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.

https://www.mdpi.com/1420-3049/21/11/1530/pdf/1

The Chemistry and Pharmacology of Citrus Limonoids

Aphanamixoid A, a Potent Defensive Limonoid, with a New Carbon Skeleton from Aphanamixis polystachya

Five new limonoids, named munronoids K-O (1-5), together with three known limonoids were isolated from Munronia unifoliola Oliv. These limonoids were involved in the skeletons of evodulone, gedunin, and peieurianin types of limonoids, and their structures were established on the basis of spectroscopic data. Compound 5 featuring a γ-lactone ring instead of the β-substituted furan ring was found in the peieurianin type for the first time. The antitobacco mosaic virus (anti-TMV) activities of compounds 1-8 were also evaluated with half-leaf, enzyme-linked immunosorbent assay, and Western blot methods, and limonoids 1, 5, and 8 showed stronger anti-TMV treatment activities than the positive control ningnanmycin. Six compounds (1-5 and 8) exhibited infection inhibition activities against TMV.

The limonoids and their antitobacco mosaic virus (TMV) activities from Munronia unifoliolata Oliv.

This review covers the isolation and structure determination of limonoids reported during 2014–2016 (with 363 new compounds in 68 papers), together with the relevant biological activities and source organisms. Furthermore, the total synthesis and structural modifications of limonoids and their analogs regarding the bioactivities reported during 2011–2016 have also been summarised.

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Recent progress in the chemistry and biology of limonoids

A novel limonoid, perforanoid A, was isolated, and an asymmetric total synthesis was achieved in 10 steps. The key steps are chiral tertiary aminonaphthol mediated enantioselective alkenylation of an aldehyde to an allylic alcohol, Pd-catalyzed coupling of the allylic alcohol with vinyl ether to form the γ-lactone ring, and cyclopentenone ring formation through a Rh-catalyzed Pauson-Khand reaction. Preliminary studies show that perforanoid A is cytotoxic towards HEL, K562, and CB3 tumor cell lines.

Isolation and Asymmetric Total Synthesis of Perforanoid A.

The Meliaceae family is rich sources of limonoid (meliacin), which are well know for their antifeedant activity and bitterness. Although their existence also could be found in Rutaceae, Cneoraceae, Ptaeroxylaceae, and Simaroubaceae family, they are especially abundant and structurally diversified in the Meliaceae family. Structurally, they are highly oxygenated and modified nortriterpenoids either containing or derived from a precursor with a 4,4,8-trimethyl-17-furanylsteroid skeleton. Nearly three decades ago, Taylor divided so far found three hundreds of the meliacins from the Meliaceae family into protolimonoids and nine classes of limonoids based on which of the four triterpenoid skeleton rings have been oxidatively opened. From then on, much progress has been made on the field. Up to very recently, approximately 1300 limonoids, exhibiting more than 35 different carbon frameworks have been observed from the four families.

Y. T. Di

Papers

The Advances in the Limonoid Chemistry of the Meliaceae Family