Viktor Kettmann

Free radical scavenging activity and lipoxygenase inhibition of Mahonia aquifolium extract and isoquinoline alkaloids

Roots and stem-bark of Mahonia aquifolium (Oregon grape) (Berberidaceae) are effectively used in the treatment of skin inflammatory conditions.In the present study, the effect of Mahonia aquifolium crude extract and its two representative alkaloid fractions containing protoberberine and bisbenzylisoquinoline (BBIQ) alkaloids on activity of 12-lipoxygenase (12-LOX), was studied. The reactivity with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), a free stable radical, was evaluated to elucidate the rate of possible lipid-derived radical scavenging in the mechanism of the enzyme inhibition.The results indicate that although the direct radical scavenging mechanism cannot be ruled out in the lipoxygenase inhibition by Mahonia aquifolium and its constituents, other mechanisms based on specific interaction between enzyme and alkaloids could play the critical role in the lipoxygenase inhibition rather than non-specific reactivity with free radicals.

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

SummaryUsing the X-ray crystal structure of the human topoisomerase I (top1) – DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the −1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.

Potential antimutagenic activity of berberine, a constituent of Mahonia aquifolium

BackgroundAs part of a study aimed at developing new pharmaceutical products from natural resources, the purpose of this research was twofold: (1) to fractionate crude extracts from the bark of Mahonia aquifolium and (2) to evaluate the strength of the antimutagenic activity of the separate components against one of the common direct-acting chemical mutagens.MethodsThe antimutagenic potency was evaluated against acridine orange (AO) by using Euglena gracilis as an eukaryotic test model, based on the ability of the test compound/fraction to prevent the mutagen-induced damage of chloroplast DNA.ResultsIt was found that the antimutagenicity of the crude Mahonia extract resides in both bis-benzylisoquinoline (BBI) and protoberberine alkaloid fractions but only the protoberberine derivatives, jatrorrhizine and berberine, showed significant concentration-dependent inhibitory effect against the AO-induced chloroplast mutagenesis of E. gracilis. Especially berberine elicited, at a very low dose, remarkable suppression of the AO-induced mutagenicity, its antimutagenic potency being almost three orders of magnitude higher when compared to its close analogue, jatrorrhizine. Possible mechanisms of the antimutagenic action are discussed in terms of recent literature data. While the potent antimutagenic activity of the protoberberines most likely results from the inhibition of DNA topoisomerase I, the actual mechanism(s) for the BBI alkaloids is hard to be identified.ConclusionsTaken together, the results indicate that berberine possesses promising antimutagenic/anticarcinogenic potential that is worth to be investigated further.

3-Butyl-1-(5-nitrobenzo(c)(1,2)thiazol-3-yl)-3-phenyltriazene

The molecule of the title compound, C(17)H(17)N(5)O(2)S, consists of three pi systems, viz. two aromatic rings and the triazene moiety, which are mutually deconjugated although coplanar. The n-butyl chain is roughly perpendicular to the molecular plane, with the terminal methylene and methyl groups disordered between two equally populated positions. The molecules in the crystal associate in an antiparallel fashion, forming dimers across the centre of symmetry, the principal intradimer interaction being stacking of the pi-electron portions of the molecules.

4-(4-Methoxyphenylamino)-3-phenylazo-3-penten-2-one

The title compound, C18H19N3O2, was obtained by an azo-coupling reaction with enaminones and is composed of a planar azoenamine skeleton which forms a six-membered ring through a symmetrical intramolecular hydrogen bond. The compound was found to exist as an equilibrium mixture of major hydrazoimino and minor azoenamine tautomers. Quantification of the relative contribution of the tautomeric forms is obscured by the existence of the hydrogen bond. Comparison of the results with those obtained for a similar structure revealed a substantial effect on the tautomeric equilibria of the nature of the substituent bonded to the amine nitrogen.

