Inhibition of protein kinase C by synthetic xanthone derivatives

The modulatory activity of two xanthones (3,4-dihydroxyxanthone and 1-formyl-4-hydroxy-3-methoxyxanthone) on isoforms alpha, betaI, delta, eta and zeta of protein kinase C (PKC) was evaluated using an in vivo yeast phenotypic assay. Both xanthones caused an effect compatible with PKC inhibition, similar to that elicited by known PKC inhibitors (chelerythrine and NPC 15437). PKC inhibition caused by xanthones was confirmed using an in vitro kinase assay. The yeast phenotypic assay revealed that xanthones present differences on their potency towards the distinct PKC isoforms tested. It is concluded that 3,4-dihydroxyxanthone and 1-formyl-4-hydroxy-3-methoxyxanthone may become useful PKC inhibitors and xanthone derivatives can be explored to develop new isoform-selective PKC inhibitors.     

Synthesis and pharmacological activities of xanthone derivatives as alpha-glucosidase inhibitors

Considerable interest has been attracted in xanthone and its derivatives because of their large variety of pharmacological activities. In this project, a series of hydroxylxanthones and their acetoxy and alkoxy derivatives were synthesized and evaluated as alpha-glucosidase inhibitors, aimed at clarifying the structure-activity correlation. The results indicated that these xanthone derivatives were capable of inhibiting in vitro alpha-glucosidase with moderate to good activities. Among them, polyhydroxylxanthones exhibited the highest activities and thus may be exploitable as a lead compound for the development of potent alpha-glucosidase inhibitors.     

Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies

Flavonoids are one of the largest classes of plant secondary metabolites and are known to possess a number of significant biological activities for human health. In this study, we examined in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of four flavonoid derivatives - quercetin, rutin, kaempferol 3-O-β-d-galactoside and macluraxanthone. The in vitro results showed that quercetin and macluraxanthone displayed a concentration-dependant inhibition of AChE and BChE. Macluraxanthone showed to be the most potent and specific inhibitor of both the enzymes having the IC₅₀ values of 8.47 and 29.8 μM, respectively. The enzyme kinetic studies revealed that quercetin inhibited both the enzymes in competitive manner, whereas the mode of inhibition of macluraxanthone was non-competitive against AChE and competitive against BChE. The inhibitory profiles of the compounds have been compared with standard AChE inhibitor galanthamine. To get insight of the intermolecular interactions, the molecular docking studies of these two compounds were performed at the active site 3D space of both the enzymes, using ICM-Dock™ module. Docking studies exhibited that macluraxanthone binds much more tightly with both the enzymes than quercetin. The calculated docking and binding energies also supported the in vitro inhibitory profiles (IC₅₀ values). Both the compounds showed several strong hydrogen bonds to several important amino acid residues of both the enzymes. A number of hydrophobic interactions could also explain the potency of the compounds to inhibit AChE and BChE.     

Anticonvulsant activity of some xanthone derivatives

A series of appropriate alkanolamine and amide derivatives of xanthone were prepared and evaluated for anticonvulsant activity using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scMet) induced seizures, and for neurotoxicity (TOX) using the rotorod test on mice and rats. The most promising compounds seem to be the appropriate aminoalkanolic derivatives of 6-chloroxanthone, among which the R-(-) and S-(+)-2amino-1-propanol derivatives of 6-chloro-2-methylxanthone (2(a) and 2(b)) displayed anti-MES activity (in mice) with a protective index (TD(50)/ED(50)) of 6.23<6.85, corresponding to that of phenytoin, carbamazepine and valproate. The most active compound, 2(b), was determined to have an affinity to the benzodiazepine (BDZ) receptor and voltage-dependent Ca(2+) channel (VDCC) by using radioligand binding assays. The enantiomeric purities of 2(a) and 2(b) were determined using an analytical liquid chromatography-mass spectrometry method.     

Antimicrobial activities of some synthetic butenolides and their pyrrolone derivatives

In the present investigation, 17 new synthetic butenolides, i.e. 2-arylidene-4-(4-chloro/ethyl-phenyl)but-3-en-4-olides (3–19) have been synthesized from 3-(4-chloro-benzoyl)propionic acid or 3-(4-ethyl-benzoyl)propionic acid using appropriate reagents. Some of the selected butenolides were reacted with ammonia and benzylamine to give the corresponding pyrrolones (20–31) and N-benzyl-pyrrolones (32–39) respectively. All the compounds were screened for their antibacterial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa and antifungal activity against Candida albicans, Aspergillus niger, and Rhizopus oryza. Minimum inhibitory concentration (MIC) values of the compounds are reported. The pyrrolone derivatives discovered in this study may provide valuable therapeutic intervention for the treatment of microbial diseases, especially against fungal species.     

