- Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4
-
A number of furanocoumarins isolated from grapefruit juice have been found to inhibit CYP3A4 activity in vitro. In this study, we have designed and synthesised a range of analogues based on bergamottin to investigate the relationship between chemical stru
- Row,Brown,Stachulski,Lennard
-
-
Read Online
- Interaction of 7-Alkoxycoumarins with the Aryl Hydrocarbon Receptor
-
The aryl hydrocarbon receptor (AhR) is a transcription factor activated by a vast array of natural and synthetic ligands. It plays a pivotal role in numerous physiological and pathological responses, such as cell proliferation and differentiation, induction of xenobiotic metabolizing enzymes, response to environmental toxins, and several others. In this study, we investigated the ability of some natural compounds (oxyprenylated ferulic acid and umbelliferone derivatives) and their semisynthetic analogues (e.g., differently substituted 7-Alkoxycoumarins) to activate AhR, using a reporter luciferase assay. Among them, we found that 7-isopentenyloxycoumarin was the best AhR activator. Boropinic acid, 7-but-2′-enyloxycoumarin, 7-(2′,2′-dimethyl-n-propyloxy)coumarin, 7-benzyloxycoumarin, and 7-(3′-hydroxymethyl-3′-methylallyloxy)coumarin were also active, although to a lesser extent. All the compounds were also analyzed for their ability to inhibit AhR activation, using a reference ligand, 6-formylindolo[3,2-b]carbazole. Data recorded in the present investigation pointed out the importance of a 3,3-dimethylallyloxy side chain attached to the coumarin ring core as a key moiety for AhR activation.
- Gargaro, Marco,Epifano, Francesco,Fiorito, Serena,Taddeo, Vito Alessandro,Genovese, Salvatore,Pirro, Matteo,Turco, Antonella,Puccetti, Paolo,Schmidt-Weber, Carsten B.,Fallarino, Francesca
-
-
Read Online
- Novel squalene-hopene cyclase inhibitors derived from hydroxycoumarins and hydroxyacetophenones
-
Squalene-hopene cyclase (SHC) is a useful model enzyme for predicting molecular interactions with oxidosqualene cyclase (OSC). Structure-activity relationships were investigated for numerous coumarin-derived inhibitors of SHC, and structural simplificatio
- Cravotto, Giancarlo,Balliano, Gianni,Tagliapietra, Silvia,Oliaro-Bosso, Simonetta,Nano, Gian Mario
-
-
Read Online
- Combined molecular modeling and cholinesterase inhibition studies on some natural and semisynthetic O-alkylcoumarin derivatives
-
Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 μM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC50 = 46.58 ± 0.91 μM). In fact, 10 of the active coumarins showed higher inhibition (IC50 = 7.01 ± 0.28 μM – 43.31 ± 3.63 μM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC50 = 7.01 ± 0.28 μM) and 7-isopentenyloxy-4-methylcoumarin (IC50 = 8.18 ± 0.74 μM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies.
- Orhan, Ilkay Erdogan,Senol Deniz, F. Sezer,Salmas, Ramin Ekhteiari,Durdagi, Serdar,Epifano, Francesco,Genovese, Salvatore,Fiorito, Serena
-
-
Read Online
- Synthesis and biological evaluation of isoprenylated coumarins as potential anti-pancreatic cancer agents
-
A series of isoprenylated coumarins has been designed, synthesized, and evaluated against human pancreatic adenocarcinoma cell line PANC-1 under nutrient-rich and nutrient-deprived conditions. The compounds described investigate the effect of isoprenyl chain length and positioning on cell growth inhibition. The majority of these compounds displayed cytotoxicity against PANC-1 cells selectively in the absence of essential amino acids, glucose, and serum, and showed no cytotoxicity under nutrient-rich conditions. In this study, compound 6 exhibited the highest cytotoxic activity with an LC50value of 4 μM and induced apoptosis-like morphological changes in PANC-1 cells after a 24-h incubation. The evaluated structure-activity relationships show that substitution at the 6-position and the presence of a farnesyl isoprenyl tail are important structural features for enhanced preferential cytotoxicity. These findings provide important information to designing other structural analogues for potential application as novel pancreatic antitumor agents.
