figure 11
Radar plot of ligand efficiency metrics (LEM) as a graphical tool to assess developability of limonin (1, blue area) and limonexic acid (5, magenta area) as anticancer agents. Sub-optimal property space corresponds to the inner hexagon showing red sides marked with “zero”. Ideally, good lead compounds would be represented by areas wider than this inner hexagon. This spider plot indicates that 5 should be preferred to 1 as a lead compound. Legend: Fsp3: fraction sp3; LRI: heterocycles/carbocycles ratio; PEI: potency efficiency index; LE: ligand efficiency; LLE: lipophilic ligand efficiency; LELP: ligand efficiency dependent lipophilicity; see text for details.
Figure 12
Figure 12
Formation of limonin (1) and its epimer epilimonin (41) from limonin 17β-d-glucopiranoside (11) via a furan-3-ylidene cationic intermediate (42); Glc = β-d-glucopyranosyl.
Figure 13
Figure 13
Structures of two new pseudoacids isolated from Citrus sudachi.
Figure 14
Figure 14
Structures of ichanexic acid (45) and isolimonic acid (46).
Figure 15
Figure 15
Structures of limonoate A-ring lactone (LARL, 47) and nomilinoate A-ring lactone (NARL, 48).
Figure 16
Figure 16
Structures of limonoid glucosides isolated from C. species through recently developed methodologies.
Figure 17
Figure 17
Structures of limonin (1); and obacunone (3) metabolites identified in liver microsomes.
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