Synthesis, and cytotoxic and antiplatelet activities of oxime- and methyloxime-containing flavone, isoflavone, and xanthone derivatives

A series of oxime- and methyloxime-containing flavone, isoflavone, and xanthone derivatives (1-12) were synthesized (Scheme) and evaluated for their cytotoxic (Table 1) and antiplatelet activities (Table 2). The in vitro anticancer assay indicated that the cytotoxicity of structurally related compounds decreases in the order isoflavones (7a-7c) > flavones (8a-8c) > xanthones (9a-9c), electron-releasing substituents (R) on the Ph ring being favorable (mean GI50 values of 2.84, 12.3, and 20.9 microM for 7c, 8c, and 9c, resp.). The inhibition of platelet aggregation induced by arachidonic acid (AA) similarly decreased from the isoflavone 1 (IC50 = 2.97 microM) to the flavone 2 (7.70 microM) to the xanthone 3 (inactive). Thereby, compound 1 seems to be a promising lead, since it was not only the most-potent aggregation inhibitor (IC50 = 2.97 microM), but was also found to be noncytotoxic at a concentration of 100 microM.     

Multidimensional optimization of promising antitumor xanthone derivatives

A promising antitumor xanthone derivative was optimized following a multidimensional approach that involved the synthesis of 17 analogues, the study of their lipophilicity and solubility, and the evaluation of their growth inhibitory activity on four human tumor cell lines. A new synthetic route for the hit xanthone derivative was also developed and applied for the synthesis of its analogues. Among the used cell lines, the HL-60 showed to be in general more sensitive to the compounds tested, with the most potent compound having a GI₅₀ of 5.1 μM, lower than the hit compound. Lipophilicity was evaluated by the partition coefficient (K_p) of a solute between buffer and two membrane models, namely liposomes and micelles. The compounds showed a log K_p between 3 and 5 and the two membrane models showed a good correlation (r² = 0.916) between each other. Studies concerning relationship between solubility and structure were developed for the hit compound and 5 of its analogues.     

Anti-herpetic and anti-inflammatory activities of two new synthetic 22,23-dihydroxylated stigmastane derivatives

Stromal keratitis resulting from ocular infection with Herpes simplex virus type 1 (HSV-1) is a common cause of blindness. This report investigates the antiviral and anti-inflammatory properties of two new synthetic stigmastane analogs in the experimental model of HSV-1-induced ocular disease in mice. (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (1) and (22S,23S)-22,23-dihydroxystigmasta-1,4-dien-3-one (2) exhibited anti-HSV-1 activity in vitro and ameliorated the signs of murine herpetic stromal keratitis (HSK), although none of the compounds showed antiviral activity in vivo. We discuss that the improvement of HSK could be due to an immunomodulatory effect of both compounds.     

Antihypertensive activity of chitin derivatives

To develop angiotensin I converting enzyme (ACE) inhibitory chitin derivatives based on the properties of ACE inhibitors, chitins with different degree of deacetylation were chemically modified by grafting 2-chloroethylamino hydrochloride onto chitin at the C-6 position. Three kinds of chitin derivatives were prepared and designated as aminoethyl-chitin (AEC) with 10% degree of deacetylation, aminoethyl-chitin with 50% degree of deacetylation (AEC50), and aminoethyl-chitin with 90% degree of deacetylation (AEC90). IC50 values of three chitin derivatives on ACE were 0.064 microM (AEC), 0.038 microM (AEC50), and 0.103 microM (AEC90). The results of Dixon plots revealed that AEC50 was a competitive inhibitor, and the inhibition constant (Ki) value was 0.021 microM. In addition, the antihypertensive effect of AEC50 on spontaneously hypertensive rats (SHR) was evaluated, and the result showed that it effectively decreased systolic blood pressure (SBP) in a dose-dependent manner.     

Preliminary evaluation of pharmacological properties of some xanthone derivatives

A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for α₁- and β₁-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures.     