- Jun, Maria,Bacay, Alyssa F.,Moyer, James,Webb, Andrew,Carrico-Moniz, Dora
-
-
Read Online
- Structure-activity relationship of natural and synthetic coumarins inhibiting the multidrug transporter P-glycoprotein
-
A set of 32 natural and synthetic coumarins were tested in order to evaluate their activity on human leukemic cells (K562/R7) overexpressing P-glycoprotein (P-gp). Their ability to reduce the P-gp-mediated drug efflux of daunorubicin out of cells was eval
- Raad, Imad,Terreux, Raphael,Richomme, Pascal,Matera, Eva-Laure,Dumontet, Charles,Raynaud, Jean,Guilet, David
-
-
Read Online
- Collection of alkenylcoumarin derivatives as Taq DNA polymerase inhibitors: SAR and in silico simulations
-
Using a feasible method, we generated a small focused library of structurally related alkenylcoumarins. These compounds were evaluated as potential antitumoral agents against Taq DNA polymerase. 6-(pent-4-enyloxy)-coumarin (7) IC50 = 48.33 ± 2.85 μM was defined as a small molecule able to disturb DNA replication. Docking and Molecular Dynamic Simulations suggest an active-site binding. Structure/activity relationship was reasonably established. Compound 7 represents a potential structure for further studies in the development of new anti-cancer DNA/polymerase binding agents.
- Bruna-Haupt, Ezequiel,Garro, Hugo A.,Gutiérrez, Lucas,Pungitore, Carlos R.
-
-
Read Online
- Investigation of the cytotoxicity of bioinspired coumarin analogues towards human breast cancer cells
-
Abstract: Coumarins possess a wide array of therapeutic capabilities, but often with unclear mechanism of action. We tested a small library of 18 coumarin derivatives against human invasive breast ductal carcinoma cells with the capacity of each compound to inhibit cell proliferation scored, and the most potent coumarin analogues selected for further studies. Interestingly, the presence of two prenyloxy groups (5,7-diprenyloxy-4-methyl-coumarin, 4g) or the presence of octyloxy substituent (coumarin 4d) was found to increase the potency of compounds in breast cancer cells, but not against healthy human fibroblasts. The activity of potent compounds on breast cancer cells cultured more similarly to the conditions of the tumour microenvironment was also investigated, and increased toxicity was observed. Results suggest that tested coumarin derivatives could potentially reduce the growth of tumour mass. Moreover, their use as (combination) therapy in cancer treatment might have the potential of causing limited side effects. Graphic abstract: [Figure not available: see fulltext.].
- Gkionis, Leonidas,Kavetsou, Eleni,Kalospyros, Alexandros,Manousakis, Dimitris,Garzon Sanz, Miguel,Butterworth, Sam,Detsi, Anastasia,Tirella, Annalisa
-
-
Read Online
- Visible-Light-Induced Direct Csp2-H Radical Trifluoroethylation of Coumarins with 1,1,1-Trifluoro-2-iodoethane (CF3CH2I)
-
Herein, we developed the first visible-light-induced direct Csp2-H radical 2,2,2-trifluoroethylation of coumarins with commercially available and cheap reagent CF3CH2I at room temperature. This transformation proceeded smoothly under mild conditions and showed excellent functional group compatibility. The synthetic value of the protocol was also demonstrated by the successful functionalization of several pharmaceuticals.
- Chen, Xiaoyu,Li, Linlin,Pei, Congcong,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
-
p. 2772 - 2783
(2021/02/27)
-
- Enzymatic O-Prenylation of Diverse Phenolic Compounds by a Permissive O-Prenyltransferase from the Medicinal Mushroom Antrodia camphorata
-
Prenylated compounds are pharmacologically attractive natural products that are widely distributed in nature. Prenyltransferases (PTs) could catalyze the transfer of prenyl moieties to aromatic acceptors and increase the structural diversity and biological activity of natural products. In this work, a permissive O-prenyltransferase AcaPT was discovered from Antrodia camphorata, a precious medicinal mushroom in Taiwan. AcaPT exhibited robust O-prenylation capability toward structurally diverse drug-like phenolic compounds, including antrodins, flavonoids, and coumarins. In total, 23 O-prenylated products were obtained by scaled-up enzymatic synthesis. AcaPT could be used as an efficient biocatalyst to synthesize O-prenylated derivatives for drug discovery. (Figure presented.).
