Theoretical study of global and local reactivities of coumarin and its hydroxylated derivatives

Abstract

Coumarins are bioactive substances of the benzo‐α‐pyrone family, which have shown antioxidant, antiviral, anti‐inflammatory and antitumor activities, among others. 7‐Hydroxycoumarin and 6,7‐dihydroxycoumarin (esculetin) are two coumarin derivatives that have been reported to exhibit antitumor activity, but the action mechanism underlying this activity remains unknown. In this work, to elucidate this mechanism, a theoretical study of the local and global electronic reactivity properties of a series of hydroxylated and dihydroxylated coumarin derivatives with possible antitumor action is performed using Density Functional Theory in aqueous solution. The substitution by one or two hydroxyl groups in the benzene ring of coumarin produces better charge‐donor than charge‐acceptor compounds. All the studied compounds are generally stable in water and exhibit permanent polarization in the solvent. With one hydroxyl substitution, 7‐hydroxycoumarin is the most polar and polarizable derivative, whereas 5,7‐dihydroxycoumarin is the most polar and polarizable compound with two hydroxyl substitutions. 5,7‐Dihydroxycoumarin is suggested to possess antitumor activity. © 2016 Wiley Periodicals, Inc.

Global reactivity indexes and nonparametric statistics in the study of the proapoptotic activity of coumarins

“…Regarding the structure‐activity correlation of coumarins, the research group is interested in regressing the structure of natural and synthetic coumarin derivatives with antitumor activity. In a previous work, a detailed study through density functional theory (DFT) methods of the electronic environment within these heterocycles led to establish the local and global reactivity of several hydroxycoumarins which are therapeutic agents against several types of cancer . The results showed, as expected, that the presence of hydroxyl groups—which are good electron donor groups—in the benzene ring have an impact in the electron rich system through an electronic delocalization; this is due to the electron withdrawing effect of the pyrone system yielding strongly polarizable systems.…”

“…In this context, it is important to demonstrate the role of the electronic environment provided by the hydroxyl substituents in the proapoptotic activity of these derivatives through the correlation of the calculated DFT [32] global reactivity parameters implemented in a previous work. [31] In this work, the experimental antileukemic activity reported by Riveiro et al is used to build a generalized logistic additive regression statistical model which correlated calculated DFT global reactivity indexes with the proapoptotic activity of structurally similar coumarins in the U-937 cellular line. [15] Consequently, it is important to gain some insight about the action mechanism in order to perform a rational design of possible anticancer agents.…”

Esculetin: A review of its pharmacology and pharmacokinetics

“…Esculetin was shown by various studies to have anticancer properties (Kostova, 2005;Melendez et al, 2016;Pinto & Silva, 2017;Sharma, Thulasingam, Chellappan, Chinnaswamy, & Nagarajan, 2017), which might be associated with apoptosis-inducing (Figure 4) and inhibitory activities in association with cancer cell proliferation (Figure 5).…”

Synergy, Additivity and Antagonism between Esculetin and Six Commonly Used Chemotherapeutics in Various Malignant Melanoma Cell Lines—An Isobolographic Analysis

“…Esculetin is considered a potential drug candidate in the treatment of diabetes and its complications, atherosclerosis, atopic dermatitis, and as an anticoagulant [9][10][11]. Esculetin exhibits dual regulation of apoptosis, including anti-apoptotic activity (associated with antioxidant and anti-inflammatory effects) [8,9], and inducing apoptosis, inhibiting the proliferation of cancer cells, which is associated with the great potential of this compound as an anticancer drug [12,13].…”