Edward Szneler

Self‐assembly of Congo Red—A theoretical and experimental approach to identify its supramolecular organization in water and salt solutions

The supramolecular organization of Congo Red molecules was studied to approach an understanding of the unusual complexation characteristics associated with the liquid crystalline nature of this dye. Differential scanning calorimetry (DSC) and nmr data indicate that Congo Red assembly arrangements differ in water and salt solutions. Compact, highly ordered material with a distinct melting transition is created, but not below 0.3% sodium chloride concentration. The twist in the assembly arrangement of Congo Red molecules, caused in water by repulsion, decreases when the charges are shielded, allowing for more overlapping of the naphthalene rings and their engagement in stacking interaction. The crystallization transition observed in DSC analysis of Congo Red fast-assembled by cooling in salt solutions indicates that the formation of compact crystalline mesophase material is a time-consuming process in which coplanarity and a highly ordered organization must be achieved. Two different superposition variants, called “direct” and “reversed” here, were considered fundamental to compact Congo Red organization. They correspond to optimal face-to-face ring stackings, and are formed by simple direct translation or alternative imposition of reversed (180° rotated) molecules, respectively. In NaCl solution (2.8%) there is a significant downfield chemical shift alteration of the nmr signal related to proton 8, which is in the naphthalene ring on the side opposite to the charged sulfonic group. It was associated selectively with the transition of Congo Red to compact form. This effect confirms the close approach of the sulfonic groups and proton 8, and indicates that formation of the reversed arrangement is favored in the Congo Red supramolecular organization. Molecular dynamics simulation based on AMBER 4.1 force field and analysis of electrostatic field densities around the molecule were used for comparative modeling. Molecular dynamics (150 ps) were simulated for two eight-molecule micelle models constructed to reflect direct and reversed arrangements of Congo Red molecules. Although both versions generally preserved their initial assembly structure in the simulations, the reversed version proved more stable. The proximity of the sulfonic group and proton 8, confirmed by computer analysis, explains the correlation between the formation of Congo Red micellar organization and the distinct shift alteration related to this proton, as found by nmr.

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 alpha(1)- and beta(1)-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.

Heat-induced formation of a specific binding site for self-assembled congo red in the V domain of immunoglobulin L chain ?

Moderate heating (40–50°C) of immunoglobulins makes them accessible for binding with Congo Red and some related highly associated dyes. The binding is specific and involves supramolecular dye ligands presenting ribbon‐like micellar bodies. The L chain λ dimer, which upon heating disclosed the same binding requirement with respect to supramolecular dye ligands, was used in this work to identify the site of their attachment. Two clearly defined dye–protein (L λ chain) complexes arise upon heating, here called complex I and complex II. The first is formed at low temperatures (up to 40–45°C) and hence by a still native protein, while the formation of the second one is associated with domain melting above 55°C. They contain 4 and 8 dye molecules bound per L chain monomer, respectively. Complex I also forms efficiently at high dye concentration even at ambient temperature. Complex I and its formation was the object of the present studies. Three structural events that could make the protein accessible to penetration by the large dye ligand were considered to occur in L chains upon heating: local polypeptide chain destabilization, VL‐VL domain incoherence, and protein melting. Of these three possibilities, local low‐energy structural alteration was found to correlate best with the formation of complex I. It was identified as decreased packing stability of the N‐terminal polypeptide chain fragment, which as a result made the V domain accessible for dye penetration. The 19‐amino acid N‐terminal fragment becomes susceptible to proteolytic cleavage after being replaced by the dye at its packing locus. Its splitting from the dye–protein complex was proved by amino acid sequence analysis. The emptied packing locus, which becomes the site that holds the dye, is bordered by strands of amino acids numbered 74–80 and 105–110, as shown by model analysis. The character of the temperature‐induced local polypeptide chain destabilization and its possible role in intramolecular antibody signaling is discussed.

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.

