Mechanism of the Vasodilator Effect of Mono-oxygenated Xanthones: A Structure-Activity Relationship Study

Abstract

The present study characterized the mechanisms involved in the vasodilator effect of two mono-oxygenated xanthones, 4-hydroxyxanthone and 4-methoxyxanthone. 9-Xanthenone, the base structure of xanthones, was used for comparison. 4-Hydroxyxanthone and 9-xanthenone induced a concentration-dependent and endothelium-independent vasodilator effect in arteries precontracted with phenylephrine (0.1 µmol · L-1) or KCl (50 mmol · L-1). 4-Methoxyxanthone induced a concentration-dependent vasodilator effect in arteries precontracted with phenylephrine, which was partially endothelium-dependent, and involved production of nitric oxide. In endothelium-denuded arteries precontracted with KCl, the vasodilator effect of 4-methoxyxanthone was abolished. The vasodilator effect of 4-hydroxyxanthone (96.22 ± 2.10 %) and 4-methoxyxanthone (96.57 ± 12.40 %) was significantly higher than observed with 9-xanthenone (53.63 ± 8.31 %). The presence of an oxygenated radical in position 4 made 4-hydroxyxanthone (pIC50 = 4.45 ± 0.07) and 4-methoxyxanthone (pIC50 = 5.04 ± 0.09) more potent as a vasodilator than 9-xanthenone (pIC50 = 3.92 ± 0.16). In addition, 4-methoxyxanthone was more potent than the other two xanthones. Ca2+ transients in vascular smooth muscle cells elicited by high K+ were abolished by 4-hydroxyxanthone and 9-xanthenone. The endothelium-independent effect of 4-methoxyxanthone was abolished by inhibition of K+ channels by tetraethylammonium. The current work shows that an oxygenated group in position 4 is essential to achieve Emax and to increase the potency of xanthones as vasodilators. Substitution of an OH by OCH3 in position 4 increases the potency of the vasodilator effect and changes the underling mechanism of action from the blockade of L-type calcium channels to an increase in NO production and activation of K+ channels.

Silver/Scandium-Cocatalyzed Bicyclization of β-Alkynyl Ketones Leading to Benzo[c]xanthenes and Naphtho[1,2-b]benzofurans

“…In a valuable class of oxygen-containing molecular families, xanthenes are common constituents in a broad array of natural products, synthetic bioactive substances, and fluorescent dyes . Compounds incorporating a xanthene core structure exhibit a wide range of biological and pharmacological activities including antiviral, antibacterial, antiplasmodial, antimalarial, antifungal, anti-inflammatory, anticancer, and antihypertensive and also act as trypanothione reductase inhibitior . With these contributions in mind, many chemists have contributed their efforts to develop efficient incorporation of xanthene unit into organic and medicinal targets.…”

Insight into and Computational Studies of the Selective Synthesis of 6H-Dibenzo[b,h]xanthenes

“…9 H -Xanthene [ 1 (Figure )] is a general class of natural and synthetic heterocyclic compounds − with many biological applications in addition to functionality as fluorescent dyes . In the biological field, these heterocyclic compounds exhibit a broad spectrum of activities, including trypanothione reductase inhibiting, antiviral, antibacterial, , antiplasmodial, , antimalarial, antifungal, anti-inflammatory, anticancer, − and antihypertensive activity, and are used in photodynamic therapy . Because of their biological properties, 9 H -xanthene derivatives have been prepared by several procedures. − …”

Experimental and DFT Studies on the FT‐IR, NMR and UV/Vis Spectra of a Xanthene Derivative: The Case of 9‐benzoyl‐3,4,5,6,7,9‐hexahydro‐1h‐xanthene‐1,8(2h)‐dione

“…Nowadays, they also found other comprehensive applications in different areas such as laser dyes, catalysts in organic synthesis, pH‐sensitive fluorescent materials and so on . The broad range of pharmaceutical and biological properties of such compounds encouraged several research groups to study their convenient medicinal properties . Xanthene derivatives can be synthesized by diverse procedures which are suffering from the use of toxic solvents, low efficiency, the requirement of special apparatus, high temperatures and high cost .…”

“…[23,27] In this work, the previously synthesized 9-benzoyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione was used as a practical organic compound to explore the applicability of different chemical theories in exploring experimental results. In this respect, IR, 1 H-NMR, 13 C-NMR and UV/Vis spectra of the title compound were measured experimentally and calculated using the high-level quantum density functional theory (DFT) methods. Furthermore, LSER method was implemented to study the observed bathochromic shift of the UV/Vis spectra at different solvents including water, ethanol, acetonitrile and nhexane.…”