Clausarin

alpha-Glucosidase and Nitric Oxide Inhibitory Activities of Pyranocoumarins and Carbazoles From the Roots of Clausena excavata and the Semisynthetic Analogs of Clausarin and Nordentatin.[Pubmed:40720625]

Chem Biodivers. 2025 Nov;22(11):e00510.

Phytochemical investigation of the methanol extract of Clausena excavata roots led to the isolation of six pyranocoumarin derivatives, including xanthyletin (1), kinocoumarin (2), Clausarin (3), nordentatin (4), dentatin (4a), and citrusarin A (5), and three carbazole alkaloids, that is, heptaphylline (6), 7-methoxymukonal (7), and clausine K (8). Seven new semisynthetic analogs of compounds 2, 3, and 4 (2a, 3b-3d, and 4b-4d) were prepared through methylation, etherification, and basic hydrolysis for biological assays. Compounds 2, 6, 3b, 3c, 4b, and 4c displayed stronger alpha-glucosidase inhibitory activity than the positive control, acarbose (IC(50) 391.47 microM), with IC(50) values in the range of 32.89-92.55 microM. Molecular docking suggested that these compounds bind near the enzyme's active site via van der Waals forces, hydrogen bonds, and hydrophobic interactions. Compound 3 showed the strongest nitric oxide (NO) inhibitory activity (IC(50) = 27.95 microM), followed by 3d (IC(50) = 33.62 microM) and 4 (IC(50) = 35.41 microM). For the two compounds tested for cytotoxicity against A549 cells, 3b (IC(50) = 11.71 microM) was more potent than cisplatin (IC(50) = 21.56 microM), whereas 4b (IC(50) = 22.39 microM) showed similar activity to cisplatin. Drug-likeness and pharmacokinetic properties of the isolated and semisynthetic compounds were also evaluated.

alpha-Glucosidase Inhibitory Activity of Prenylated Pyranocoumarins from Clausena excavata: Mechanism of Action, ADMET and Molecular Docking.[Pubmed:38923383]

Chem Biodivers. 2024 Sep;21(9):e202401141.

Three naturally occurring prenylated pyranocoumarins, nordentatin (1), dentatin (2), and Clausarin (3), isolated from the roots of Clausena excavata (Family Rutaceae), and O-methylClausarin (4) which was obtained by methylation of 3, were investigated for their alpha-glucosidase inhibitory activity. The mechanism of action and the in silico prediction of their physicochemical and ADMET properties as well as the molecular docking were also studied. Compounds 1-4 exhibited stronger alpha-glucosidase inhibitory activity than the positive control, acarbose, through a non-competitive mechanism. Among them, 3 exhibited the highest activity, with an IC(50) of 8.36 muM, which is significantly stronger than that of acarbose (IC(50)=430.35 muM). The prenyl group on C-3 and the hydroxyl group on C-5 in 3 may play important roles in enhancing the activity. Calculated physicochemical and ADMET parameters of 1-4 satisfied the Lipinski's and Veber's rules. Molecular simulation analysis indicated they are promising drug candidates with no hepatotoxicity. Compound 3 exhibited potent activity in the experiment and demonstrated good drug properties based on the calculations. A molecular docking study revealed that 3 showed H-bonding and pi-pi stacking interactions with selective Phe321, as well as interactions with thirteen other amino acid residues of the alpha-glucosidase.

Bioassay-Guided Isolation and Identification of Antiplasmodial Compounds from the Stem Bark of Clausena excavata.[Pubmed:37414059]

Planta Med. 2023 Oct;89(12):1165-1169.

Clausena excavata is a medicinal plant widely distributed in Southeast Asia. It is used for a variety of indications, including to treat malaria. In our present study, a phytochemical study of the methanol extract from the stem bark of C. excavata led to the isolation of five pyranocoumarins, nordentatin (1: ), dentatin (2: ), kinocoumarin (3: ), Clausarin (4: ), and clausenidin (5: ), and a coumarin, 8-hydroxy-3'',4''-dihydrocapnolactone-2',3'-diol (6: ). The isolation of compound 6: from C. excavata and the antiplasmodial activities against a multidrug-resistant K1 strain of Plasmodium falciparum of 1, 3: , and 5: were reported for the first time. Compounds 3: and 4: exhibited potent antiplasmodial activities with EC(50) values of 1.10 and 0.58 microM, respectively, while 1: and 5: had EC(50) values of 5.62 and 7.15 microM, respectively. A prenyl group attached to the C-3 or C-12 position on the pyranocoumarin ring probably plays an important role on the activity. A hydroxyl group at the C-10 position is also likely to enhance the activity.

Cytotoxicity and Apoptosis Induction of Coumarins and Carbazole Alkaloids from Clausena harmandiana.[Pubmed:31540345]

Molecules. 2019 Sep 18;24(18):3385.

