Synthesis and biological activity of 1<i>H</i>-pyrrol-2(5<i>H</i>)-ones

ZHAO Fang-zhen; ZHUANG Chun-lin; GUO Zi-zhao; SHENG Chun-quan; YAO Jian-zhong; MIAO Zhen-yuan; ZHANG Wan-nian

doi:10.3969/j.issn.1006-0111.2012.06.009

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Objective To study the biological activity of 1H-pyrrol-2(5H)-ones which introduced substituted phenyl group as side chain. Methods By introduction of 5-substituted phenyl group, a serial 1H-pyrrol-2(5H)-ones were synthesized and their structures were confirmed by ¹H NMR and MS. The binding constant K_i was assayed by the fluorescence polarization binding assay method. Results Thirteen title compounds exhibited stronger protein binding activities and compound 4e showed five times higher than positive drug. Conclusion The introduction of electron-attracting groups was beneficial to improve their activities. Among them, the nitro group was preferred group.

Synthesis and biological activity of 1H-pyrrol-2(5H)-ones

Department of Medicinal Chemistry, Second Military Medicinal University, Shanghai 200433, China

Received Date: 2012-05-11

Rev Recd Date: 2012-06-20

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Abstract: Objective To study the biological activity of 1H-pyrrol-2(5H)-ones which introduced substituted phenyl group as side chain. Methods By introduction of 5-substituted phenyl group, a serial 1H-pyrrol-2(5H)-ones were synthesized and their structures were confirmed by ¹H NMR and MS. The binding constant K_i was assayed by the fluorescence polarization binding assay method. Results Thirteen title compounds exhibited stronger protein binding activities and compound 4e showed five times higher than positive drug. Conclusion The introduction of electron-attracting groups was beneficial to improve their activities. Among them, the nitro group was preferred group.

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[1]	Moll UM, Petrenko O. The MDM2-p53 Interaction[J]. Mol Cancer Res,2003, 1:1001.
[2]	Kussie PH, Gorina S, Marechal V, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain[J]. Science, 1996, 274:948.
[3]	Garcia-Echeverria C, Chene P, Blommers MJJ. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53[J].J Med Chem, 2000, 43:3205.
[4]	Baek S, Kutchukian PS, Verdine GL, et al. Structure of the stapled p53 peptide bound to Mdm2[J].J Am Chem Soc, 2012, 134:103.
[5]	Lyubomir T, Vassilev BT, Bradford G, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J]. Science, 2004, 303:844.
[6]	Yu S, Qin D, Shangary S, et al. Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction[J]. J Med Chem, 2009, 52:7970.
[7]	Marugan JJ, Leonard K, Raboisson P, et al. Enantiomerically pure 1,4-benzo-diazepine-2,5-diones as MDM2 antagonists[J]. Bioorg Med Chem Lett, 2006,16:3115.

[1]	Moll UM, Petrenko O. The MDM2-p53 Interaction[J]. Mol Cancer Res,2003, 1:1001.
[2]	Kussie PH, Gorina S, Marechal V, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain[J]. Science, 1996, 274:948.
[3]	Garcia-Echeverria C, Chene P, Blommers MJJ. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53[J].J Med Chem, 2000, 43:3205.
[4]	Baek S, Kutchukian PS, Verdine GL, et al. Structure of the stapled p53 peptide bound to Mdm2[J].J Am Chem Soc, 2012, 134:103.
[5]	Lyubomir T, Vassilev BT, Bradford G, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J]. Science, 2004, 303:844.
[6]	Yu S, Qin D, Shangary S, et al. Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction[J]. J Med Chem, 2009, 52:7970.
[7]	Marugan JJ, Leonard K, Raboisson P, et al. Enantiomerically pure 1,4-benzo-diazepine-2,5-diones as MDM2 antagonists[J]. Bioorg Med Chem Lett, 2006,16:3115.

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Synthesis and biological activity of 1H-pyrrol-2(5H)-ones

doi: 10.3969/j.issn.1006-0111.2012.06.009

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Synthesis and biological activity of 1H-pyrrol-2(5H)-ones

doi: 10.3969/j.issn.1006-0111.2012.06.009

Department of Medicinal Chemistry, Second Military Medicinal University, Shanghai 200433, China

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Synthesis and biological activity of 1H-pyrrol-2(5H)-ones

doi: 10.3969/j.issn.1006-0111.2012.06.009

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References

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通讯作者: 陈斌, bchen63@163.com

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Synthesis and biological activity of 1H-pyrrol-2(5H)-ones

doi: 10.3969/j.issn.1006-0111.2012.06.009

Department of Medicinal Chemistry, Second Military Medicinal University, Shanghai 200433, China

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