- Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment
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Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (Ki = 0.21 ± 0.02 μM, IC50 = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.
- Xia, Yang-Liu,Wang, Jing-Jing,Li, Shi-Yang,Liu, Yong,Gonzalez, Frank J.,Wang, Ping,Ge, Guang-Bo
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- Antagonistic activity of hydroxycoumarin-based antioxidants as possible singlet oxygen precursor photosensitizers
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Coumarins are phenolic-type compounds with efficient antioxidant activity due to their ability to scavenge reactive oxygen species. Nevertheless, their ability to behave as photosensitizers capable of generating reactive oxygen species, such as singlet oxygen, has been less studied. In this work, the photosensitizing ability of seven hydroxycoumarins was evaluated through the photooxidation of ergosterol by quantifying the conversion of ergosterol into ergosterol peroxide. In our experimental conditions, we found that almost every tested antioxidant coumarin promotes the peroxidation of ergosterol. The results suggest that the hydroxycoumarins exhibit potential photosensitizing activity by promoting singlet oxygen generation by a Type II photochemical mechanism. Density functional theory (DFT) calculations were also performed to obtain further insight into the chemical reactivity of tested compounds; the observed tendency in the group of antioxidant coumarins to promote the reaction was their hardness due to the principle of maximum hardness. To evaluate our conclusion, we performed the reaction using a highly polarizable coumarin as a photosensitizer, which resulted in an increased photosensitizing capacity supported with DFT calculations, which reinforces our analysis. Finally, we found that hydroxycoumarins can be potentially pro-oxidants since some of them can act as photosensitizers and generate singlet oxygen in the presence of UV–Vis light, a characteristic that must be considered when these compounds are used as antioxidants.
- Guerrero, Tomás,Vázquez-Ortega, Fernanda,Lagunes, Irene,Ortiz-Blanco, Erik,Sosa-Ortiz, Gabriela,Tovar-Miranda, Ricardo,Medina, Manuel E.,Trigos, ángel
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- Mannich bases of hydroxycoumarins: Synthesis, DFT/QTAIM computational study and assessment of biological activity
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The synthesis of six Mannich bases derived from hydroxycoumarins was carried out in moderate yields, two of these derivatives were described for the first time. Conformational analysis was performed through DFT theoretical calculations explaining the formation of stable six membered rings based on intramolecular hydrogen bonds within the structure. These findings were correlated with the antiproliferative activity. The biological activity of the Mannich bases through their antiproliferative activity in the HeLa cancer cell line is described for the first time, showing that the compounds were able to inhibit proliferation in cervical cancer by more than 60%. Likewise, the theoretical modeling of the photophysical properties was realized with promising results, showing that the HOMO-LUMO energies of the new compounds present the lowest electronic gap values for those with donor groups in their structure, which makes them potential fluorophores. This journal is
- Castro, María Eugenia,Durand-Niconoff, J. Sergio,Fernández-Pomares, Cynthia,Guerrero, Tomás,Juárez-Aguilar, Enrique,Melendez, Francisco J.,Montoya-Hernández, Eva Luz,Olivares-Romero, José L.,Ortiz-Blanco, Erik,Sosa-Ortiz, Gabriela,Tovar-Miranda, Ricardo
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p. 31260 - 31271
(2021/11/30)
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- Study of the Oxidative Cleavage Proposed in the Biogenesis of Transtaganolides/Basiliolides: Pyran-2-one Aromaticity-Mediated Regioselective Control and Biogenetic Implications
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The synthetic feasibility of the oxidative cleavage: epoxidation of 7-O-geranylscopoletin followed by electrocyclic ring-opening, proposed in the biogenesis of transtaganolides/basiliolides is studied. Unlike the proposed pericyclic reactions, this pathway has not yet been addressed. Three synthetic strategies have been tested consisting of: i) Baeyer–Villiger oxidation of p-quinoids, ii) hydrolysis of quinone monoketals, or iii) direct fragmentation by using oxygen donors. Oxidation of the benzene ring of hydroxylated coumarins has been achieved using peroxyacids, but cleavage took place between undesired positions. The aromaticity conservation of the pyran-2-one cycle during oxidation is the controlling factor of these observed regioselectivities. The use of a 4,5-dihydroxy-2-methoxycinnamate model, in which the pyran-2-one ring does not exert influence on oxidation, has allowed the design of a synthetic sequence toward an analogue of the natural pyran-2-one isolated from Thapsia transtagana, key in the biogenesis. Mechanistic proposals for the obtained results as well as their biogenetic implications are raised.
- álvarez, José María,Jorge, Zacarías D.,Massanet, Guillermo M.