Antifungal and Antibacterial Activity of the Newly Synthesized 2-Xanthone Derivatives

A series of 2‐substituted xanthone derivatives 8–20 containing selected allyl, cinnamyl, morpholine, and imidazole moieties were synthesized and tested for their antifungal and antibacterial in‐vitro properties. Of the newly synthesized derivatives, ten revealed antifungal activity especially against Trichophyton mentagrophytes (the biggest inhibition zones ranged 35 mm for 11 and 13). 2‐(3‐(Allylamino)propoxy)‐9H‐xanthen‐9‐one hydrochloride 9 inhibited growth of all of the examined fungal species. Significant efficacy against evaluated yeasts and dermatophytes was also observed for 6‐chloro‐2‐methyl‐9H‐xanthen‐9‐one derivatives 11–13 containing encyclic amine moieties. Additionally, compounds 9, 11, and 12 hindered development of bacteria species but in a lesser degree. They were efficacious against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis.

Synthesis and evaluation of some xanthone derivatives for anti-arrhythmic, hypotensive properties and their affinity for adrenergic receptors.

A series of 2‐, 4‐ or 2‐methyl‐6‐substituted xanthone derivatives 8–17 containing selected piperazine moieties were synthesized and tested for their electrocardiographic, anti‐arrhythmic, and antihypertensive activity, as well as for the α1‐ and β1‐adrenoceptor binding affinities. Of the newly synthesized derivatives, 2‐(2‐hydroxy‐3‐(4‐(2‐phenoxyethyl)piperazin‐1‐yl)propoxy)‐9H‐xanthen‐9‐one dihydrochloride 9, 4‐(2‐hydroxy‐3‐(4‐(2‐phenoxyethyl)piperazin‐1‐yl)propoxy)‐9H‐xanthen‐9‐one dihydrochloride 12, and 4‐(2‐(4‐(pyridin‐2‐yl)piperazin‐1‐yl)ethoxy)‐9H‐xanthen‐9‐one dihydrochloride 15 possessed significant anti‐arrhythmic activity in the adrenaline‐induced model of arrhythmia, with the ED50 values ranging 1.7–7.2 mg/kg. Compound 15 had the lowest ED50 value equaling 1.7 mg/kg, which was comparable with ED50 value of propranolol, which was used in this test as a reference compound. Compound 9 showed also the strongest hypotensive activity, which persisted for 60 minutes at the dose of 2.5 mg/kg. 2‐(2‐(4‐(2‐Phenoxyethyl)piperazin‐1‐yl)ethoxy)‐9H‐xanthen‐9‐one dihydrochloride 8 also significantly lowered blood pressure at a dose of 2.5 mg/kg but much weaker than compound 9. Binding studies are in agreement with our pharmacological results and could explain anti‐arrhythmic effect of compound 15 and anti‐arrhythmic and hypotensive effects of compounds 9 and 12.

Sesquiterpene lactones from Lactuca tatarica

Abstract From the roots of Lactuca tatarica, one new and two known guaianolides were isolated together with five known guaianolide glycosides, three known germacrolide glycosides and benzyl-β-glucopyranoside. The structure of the new compound was elucidated as 11βH, 13-dihydrolactucin-8-O-p-methoxyphenylacetate by spectral methods.

Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT₁A, 5-HT₆ and 5-HT₇b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT₁A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.

Furofuran lignans from a callus culture of Cichorium intybus

Three new and one known furofuran lignans—syringaresinol derivatives—along with the known phenylpropanoids cichoriin and syringin were isolated from a callus tissue of Cichorium intybus. The compounds were characterised by spectral methods. This is the first report on the presence of furofuran lignans in Cichorium species.

Anticonvulsant evaluation of aminoalkanol derivatives of 2- and 4-methylxanthone.

A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED(50) value of 47.57 mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD(50) was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD(50)/ED(50)) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED(50) values in MES test (mice, ip) ranged 80-110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.