- He, Junbin,Hu, Zhimin,Dong, Zeyuan,Li, Bin,Chen, Kuan,Shang, Zhanpeng,Zhang, Meng,Qiao, Xue,Ye, Min
-
supporting information
p. 528 - 532
(2019/12/24)
-
- Design, synthesis and biological evaluation of O-alkyl umbelliferone derivatives as pancreatic lipase inhibitors
-
A series of coumarin derivatives were synthesised through O-alkylation of umbelliferone. These derivatives were screened for their pancreatic lipase (PL) inhibitory potential. The PL inhibitory effect of compounds with various benzyl and long chain alkyl substituents on umbelliferone were analysed. The compound 1g, having the geranyl substituent was found to have better PL inhibitory potential with an IC50 of 21.64 M. The compounds 1a-j were subjected to molecular docking into the crystal structure of human PL. The molecular docking results are in correlation with the in vitro PL inhibition activity, wherein compound 1g showed a higher MolDock score of -122.12 kcal/mol. The long chain alkyl groups were found to have PL inhibition due to additional interactions with lid domain amino acids (Phe215, Tyr114, Phe77), as revealed by molecular docking study.
- Yadav, Nisha,Auti, Prashant,George, Ginson,Paul, Atish T.
-
p. 1265 - 1271
(2020/12/04)
-
- Natural and semisynthetic oxyprenylated aromatic compounds as stimulators or inhibitors of melanogenesis
-
It has been very recently shown how naturally occurring oxyprenylated coumarins are effective modulators of melanogenesis. In this short communication we wish to generalize the potentialities as skin tanning or whitening agents of a wider panel of natural and semisynthetic aromatic compounds, including coumarins, cinnamic and benzoic acids, cinnamaldehydes, benzaldehyde, and anthraquinone derivatives. A total number of 43 compounds have been tested assaying their capacity to inhibit or stimulate melanin biosynthesis in cultured murine Melan A cells. The wider number of chemicals herein under investigation allowed to depict a detailed structure-activity relationship, as the following: (a) benzoic acid derivatives are slightly pigmenting agent, for which the effect is more pronounced in compounds with longer O-side chains; (b) independently from the type of substitution, cinnamic acids are able to increase melanin biosynthesis, while benzaldehydes are able to decrease it; (c) coumarins with a 3,3-dimethylallyl or shorter skeletons as substituents in position 7 are tanning agents, while coumarins with farnesyloxy groups are whitening ones; (d) double oxyprenylation in position 6 and 7 and 3,3-dimethylallyl or geranyl skeletons have slight depigmenting capacities, while farnesyl skeletons tend to marginally increase the tanning effect; (e) the presence of electron withdrawing groups (acetyl, COOH, and -Cl) and geranyl or farnesyl oxyprenylated chains respectively in positions 3 and 7 of the coumarin nucleus lead to a whitening effect, and finally (f) oxyprenylated anthraquinones have only a weak depigmenting capacity.
- Genovese, Salvatore,Epifano, Francesco,Medina, Philippe de,Caron, Nicolas,Rives, Arnaud,Poirot, Marc,Poirot, Sandrine Silvent,Fiorito, Serena
-
p. 181 - 190
(2019/03/23)
-
- Natural oxyprenylated coumarins are modulators of melanogenesis
-
Naturally occurring coumarins 7-isopentenyloxycoumarin, auraptene, and umbelliprenin are able to modulate the biosynthesis of melanin in murine Melan-a cells probably through the interaction with selected biological targets like estrogen receptor β and aryl hydrocarbon receptor. Such a modulation strictly depends on the individual structure of the coumarin: the presence of a 3,3-dimethylallyloxy side chain is a structural determinant for tanning activation whereas a farnesyl one leads to the opposite effect. The parent compound with a free OH group, umbelliferone, did not provide any interaction. Other coumarins assayed, having shorter chains and/or being substituted in other positions, and prenyloxypsoralens, were not active or not further investigated in this context being cytotoxic at low doses.
