529-84-0Relevant articles and documents
Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment
Xia, Yang-Liu,Wang, Jing-Jing,Li, Shi-Yang,Liu, Yong,Gonzalez, Frank J.,Wang, Ping,Ge, Guang-Bo
, (2020/11/25)
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.
Mannich bases of hydroxycoumarins: Synthesis, DFT/QTAIM computational study and assessment of biological activity
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
, p. 31260 - 31271 (2021/11/30)
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
Biotransformation of 4-methylcoumarins by cambial meristematic cells of Camptotheca acuminata
Zhang, Yuhua,Jiang, Jiayi,Qin, Ningbo,Zhang, Qian,Yan, Chunyan
, p. 9449 - 9456 (2019/04/01)
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.
