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Synthesis and Biological Evaluation of Phenanthrenes as Cytotoxic Agents with Pharmacophore Modeling and ChemGPS-NP Prediction as Topo II Inhibitors
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2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 5, e37897- p.Article in journal (Refereed) Published
Abstract [en]

In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC50 0.08-1.66 mu g/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a-b and for the carbonyl group of 5-OCOCH3 in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH3), and highly active 6a-b and 7a-b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a-b as topoisomerase II inhibitors.

Place, publisher, year, edition, pages
2012. Vol. 7, no 5, e37897- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-177618DOI: 10.1371/journal.pone.0037897ISI: 000305349600038OAI: diva2:541414
Available from: 2012-07-17 Created: 2012-07-17 Last updated: 2012-07-17Bibliographically approved

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