- Fiorito, Serena,Epifano, Francesco,Preziuso, Francesca,Cacciatore, Ivana,di Stefano, Antonio,Taddeo, Vito Alessandro,de Medina, Philippe,Genovese, Salvatore
-
p. 274 - 282
(2018/05/14)
-
- Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor
-
The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC50 value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5- methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC50 values 25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.
- Marumoto, Shinsuke,Miyazawa, Mitsuo
-
supporting information; experimental part
p. 784 - 788
(2012/03/22)
-
- Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors
-
All of the mono isopentenyloxy, -geranyloxy and -farnesyloxy derivatives of coumarin were synthesized and their inhibitory potency against soybean 15-lipoxygenase (SLO) and human 15-lipoxygenase-1 (HLO-1) were determined. Amongst the synthetic analogs, 5-farnesyloxycoumarin showed the most potent inhibitory activity against SLO (IC50 = 0.8 μM) while 6-farnesyloxycoumarin was the strongest HLO-1 inhibitor (IC50 = 1.3 μM). The IC50 variations of the farnesyl derivatives for HLO-1 (1.3 to ~75 μM) were much higher than that observed for SLO (0.8-5.8 μM). SAR studies showed that hydrogen bonding, CH/π, anion-π and S-OC interactions with FeIII-OH, Leu408, Glu357 and Met419 were the distinct intermolecular interactions which can lead to important role of the coumarin substitution site in HLO-1 inhibitory potency, respectively.
- Iranshahi, Mehrdad,Jabbari, Atena,Orafaie, Ala,Mehri, Robabeh,Zeraatkar, Soudabeh,Ahmadi, Taraneh,Alimardani, Maliheh,Sadeghian, Hamid
-
p. 134 - 142
(2013/01/15)
-
- Pancreatic anticancer activity of a novel geranylgeranylated coumarin derivative
-
A series of hydroxycoumarin derivatives has been synthesized and evaluated against human pancreatic PANC-1 cancer cells under nutrient-deprived conditions. Several compounds exhibited 100% preferential cytotoxicity at low micromolar concentrations under n
- Devji, Tehsina,Reddy, Claire,Woo, Christina,Awale, Suresh,Kadota, Shigetoshi,Carrico-Moniz, Dora
-
experimental part
p. 5770 - 5773
(2011/10/18)
-
- Enzyme activity fingerprinting with substrate cocktails
-
In the postgenomic era, emphasis is shifting from protein identification to protein functional analysis. Enzyme function can be characterized by measuring activity across series of substrates, which generates an activity profile or fingerprint. Activity f
- Goddard, Jean-Philippe,Reymond, Jean-Louis
-
p. 11116 - 11117
(2007/10/03)
-
- Mitsunobu coupling of 7-hydroxycoumarins with allylic and propargylic alcohols: A facile direct access to tertiary allyl coumarinyl ethers
-
Allylic and propargylic alcohols are coupled with 7-hydroxycoumarins under Mitsunobu conditions using diethyl azodicarboxylate (DEAD) and triphenylphosphine to afford the corresponding coumarinyl ethers without any rearrangement in good-to-acceptable yields. This route provides direct access to the 1,1-dimethylallyloxycoumarins which are key intermediates for the Claisen rearrangement-based synthesis of linear and angular coumarins.
- Ganguly, Nemai C.,Sukai, Arun K.,Dutta, Sanjoy,De, Prithwiraj
-
p. 380 - 382
(2007/10/03)
-
- Synthesis of 3-(1,1-Dimethylallyl)xanthyletin, 3-(1,1-Dimethylallyl)-8-(3,3-dimethylallyl)xanthyletin, Gravelliferone and dl-Chalepin
-
The synthesis of title compounds has been achieved from the key intermediate 3-(1,1-dimethylallyl)-7-hydroxycoumarin (7) which, in turn, is obtained by triple Claisen rearrangement of 7-(3,3-dimethylallyl)oxycoumarin (2) using butyric anhydride as the trapping reagent.
- Sharma, R. B.,Kapil, R. S.
-
p. 538 - 541
(2007/10/02)
-