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Furan ring of limoninoids is critical in exhibiting insecticidal activity. Herein, fraxinellone (1) was used as a template of furan-containing natural products and a series of its derivatives was synthesized by selective bromination in good yields on gram-scale and following Suzuki-Miyaura or Sonogashira coupling reactions in moderate to good yield...
Citations
... Furans have wide applications in pharmaceuticals because of their biological activities. The furan derivatives showed interesting biological activity in many bio-based products such as antioxidant [11], anti-inflammatory [12], antibacterial [13], antiviral [14], insecticidal [15], and antifungal [16] properties. They are considered the green substituents to replace fossilbased fuels and materials [17]. ...
The applications of lignocellulosic wastes to produce a wide variety of products, including biochemicals, biomaterials, and biofuels, can be an effective solution for utilizing these valuable waste materials. In this study, the production of furan building blocks from bagasse fibers was investigated by treating unbleached fibers with NMMO, [Bmim]Cl, and TMAH at different temperatures using AlCl3 and CrCl2 as the catalysts. The resulted liquors were extracted with CH2Cl2 to obtain furan rich fraction. Analysis of extracted fractions with GC/MS indicates the production of various furanic compounds due to catalytic solvolysis with different solvents at elevated temperatures. 2(3H)-Furanone and 2-methyl-THF were the main products of catalytic treatment of bagasse fibers with NMMO. Treatment by [Bmim]Cl resulted in 2,5-dihydro furanone as the dominant product at elevated temperatures. Furan carboxylic acid methyl ester and 2,5-furan dicarboxylic acid dimethyl ester were the main TMAH reaction products with unbleached fibers. The results indicate that the type of solvent affects the solvolysis rate and dehydration of cellulose to furanic compounds. Moreover, increasing the temperature led to an increase in the formation of the furanic compounds.
Graphical abstract
... Molecules 2020, 25, 1109 2 of 9 remains with few modifications. Recently, the modification of aromatic (furan ring) functionalities was reported by us [19,20]. A series of C-ring selective brominations and further palladium-catalyzed transformations analogues of fraxinellone have been prepared. ...
... To our delight, some compounds displayed more potent insecticidal activity than toosendanin. On the basis of the above furan-modified results and in our endeavor aiming at finding more active natural-product-based insecticidal hits [19,[21][22][23][24], herein, we semi-synthesized C-ring cyclopropyl analogues of fraxinellone by Rh(II)-catalyzed cyclopropanation as insecticidal agents against M. separata. ...
... Many malformed moths of the treated groups appeared with imperfect wings during the emergence period (Figure 3b), implying that these analogues might have affected the insect molting hormone [31,32]. These symptoms in the three different periods tested by compounds were consistent with those of fraxinellone funan ring-coupling analogues [19]. This demonstrated that inserting the clopropyl group on C-ring of fraxinellone resulted in more promising analogues. ...
Fraxinellone (1) is a naturally occurring degraded limonoid isolated from Meliaceae and Rutaceae plants. As a potential natural-product-based insecticidal agent, fraxinellone has been structurally modified to improve its activity. Furan ring of fraxinellone is critical in exhibiting its insecticidal activity, but with few modifications. Herein, C-ring-modified cyclopropyl analogues were semi-synthesized by Rh(II)-catalyzed cyclopropanation. The structures of the target compounds were well characterized by NMR and HRMS. The precise three-dimensional structural information of 3a was established by X-ray crystallography. Their insecticidal activity was evaluated against Mythimna separata Walker by a leaf-dipping method. Compound 3c exhibited stronger insecticidal activity than 1 and toosendanin against M. separata with teratogenic symptoms during the different periods, implying that cyclopropanation of the furan ring could strengthen the insecticidal activity of fraxinellone.
... Recently, we reported the bromination of fraxinellone by N-bromosuccinimide (NBS, as a brominating reagent) and Br 2 (as a catalyst) or by 1,3-dibromo-5,5dimethylhy-dantoin (DBDMH, another brominating reagent) and following couplings, and found some furan-site modified derivatives displayed more potent insecticidal activity than toosendanin [36]. In our endeavor aiming at finding more active natural product-based insecticidal hits [36,37,38,39,40], herein we prepared a series of furan-site transformed derivatives of obacunone (1) by selectively altering furan ring (Fig. 2). ...
... Recently, we reported the bromination of fraxinellone by N-bromosuccinimide (NBS, as a brominating reagent) and Br 2 (as a catalyst) or by 1,3-dibromo-5,5dimethylhy-dantoin (DBDMH, another brominating reagent) and following couplings, and found some furan-site modified derivatives displayed more potent insecticidal activity than toosendanin [36]. In our endeavor aiming at finding more active natural product-based insecticidal hits [36,37,38,39,40], herein we prepared a series of furan-site transformed derivatives of obacunone (1) by selectively altering furan ring (Fig. 2). Besides, their insecticidal activity were tested against M. separata Walker. ...
