Abstract：
:Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G(2)/M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC(50) of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the βIII isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Hartley RM,Peng J,Fest GA,Dakshanamurthy S,Frantz DE,Brown ML,Mooberry SLdoi
10.1124/mol.111.075838subject
Has Abstractpub_date
2012-03-01 00:00:00pages
431-9issue
3eissn
0026-895Xissn
1521-0111pii
mol.111.075838journal_volume
81pub_type
杂志文章abstract：:The effects of ethanol on a number of electrophysiological parameters were examined in 10 different voltage-gated potassium channels expressed in Xenopus oocytes. None of the channels examined was highly sensitive to ethanol, but there was significant variability among the channels tested at concentrations of ethanol ...
journal_title：Molecular pharmacology
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更新日期：1988-09-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-12-01 00:00:00
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journal_title：Molecular pharmacology
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更新日期：1985-05-01 00:00:00
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pub_type： 杂志文章,评审
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更新日期：2004-11-01 00:00:00
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doi：10.1124/mol.109.055384
更新日期：2009-07-01 00:00:00
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doi：10.1124/mol.58.3.483
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pub_type： 杂志文章
doi：10.1124/mol.60.6.1235
更新日期：2001-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-05-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.054155
更新日期：2009-05-01 00:00:00
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doi：10.1124/mol.106.025403
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.020057
更新日期：2006-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-11-01 00:00:00
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journal_title：Molecular pharmacology
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-03-01 00:00:00
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journal_title：Molecular pharmacology
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doi：
更新日期：1986-10-01 00:00:00
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pub_type： 杂志文章,评审
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journal_title：Molecular pharmacology
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doi：
更新日期：1989-05-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.56.1.20
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pub_type： 杂志文章
doi：10.1124/mol.106.033621
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-02-01 00:00:00
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