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supporting information
(2020/03/05)
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- Biotransformation of 4-methylcoumarins by cambial meristematic cells of Camptotheca acuminata
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Cambial meristematic cell (CMC) suspension cultures were investigated as a new biotransformation system for the first time. Four 4-methylcoumarins substrates were transformed by CMCs of Camptotheca acuminata into four corresponding products, including 4,8-dimethylcoumarin-7-O-β-d-glucopyranoside (I-1), 4,7-dimethylcoumarin-6-O-β-d-glucopyranoside (II-1), 6-hydroxy-7-methoxyl-4- methylcoumarin (III-1), and 4,7-dimethylcoumarin-5-O-β-d-glucopyranoside (IV-1), of which I-1, II-1, and IV-1 were new compounds. In addition, the biotransformation time and the amount of substrate were investigated to compare the biotransformation rate and optimize the biotransformation conditions of the four substrates in C. acuminata CMCs suspension cultures. The results suggested C. acuminata CMCs were able to select glycosylate phenolic hydroxyl groups of 4-methylcoumarins I, II, and IV, with high regio- and stereoselectivity, but no corresponding glycoside of any phenolic hydroxyl group of compound III was detected. Simultaneously, the result also showed that the C. acuminata CMCs were able to transform the 7-hydroxy groups of substrate III to its corresponding methylated products. Furthermore, the monoamine oxidase (MAO) inhibition activities of biotransformed products were evaluated, and the data showed that all the products possessed good MAO inhibition activities in vitro. In conclusion, C. acuminata CMCs could be applied to glycosylation biotransformation as a novel plant-based system due to the successful application of bioconversion of exogenous coumarins.
- Zhang, Yuhua,Jiang, Jiayi,Qin, Ningbo,Zhang, Qian,Yan, Chunyan
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p. 9449 - 9456
(2019/04/01)
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- Design, synthesis and biological evaluation of esculetin derivatives as anti-tumour agents
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Esculetin, a naturally catecholic coumarin, possess multiple pharmacological activities including anti-tumour, anti-inflammatory and anti-oxidant. However, the extensive phase II metabolism and rapid elimination from the human body significantly hinder esculetin and its derivatives as drug leads/candidates. To improve both the metabolic stability and the anti-tumour activity of esculetin via rational modification, a series of C-4 and C-8 substituted derivatives were designed and synthesized by perchloric acid catalysed von Pechmann reaction and Mannich reaction, respectively. The in vitro metabolic half-life in human liver S9 and anti-tumour activities in A549 and B16 cell lines of the newly synthesized compounds were assayed. Of these compounds, 8-(pyrrolidin-1-ylmethyl)-4-trifluoromethyl esculetin 15 was the most potent candidate compound, with almost a 20-fold increase in antiproliferative activity and a 3-fold prolonged half-life in human liver S9 compared with the parent compound 1. In addition, the potential structure-activity relationship and structure-metabolic stability relationship were discussed. Notably, the introduction of a nitrogen containing group as a hydrogen bond acceptor at the C-8 position of esculetin can improve both the metabolic stability and anti-tumour activity. All of these findings are very helpful for the structural modification of esculetin and other bioactive phenolic compounds to improve their phase II metabolic stability and bioactivity synchronously.
- Wang,Xia,Yu, Yang,Lu, Jun-Xia,Zou, Li-Wei,Feng, Lei,Ge, Guang-Bo,Yang, Ling
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p. 53477 - 53483
(2015/06/30)
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- A selective turn-on fluorescent sensor for sulfur mustard simulants
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A fluorescent turn-on sensor for the selective and sensitive detection of sulfur mustard simulants in water that uses a metal-ion indicator displacement assay (IDA) has been devised. In this IDA approach, a sulfur mustard simulant (the analyte) is allowed to react with a dithiol (1) to form a podand (2). This podand has a strong affinity to bind with Cd2+ and displaces an indicator (4-methylesculetin, ME) from a Cd2+-indicator complex (8) to give a turn-on of fluorescence. The detection is rapid and highly selective, as we did not observe any interference from other electrophiles, even from the oxygen analogue of the mustard simulant. The protocol was successfully used for the detection of the simulant present on surfaces and in soil samples.
- Kumar, Vinod,Anslyn, Eric V.
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p. 6338 - 6344
(2013/06/04)
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- Novel Fe3+-based 1H MRI β-galactosidase reporter molecules
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There is increasing interest in the development of reporter agents to reveal enzyme activity in vivo using imaging in small animals. We have previously demonstrated the feasibility of detecting lacZ gene activity using the commercially available 3,4-cyclohexenoesculetin-β-D-galactopyranoside (S-Gal) as a 1H MRI reporter. Specifically, β-galactosidase (β-gal) releases the aglycone, which forms a magnetic resonance contrast-inducing paramagnetic precipitate in the presence of Fe3+. Contrast was primarily T2-weighted signal loss, but T1 effects were also observed. Since T1-contrast generally provides signal enhancement as opposed to loss, it appeared attractive to explore whether analogues could be generated with enhanced characteristics. We now report the design and synthesis of novel analogues together with characterization of 1H MRI contrast based on both T1 and T2 response to b-gal activity in vitro for the lead agent.
