Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.
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 al...
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2012
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oai:doaj.org-article:5dd210b9d8134dde9b990dd2ef11534c2021-11-18T07:17:07ZSynthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors.1932-620310.1371/journal.pone.0037897https://doaj.org/article/5dd210b9d8134dde9b990dd2ef11534c2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666407/?tool=EBIhttps://doaj.org/toc/1932-6203In 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.Chia-Lin LeeYing-Ting LinFang-Rong ChangGuan-Yu ChenAnders BacklundJuan-Chang YangShu-Li ChenYang-Chang WuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e37897 (2012) |
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Medicine R Science Q Chia-Lin Lee Ying-Ting Lin Fang-Rong Chang Guan-Yu Chen Anders Backlund Juan-Chang Yang Shu-Li Chen Yang-Chang Wu Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors. |
| description |
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. |
| format |
article |
| author |
Chia-Lin Lee Ying-Ting Lin Fang-Rong Chang Guan-Yu Chen Anders Backlund Juan-Chang Yang Shu-Li Chen Yang-Chang Wu |
| author_facet |
Chia-Lin Lee Ying-Ting Lin Fang-Rong Chang Guan-Yu Chen Anders Backlund Juan-Chang Yang Shu-Li Chen Yang-Chang Wu |
| author_sort |
Chia-Lin Lee |
| title |
Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors. |
| title_short |
Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors. |
| title_full |
Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors. |
| title_fullStr |
Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors. |
| title_full_unstemmed |
Synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and ChemGPS-NP prediction as topo II inhibitors. |
| title_sort |
synthesis and biological evaluation of phenanthrenes as cytotoxic agents with pharmacophore modeling and chemgps-np prediction as topo ii inhibitors. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/5dd210b9d8134dde9b990dd2ef11534c |
| work_keys_str_mv |
AT chialinlee synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT yingtinglin synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT fangrongchang synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT guanyuchen synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT andersbacklund synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT juanchangyang synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT shulichen synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors AT yangchangwu synthesisandbiologicalevaluationofphenanthrenesascytotoxicagentswithpharmacophoremodelingandchemgpsnppredictionastopoiiinhibitors |
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