Influence of S-Oxidation on Cytotoxic Activity of Oxathiole-Fused Chalcones.

Synthesis, in vitro cytotoxic activity, and interaction with tubulin of oxidized, isomeric 1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-ones and 1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-ones are described. Most of the compounds demonstrated cytotoxic activity at submicromolar concentrations. It was found that oxidation of sulfur atom of the oxathiole-fused chalcones strongly influenced activity of the parent compounds, and that depending on relative position of the sulfur atom in the molecule, the activity was either increased or diminished. For isomers with sulfur atom para to the chalcone carbonyl group, oxidation led to increase in activity, while for isomers with sulfur atom meta to the carbonyl the activity dropped down. It was demonstrated that the compounds interact with tubulin at the colchicine binding site, and the interaction was evaluated using molecular modeling. It was concluded that the observed profound influence of oxidation of the sulfur atom on cytotoxic activity cannot be solely related to interaction of the compounds with tubulin.

Structural factors affecting affinity of cytotoxic oxathiole-fused chalcones toward tubulin.

Synthesis, in vitro cytotoxic activity, and interaction with tubulin of (E)-1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-one derivatives (2) are described. Some of the compounds demonstrated cytotoxic activity at submicromolar concentrations, and the activity could be related to interaction with tubulin at the colchicine binding site. Interaction of selected derivatives with tubulin was evaluated using molecular modeling, and two different modes of the interaction were identified. The proposed models demonstrate how particular structural fragments participate in binding to the tubulin and explain the importance of the fragments for cytotoxic activity. It was demonstrated that concerning binding to tubulin, the 6-alkoxybenzoxathiole ring can be considered as structural equivalent of trimethoxyphenyl motif of colchicine, podophyllotoxin or combretastatin A4. The observation opened new ways of rational modifications of several groups of tubulin binders.

Structural factors affecting cytotoxic activity of (E)-1-(Benzo[d ][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one derivatives.

Derivatives of (E)-1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one demonstrated exceptionally high in vitro cytotoxic activity, with IC50 values of the most active derivatives in the nanomolar range. To identify structural fragments necessary for the activity, several analogs deprived of selected fragments were prepared, and their cytotoxic activity was tested. It was found that the activity depends on combined effects of (i) the heterocyclic ring, (ii) the alkoxy group at position 5 of the benzoxathiole ring, and (iii) the substituents in the phenyl ring B. Replacement of the sulfur atom by oxygen does not influence the activity. None of the listed structural fragments alone assured high cytotoxic activity.

Synthesis of isomeric, oxathiolone fused chalcones, and comparison of their activity toward various microorganisms and human cancer cells line.

Isomeric oxathiolone fused chalcones were prepared by condensation of appropriate acetylbenzo[1,3]oxathiol-2-ones with benzaldehydes under acidic conditions. The synthesized compounds were screened for cytotoxic activity using HeLa cells, as well as for antibacterial activity against Micrococcus luteus, Staphylococcus aureus, Salmonella typhimurium, Escherichia coli, Proteus vulgaris, antifungal activity against Candida albicans, and tuberculostatic activity against Mycobacterium tuberculosis H(37)Rv and Mycobacterium kansasii strains.

Acid-catalyzed synthesis of oxathiolone fused chalcones. Comparison of their activity toward various microorganisms and human cancer cells line.

Substituted oxathiolone fused chalcones were prepared by condensation of 4-acetyl-5-methoxy-2-oxo-benz[1,3]oxathiole with benzaldehydes under acidic conditions. The compounds were tested for cytotoxic, antibacterial, antifungal and tuberculostatic activity. Three derivatives demonstrated weak activity against HeLa cells, two were slightly active against Micrococcus luteus and Staphylococcus aureus, and one was active against Mycobacterium tuberculosis H(37)Rv.

Synthesis and cytostatic activity of 4,7-dihydroxythioaurone derivatives. Effect of B ring substitution on the activity.

Biological activity of thioaurones was not tested so far and the group constitute completely unexplored source of new molecules of pharmacological interest. We report synthesis and evaluation of cytotoxic activity of thioaurone derivatives bearing p-hydroquinone system in ring A. Their activity was found to depend strongly on substitution pattern, so eventually both the activity and pharmacokinetic parameters of the molecules could be tailored by further structural modifications.