482-82-6Relevant articles and documents
Dissociation Constants and Solubilities of Dalbergin and Nordalbergin in Different Solvents
Kong, Wanjun,Sun, Rui,Gao, Yanjuan,Nan, Guanjun,Yang, Guangde,Li, Yiping
, p. 2585 - 2593 (2015)
The dissociation constants (pKa) of dalbergin and nordalbergin were measured at 298.2 K using ultraviolet (UV) spectroscopy method. The solubilities of dalbergin and nordalbergin in water, methanol, propanone, ethyl ethanoate, trichloromethane, and hexane have been determined by the UV spectrophotometric method from 283.2 to 308.2 K at atmospheric pressure. The experimental solubility values were correlated with a modified Apelblat equation, λh model, and ideal model. The pKa value of dalbergin is 8.91 ± 0.12, and the pKa1 and pKa2 values of nordalbergin are 7.31 ± 0.29 and 9.79 ± 0.39, respectively. The solubilities of dalbergin and nordalbergin in six solvents increase with an increase in temperature. The solubility order of dalbergin in six pure solvents was trichloromethane > propanone > ethyl ethanoate > methanol > hexane > water, whereas that of nordalbergin was propanone > methanol > ethyl ethanoate > trichloromethane > water > hexane. A comparison of the solubility of dalbergin with that of nordalbergin shows that the 7-methoxyl moiety of dalbergin leads to a significantly higher solubility in trichloromethane and hexane, a little higher solubility in ethyl ethanoate, an approximately equal solubility in propanone, and a little lower solubility in methanol and water (exception 283.2 K). For dalbergin, the modified Apelblat equation shows the best correlation for all solvents, and for nordalbergin, correlation results by three models are similar.
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.
Design, synthesis and biological evaluation of esculetin derivatives as anti-tumour agents
Wang,Xia,Yu, Yang,Lu, Jun-Xia,Zou, Li-Wei,Feng, Lei,Ge, Guang-Bo,Yang, Ling
, p. 53477 - 53483 (2015/06/30)
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.
