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Design, synthesis, and in vitro cancer cell growth inhibition evaluation and antimalarial testing of trioxanes installed in cyclic 2-enoate substructures

Hossain, Md Imran and Switalska, Marta and Peng, Wei and Takashima, Mariko and Wang, Ning and Kaiser, Marcel and Wietrzyk, Joanna and Dan, Shingo and Yamori, Takao and Inokuchi, Tsutomu. (2013) Design, synthesis, and in vitro cancer cell growth inhibition evaluation and antimalarial testing of trioxanes installed in cyclic 2-enoate substructures. European journal of medicinal chemistry, 69. pp. 294-309.

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Official URL: http://edoc.unibas.ch/dok/A6194657

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Abstract

A novel series of 1,2,4-trioxanes were synthesized from 2H-pyrans via photooxidation, and their antiproliferative and growth factor inhibitory activity has been investigated across a variety of human cancer cell lines. Compounds 5k, 5l, 5s, 7a and 7c exhibited the highest activity and selectivity against a human leukemia (MV4-11) cell line (IC50 = 0.5 μM). Compound 5o showed the highest growth factor inhibitory activity against a melanoma (LOX-IMVI) cancer cell line (GI50 = 1.0 μM). A SAR study has confirmed the importance of the 1,2,4-trioxane unit as a pharmacophore for anticancer activity. The computer-assisted database analysis, COMPARE, has suggested that the compounds have unique mechanisms of actions that were different from those of known anticancer drugs. Some of the selected trioxanes were tested against the NF54 strain, albeit showing weak antiplasmodial activity. The molecular docking of trioxanes and hemin reveals that a short distance (1.30 Å) leads to their physical contact. The UV-vis spectroscopic analysis ensured the definite complexation between 1,2,4-trioxanes and hemin. The role of hemin-trioxane interaction in the hemin-induced oxidative damage has been studied using methylene blue as a substrate by UV-vis spectroscopy.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0223-5234
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Dec 2017 10:30
Deposited On:27 Mar 2014 13:12

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