- Yu, Jian-Xin,Gulaka, Praveen K.,Liu, Li,Kodibagkar, Vikram D.,Mason, Ralph P.
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p. 370 - 378
(2014/01/17)
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- Establishing a flow process to coumarin-8-carbaldehydes as important synthetic scaffolds
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Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe here a high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up, giving access to multigram quantities of the aldehyde product. Aldehyde on tap: Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8- carbaldehydes are lacking. A high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up is described, giving access to multigram quantities of aldehyde product (see scheme). Copyright
- Zak, Jaroslav,Ron, David,Riva, Elena,Harding, Heather P.,Cross, Benedict C. S.,Baxendale, Ian R.
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supporting information; experimental part
p. 9901 - 9910
(2012/09/07)
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- Hydroxycoumarin derivatives: Novel and potent α-glucosidase inhibitors
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A novel class of hydroxycoumarin derivatives were found to be potent α-glucosidase inhibitors. Their syntheses were reported and the structure-activity relationship was established. Kinetic enzymatic assays indicated that compound 10 was a slow-binding and noncompetitive inhibitor with a Ki value of 589 nM, while compound 11 was a competitive inhibitor with a Ki value of 4.810 μM. Among all hydroxycoumarin derivatives studied, compounds 10 and 11 exhibited the highest activities, were specific inhibitors of α-glucosidase, and could be exploited as the lead compounds for the development of potent α-glucosidase inhibitors. Compounds 10 and 11 were also selected for further discussion for the mechanism of enzymatic inhibition.
- Shen, Qiong,Shao, Jialiang,Peng, Quan,Zhang, Wanjin,Ma, Lin,Chan, Albert S. C.,Gu, Lianquan
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supporting information; experimental part
p. 8252 - 8259
(2011/02/23)
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- H3PW12O40 catalyzed efficient synthesis of 4-substituted coumarins
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Phosphotungstic acid is commercially available and environmentally benign catalyst to promote the Pechmann condensation of various phenols with β-Ketoesters afford 4-substituted coumarins 3a-g in very good yields. This method is practical and provides several advantages.
- Raju, B. China,Babu, T. Hari,Rao, J. Madhusudana
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experimental part
p. 120 - 123
(2009/12/03)
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- Novel dioxin analogues and methods and kits for searching out dioxins-decomposing organisms or emzymes or dioxin-decoposing enzyme genes
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The present invention provides a novel dioxin analogue for use in the search for organisms capable of degrading dioxin. The dioxin analogue is represented by the following chemical formula (1) or (2):
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- Selective methylation of coumarins and naphthoquinones using dimethyl sulfoxide
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On UV irradiation, coumarins 1-6 and 1,4-naphthoquinones 7-11 with dimethyl sulfoxide in tertiary butyl alcohol under nitrogen atmosphere give corresponding 4-methylcoumarins 12-17 and 2-methyl-1,4-naphthoquinones 18-22 selectively in a single step facile reaction with good yields.
- Thapliyal, Prakash Chander
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p. 726 - 727
(2007/10/03)
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- Montmorillonite clay as condensing agent in Pechmann reaction for the synthesis of coumarin derivatives
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Montrmorillonite clay has been found to be an effective condensing agent in Pechmann reaction for the synthesis of coumarin derivatives
- Biswas, G K,Basu, K,Barua, A K,Bhattacharyya, P
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- A New Deprotection Method for Levulinyl Protecting Groups under Neutral Conditions
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Sulfit ion-induced cleavage of the levulinyl group under neutral conditions provides a convenient and mild deprotection method especially for alkali labile and/or oxygen sensitive compounds.
- Ono, Mitsunori,Itoh, Isamu
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p. 585 - 588
(2007/10/02)
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- Complexes of Cu(II) with Some Biologically Active Dihydroxycoumarins
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Complexes of Cu(II) with hydroxycoumarins, viz. esculetin, daphnetin and their 4-methyl and 4-phenyl derivatives have been prepared.The general composition of the complexes is .The water molecules are replaced on reaction with pyridine or ammonia to give complexes of the type (where X = NH3 or C5H5N).IR studies show that more acidic of the two phenolic hydroxyl groups present at C-7 in the ligand is involved in complexation in the parent complexes.Thermal studies on the parent complexes indicate the formation of two intermediate compounds which correspond to the compositions and but only one intermediate, , is formed on heating the pyridine or ammonia adducts.
- Singh, H. B.,Negi, R. K.,Srivastava, Smita
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p. 1026 - 1028
(2007/10/02)
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