(5R*,11R*)-5-Methyl-1,2-dihydro-5,11-methano-5H,11H-1,3-thia­zolo[2,3-d][1,3,5]benzoxadiazo­cine

The title compound, C(13)H(14)N(2)OS, crystallizes as a racemate in a non-chiral space group. It represents a conformationally restricted analogue of so-called Biginelli compounds known to exhibit multiple pharmacological activities and was selected for a single-crystal X-ray analysis in order to probe the chemical and spatial requirements of some kinds of activity. It was found that the state of hybridization of the formally aminic nitro-gen of the heterocycle is between sp(2) and sp(3) with the lone-pair electrons partially delocalized through conjugation with the sulfur atom rather than the double bond of the pyrimidine nucleus. As a result, the thia-zolo ring adopts a flat-envelope conformation and the puckering of the central pyrimidine ring is close to a half-chair. The critical phenyl ring is fixed in a pseudo-axial and perpendicular [dihedral angle 84.6 (1)°] orientation with respect to the pyrimidine ring via an oxygen bridge.

5-Amino-1-methyl-1H-benzimidazole

The structure of the title compound, C8H9N3, a potential antitumour drug, was determined in order to give more insight into its structure–function relationships. The benzimidazole core of the molecule was found to be exactly planar, while the substituents are displaced slightly from the molecular plane [C—C—N—C and C—C—C—N torsion angles of 0.8 (3) and 179.0 (1)° for the methyl and amino groups, respectively]. The bond lengths are analysed in detail and compared with those of the parent unsubstituted analogues. The results show that the lone-pair electrons on the amino N atom are involved in conjugation with the adjacent π system and hence affect the charge distribution in the heterocycle. Two intermolecular N—H⋯N and C—H⋯N hydrogen bonds have been identified.

Ethyl 6-ethoxy-carbonyl-methyl-4-(2-hydroxy-phen-yl)-2-oxo-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl-ate.

The title compound, C17H20N2O6, belongs to the monastrol-type of anticancer agents and was selected for crystal structure determination in order to confirm its molecular structure and explore some aspects of its structure–activity relationships. The central tetrahydropyrimidine ring has a flat-envelope conformation. The 4-hydroxyphenyl group occupies a pseudo-axial position and is inclined at an angle of 87.7 (2)° to the mean plane of the heterocyclic ring. Of the two ethyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) is in a perpendicular orientation with respect to the heterocyclic plane. There is a three-dimensional hydrogen-bonding network in which all hydrogen-bond donors and acceptors are involved.

4,5-Dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole-1-carboxamide.

The reaction between 4-(4-methylphenyl)but-3-en-2-one and aminoguanidine produced an unexpected product of formula C(12)H(15)N(3)O, consisting of a carboxamide moiety joined to a substituted pyrazoline ring at one of the N atoms. The pyrazoline ring adopts a flat-envelope conformation and the substituted phenyl ring is oriented almost perpendicular to the heterocycle. The carbonyl O atom has partial anionic character as a result of the transfer of pi density from the two adjacent sp(2) N atoms and is involved in an intermolecular hydrogen bond with the amide group.

4,5-Dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole-1-carboxamidinium acetate acetone hemisolvate.

The X-ray structure analysis of the unexpected product of the reaction between 4-(4-methylphenyl)but-3-en-2-one and aminoguanidine revealed the title compound, C(12)H(17)N(4)(+) x -C(2)H(3)O(2)(-) x 0.5C(3)H(6)O, consisting of a protonated amidine moiety joined to a substituted pyrazoline ring at the N1 atom. The amidine group is protonated and the positive charge is delocalized over the three C[bond]N bonds in a similar manner to that found in guanidinium salts. The amidinium moiety of the cation is linked to the acetate anions through four N[bond]H...O hydrogen bonds, with N...O distances of 2.749 (4), 2.848 (4), 2.904 (4) and 2.911 (4) A. The pyrazoline ring adopts a flattened envelope conformation and the substituted phenyl ring is oriented perpendicular to the attached heterocycle. The acetone solvate molecule lies across a twofold rotation axis.