Seven compounds, carbazole alkaloids (heptaphylline, 7-methoxyheptaphylline, 7-methoxymukonal) and coumarins (Clausarin, dentatin, nordentatin, and xanthoxyletin), were isolated from the root bark of Clausena harmandiana. Antioxidation, cytotoxicity and apoptosis induction were evaluated in vitro. Results showed that Clausarin exerted the highest DPPH radical scavenging and 7-methoxymukonal had the highest ferric reducing antioxidant power. In contrary, dentatin was the least DPPH radical scavenger, and heptaphylline was the least reducing antioxidant power. The isolated compounds showed different cytotoxicity. The hepatocellular carcinoma (HepG2) was generally more sensitive to the isolated compounds than lung cancer (SK-LU-1), colon cancer (HCT-116), and noncancerous (Vero) cell lines, respectively. Clausarin possessed the highest cytotoxicity selectively against cancer cell lines tested. 7-Methoxymukonal and 7-methoxyheptaphylline exhibited less cytotoxicity only in HepG2 cells and were inactive in the SK-LU-1 and HCT116 cells. Despite xantoxyletin possessing low antioxidant and low cytotoxic activity, it induced the highest apoptosis percentage with the lowest necrosis percentage of HepG2 cells after 24 h. In conclusion, xantoxyletin primarily show potential anticancer activity. The root bark of C. harmandiana is a good source of bioactive compounds or the lead for the development of new pharmaceutical agent.

Anti-HBV and cytotoxic activities of pyranocoumarin derivatives.[Pubmed:19635670]

Bioorg Med Chem. 2009 Aug 15;17(16):6137-43.

Four natural pyranocoumarins clausenidin (1), nordentatin (2), Clausarin (3), and xanthoxyletin (4) were isolated from the medicinal plant Clausena excavata. Recently, we found that 1 and 2 suppressed hepatitis B virus surface antigen in HepA2 cells, and in addition, 1-3 showed cytotoxic activity against four human cancer cell lines (A549, MCF7, KB, and KB-VIN). To explore the SAR of 1-4, 17 pyranocoumarin analogues (5-21) were designed and synthesized. Among these analogues, 5 and 10 were the most potent against hepatitis B virus with EC(50) values of 1.14 and 1.34microM, respectively. The most interesting result in the cytotoxicity assay was the significant activity of 1, 5, and 6 against the multi-drug resistant cell line, KB-VIN, without activity against the KB cell line. These data suggest that these three compounds could be useful hits for developing MDR-inverse drugs.

Modulation of P-glycoprotein activity by acridones and coumarins from Citrus sinensis.[Pubmed:17236173]

Phytother Res. 2007 Apr;21(4):386-90.

Bioguided fractionation of the roots of Citrus sinensis (Rutaceae) led to the isolation and identification of five coumarins, namely, Clausarin, suberosin, poncitrin, xanthyletin and thamnosmonin, seven acridones, namely, acrimarine B, 2-methoxycitpressine I, citpressine I, buntanine, acrimarine E, honyumine and acrimarine C, and one terpenoid, namely, limonin. Among these compounds, Clausarin, 2-methoxycitpressine I and acrimarine E inhibited P-glycoprotein-mediated drug efflux in K562/R7 human leukemic cells over-expressing P-glycoprotein.

Antiproliferative effect of isopentenylated coumarins on several cancer cell lines.[Pubmed:11497276]

Anticancer Res. 2001 May-Jun;21(3B):1905-11.

33 coumarins, mainly the simple isopentenylated coumarins and derived pyrano- and furanocoumarins, were examined for their antiproliferative activity towards several cancer and normal human cell lines. The pyrano- and furanocoumarins showed strong activity against the cancer cell lines, whereas they had weak antiproliferative activity against the normal human cell lines. The decreasing rank order of potency was osthenone (10), Clausarin (25), clausenidin (26), dentatin (24), nordentatin (23), imperatorin (29), seselin (27), xanthyletin (21), suberosin (17), phebalosin (8) and osthol (12). The structure-activity relationship established from the results revealed that the 1,1-dimethylallyl and isopentenyl groups have an important role for antiproliferative activity.

Coumarins and carbazoles with antiplasmodial activity from Clausena harmandiana.[Pubmed:10821058]

Planta Med. 2000 Apr;66(3):277-9.

Activity guided fractionation of extracts from Clausena harmandiana have led to the identification of four known compounds, heptaphylline (1), clausine K (2), dentatin (5), and Clausarin (6). All these compounds, except clausine K (2), exhibited antiplasmodial activity against Plasmodium falciparum. While the new dimethylated derivative 4, derived from 2, showed no antiplasmodial activity, the monomethylated product 3 (clausine H) exhibited activity comparable to that observed for compounds 1 and 5.

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