Promiscuous enzyme-catalyzed cascade reaction: Synthesis of xanthone derivatives

Based on the screening of biocatalysts and reaction conditions including organic solvent, water content, lipase loading, reaction temperature and time, lipase TLIM exhibited the prominent promiscuity for the Knoevenagel-Michael cascade reactions of 1, 3-diketones with aromatic aldehydes to synthesize xanthone derivatives. This procedure provides satisfactory advantages such as environmental begin, simple work-up, generality, obtaining in excellent yields (80–97%), and potential for recycling of biocatalyst.     

Discovery of novel xanthone derivatives as xanthine oxidase inhibitors

Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. In this study, a series of xanthone derivatives were synthesized as effective and a new class of xanthine oxidase inhibitor. Compounds 8a, 8c, 8i, 8g and 8r showed good inhibition against xanthine oxidase. The presence of a cyano group at the para position of benzyl moiety turned out to be the preferred substitution pattern. Molecular modeling studies were performed to gain an insight into its binding mode with xanthine oxidase, and to provide the basis for further structure-guided design of new non-purine xanthine oxidase inhibitors associated with the xanthone framework.     

Cytotoxic prenylated xanthone and coumarin derivatives from Malaysian Mesua beccariana

Our recent research on the phytochemical constituents of the stem bark of Mesua beccariana gave one new xanthone, beccarixanthone T (1) and one new coumarin, beccamarin T (2) together with three known xanthones mesuarianone (3), mesuasinone (4), 1,5-dihydroxyxanthone (5) and four known terpenoids, friedelin (6), stigmasterol (7), beta-sitosterol (8) and gamma-sitosterol (9). The structures of these compounds were elucidated and determined using spectroscopic techniques such as NMR and MS. The cytotoxic activities of compounds 1-4 as well as the crude extracts were tested against two cancer cell lines, Hep G2 (liver cancer cell line) and HT-29 (colon cancer cell line) using MTT assays. Mesuarianone (3) gave a significant activity on the HT-29 cell line while mesuasinone (4) gave moderate activity against HT-29 cell line.     

New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC₅₀ values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π–π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π–π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.     

Design,synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α₁-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α₁/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.     

QSAR of aromatic substances: MAO inhibitory activity of xanthone derivatives

The flip regression procedure that we used earlier for handling the dibenzofuran system has been applied to xanthones. The MAO-A inhibitory activity expressed as IC50 of the xanthones is known to correlate with E-state, molecular connectivity, shape indices and in this contribution it is shown that the orientation of nodes in their occupied pi orbitals explain a further large portion of the variance in their inhibitory activity.     

Synthesis and anticancer potential of novel xanthone derivatives with 3,6-substituted chains

In an effort to develop new drug candidates with enhanced anticancer activity, our team synthesized and assessed the cytotoxicity of a series of novel xanthone derivatives with two longer 3,6-disubstituted amine carbonyl methoxy side chains on either benzene ring in selected human cancer cell lines. An MTT assay revealed that a set of compounds with lower IC₅₀ values than the positive control, 5-FU, exhibited greater anticancer effects. The most potent derivative (XD8) exhibited anticancer activity in MDA-MB-231, PC-3, A549, AsPC-1, and HCT116 cells lines with IC₅₀ values of 8.06, 6.18, 4.59, 4.76, and 6.09 μM, respectively. Cell cycle analysis and apoptosis activation suggested that the mechanism of action of these derivatives includes cell cycle regulation and apoptosis induction.     

Antimicrobial activities of the bromophenols from the red alga Odonthalia corymbifera and some synthetic derivatives

A series of bromophenols was obtained by isolation from red alga Odonthalia corymbifera and by reactions of bis(hydroxyphenyl)methanes with bromine. New bromophenols including 3,3',5,5'-tetrabromo-2,2',4,4'-tetrahydroxydiphenylmethane (10), a regioisomer of the potent antimicrobial natural product, together with known derivatives were synthesized in high yield. All of the isolated and synthesized compounds were tested for antimicrobial activity against gram-negative, gram-positive bacteria and fungi. The preliminary structure-activity relationship, to elucidate the essential structure requirements for antimicrobial activity, has been described. Among the isolated natural products 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxydiphenylmethane (4) was found to be the most active derivative against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, and Trichophyton mentagrophytes. The synthetic bromophenols 3,3'-dibromo-6,6'-dihydroxydiphenylmethane (13) and 3,3',5,5'-tetrabromo-6,6'-dihydroxydiphenylmethane (14) showed potent antibacterial effect against Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Proteus vulgaris, and Salmonella typhimurium.