Limonoids From the Genus Melia (Meliaceae): Phytochemistry, Synthesis, Bioactivities, Pharmacokinetics, and Toxicology

Abstract

Limonoids, as the vital bioactive chemical compounds in genus Melia plants, have attracted significant attention owing to their exclusive structural characteristics and remarkable biological activity. These compounds can be usually classified into two categories, including the ring-intact group and the ring-C-seco group. Benefiting from the development of separation and analysis technology, more than 200 limonoids have been isolated and identified from this genus. There is growing evidence that limonoids from genus Melia possess diverse pharmacological activities, especially anti-cancer effects, insecticidal activities, and anti-botulism effects. Toosendanin, one of the paramount limonoids, was considered as the pivotal bioactive marker in two medicinal herbs, including Melia toosendan Sieb. et Zucc and Melia azedarach L. In particular, limonoids are found to exhibit non-negligible toxic effects, a finding which needs further research. Besides this, the lack of clinical research data seriously hinders its further development and utilization, and necessary clinical trials should be taken into consideration. In this review, we systematically summarized the phytochemical compounds and their synthesis methods, pharmacological activities, and the structure–activity relationship, pharmacokinetics, and toxicology of genus Melia-derived limonoids. We believe that this up-to-date review could provide scientific evidence for the application of limonoids as agents beneficial to health in future clinical practice.

Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview

“…Toosendanin is a natural insecticide that has been shown in lung cancer models to switch EMT markers expression via ERK/Snail signaling pathway [ 96 ].…”

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

“…Toosendanin (TSN) ( 75 ), a natural trichilin-type limonoid triterpenoid congener (Figure ) found in the bark of Melia toosendan Sieb et Zucc in the 1950s, has an ascarifuge effect. Its first isolation and structural elucidation occurred in 1975, and its chemical structure was corrected in 1980. − TSN is considered a potential lead compound for the development of anticancer, antibotulism, anti-inflammatory, and insecticide drugs . TSN was reported to effectively block STAT3 by directly binding to its SH2 domain, which suppressed osteosarcoma growth and metastasis in a mouse model .…”

“…129−131 TSN is considered a potential lead compound for the development of anticancer, antibotulism, anti-inflammatory, and insecticide drugs. 132 TSN was reported to effectively block STAT3 by directly binding to its SH2 domain, which suppressed osteosarcoma growth and metastasis in a mouse model. 133 Subsequently, a series of PROTACs derived from TSN as the STAT3 ligand and bound to the CRBN recruiter thalidomide via a linker were designed and synthesized.…”

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

“…Limonoids are highly oxygenated triterpenoids, and over 300 limonin analogs have been isolated from natural sources with various therapeutic effects [ 1 , 2 ]. Limonin ( Figure 1 a) is representative of those compounds, and is the most abundant limonoid in the natural environment.…”

“…Moreover, limonin was gradually metabolized after entering the blood, and the elimination half-life was short [ 22 , 24 , 26 ]. Currently, research on the structure–activity relationship and pharmacological effects of limonin analogues is very in-depth [ 1 , 5 ], but there are few studies on their pharmacokinetics, and it is not clear whether the structural modifications ameliorate their pharmacokinetic profiles. Pharmacokinetic studies of HY-071085 in experimental animals are essential for the further development of HY-071085.…”