Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.

Abstract

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 (IC(50) 0.08-1.66 µg/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-OCOCH(3) in 7a-b, important for their cytotoxic properties. The SAR for moderately active 5a-b (5-OCH(3)), 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.

• Authors: Chia-Lin Lee, Ying-Ting Lin, Fang-Rong Chang, Guan-Yu Chen, Anders Backlund, Juan-Chang Yang, Shu-Li Chen, Yang-Chang Wu
• Journal: PloS one (PLoS One) Vol. 7 Issue 5 Pg. e37897 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22666407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phenanthrenes
• Topoisomerase II Inhibitors
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Chemistry Techniques, Synthetic
• Computational Biology
• DNA Topoisomerases, Type II (metabolism)
• Humans
• Models, Molecular
• Molecular Conformation
• Phenanthrenes (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Topoisomerase II Inhibitors (chemical synthesis, chemistry, pharmacology)