... However, treatment with 0.5 eq DBDMH gave the mixture of at least three components containing monobromination 2 (21%), dibromination 3 (<5%) and recovered 1 (21%). When NBS or NBS with catalytic Br 2 was carried out this reaction, no product was obtained (data not shown), which was different from previous studies on fraxinellone [36], indicating that DBDMH is more suitable for the furan-site bromination of obacunone. Consequently, 3 was prepared in gram-scale with 1.4 eq DBDMH in 58% yield in Fig. 3. ...
Furan ring is a key pharmacophore for insecticidal activity of limoninoids. To develop natural-product-based insecticidal agents, a series of furan-site transformations (2, 3 and 3a–j) of obacunone were synthesized by selective bromination and following coupling reactions without altering other functional groups. Bioassays indicated that derivatives 3e, 3f and 3j displayed more potent insecticidal activity than obacunone and toosendanin against the instar larvae of Mythimna separate Walker. Besides, their structure–activity relationships were discussed.
The rate constants of the Diels-Alder reaction of 2,5-dimethylfuran (1) with N -phenylmaleimide (2) in 5 solvents in the range of temperature 25-45°C and pressure 1-1000 bar have been determined. Activation enthalpy, entropy, Gibbs free energy and volume parameters have been calculated. The equilibrium constants of the 1 + 2 reaction in benzene in the temperature range 25-55°C have been determined, and the reaction enthalpy and entropy have been calculated.
Phytochemical studies on the roots, twigs and leaves of Meliaceae and Rutaceae family plants have revealed the presence of non-complex terpenes derived from limonoid fragmentation. The occurrence and chemical structure of these degraded limonoids isolated from 1930 to March 2022 are reported in this review. Particular attention is given to the degradation levels in these compounds and their absolute configuration to discover presumable deconstruction pathways from more complex limonoids. Plausible intermediates have been postulated for most of them that would explain their origin from limonoids. The total or semi-synthesis of the most isolated degraded limonoids or analogues remains undescribed. This review focuses on the bioactivity of these fragmented limonoids and their synthesized analogues. Based on pharmacological and agrochemical studies, degraded limonoids appear to be excellent structural leads to consider for the total or semi-synthesis of more potent derivatives with the aim of discovering new hits and clarifying their modes of action.
The pharmacological activities of dictamnine and fraxinellone have been well reported; however, only a few studies have focused on the pharmacokinetics and bioavailability of concomitant delivery of these drugs in vivo. To shed light on this neglected area, we developed a rapid and sensitive UPLC-MS/MS method that quantified the levels of dictamnine and fraxinellone simultaneously in rat plasma. This method was initiated by a one-step protein precipitation strategy to purify plasma samples collected from rats treated with either oral or intravenous administration of dictamnine and fraxinellone. The mobile phase contained acetonitrile and 0.1% formic acid at a steady flow rate of 0.6 mL/min. As a result, an excellent analyte peak resolution was achieved, and the entire process took only 3 min per sample. The results were indicative of the desired linearity (r2 ≥ 0.999), precision (RSD% was within 15%), accuracy (RE% was within 15%), recoveries (≥80.66 and 68.15% for dictamnine and fraxinellone, respectively) and matrix effects (≥94.66 and 91.37% for dictamnine and fraxinellone, respectively). Additionally, the detectable limits of these two compounds were both low even when they reached 5 ng/mL. Taken together, these findings contribute to a better understanding of the pharmacokinetics and bioavailability properties of concomitant delivery of dictamnine and fraxinellone.
Fraxinellone (FRA) is a degraded limonoid isolated from the root bark of Dictamnus plants. The potent insecticidal activity of FRA has led to the synthesis of numerous derivatives (presented here with the structure-activity relationships) active against the oriental armyworm Mythimna separata Walker. In addition to its pesticidal activity, the natural product displays potent anti-inflammatory and immuno-modulatory effects at the origin of hepatoprotective and anticancer properties. This mini-review provides an update of the mechanism of action of FRA to highlight the recently discovered capacity of the compound to deactivate cancer-associated fibroblasts and thus to limit the immunosuppressive tumor microenvironment. The anticancer mode of action of FRA raises new ideas to better understand its primary insecticidal activity. The relationship between drug-induced cancer cell death and insect cell death is discussed. A drug interaction with the insect cytokine growth-blocking peptide (GBP), a member of the large EGF family, is proposed, supported by preliminary molecular modeling data. Altogether, the review shed light on the pharmacological properties of fraxinellone as an antitumor agent and a natural insecticide.
