Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents
A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by X-ray analysis. Using a radiolabelled binding assay, potent CCK 1 selective ligands were identified (CCK 1 : 12 nM) and the antagonism was con...
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| Veröffentlicht in: | MedChemComm 2016-01, Vol.7 (6), p.1138-1145 |
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| creator | Lattmann, E Russell, S. T Schwalbe, C. H Shortt, A Balaram, P. N Theochari, E Alharbi, M Narayanan, R Lattmann, P |
| description | A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by X-ray analysis. Using a radiolabelled binding assay, potent CCK
1
selective ligands were identified (CCK
1
: 12 nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and
in vitro
excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X = H and X = F a fluorinated analogue (PNB-028 ), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer-(MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg kg
−1
by oral administration.
Hydroxy-pyrrolones, which were potent CCK1R antagonists, showed nanomolar
in vitro
activity and anticancer activity
in vivo
for colon and pancreatic cancer. |
| doi_str_mv | 10.1039/c6md00052e |
| format | Article |
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1
selective ligands were identified (CCK
1
: 12 nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and
in vitro
excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X = H and X = F a fluorinated analogue (PNB-028 ), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer-(MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg kg
−1
by oral administration.
Hydroxy-pyrrolones, which were potent CCK1R antagonists, showed nanomolar
in vitro
activity and anticancer activity
in vivo
for colon and pancreatic cancer.</description><identifier>ISSN: 2040-2503</identifier><identifier>EISSN: 2040-2511</identifier><identifier>DOI: 10.1039/c6md00052e</identifier><language>eng</language><ispartof>MedChemComm, 2016-01, Vol.7 (6), p.1138-1145</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c322t-d57ab9d9a947259f95351682f052c47bca15fdb2ff2ea874e883f67f4f4d6c1f3</citedby><cites>FETCH-LOGICAL-c322t-d57ab9d9a947259f95351682f052c47bca15fdb2ff2ea874e883f67f4f4d6c1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Lattmann, E</creatorcontrib><creatorcontrib>Russell, S. T</creatorcontrib><creatorcontrib>Schwalbe, C. H</creatorcontrib><creatorcontrib>Shortt, A</creatorcontrib><creatorcontrib>Balaram, P. N</creatorcontrib><creatorcontrib>Theochari, E</creatorcontrib><creatorcontrib>Alharbi, M</creatorcontrib><creatorcontrib>Narayanan, R</creatorcontrib><creatorcontrib>Lattmann, P</creatorcontrib><title>Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents</title><title>MedChemComm</title><description>A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by X-ray analysis. Using a radiolabelled binding assay, potent CCK
1
selective ligands were identified (CCK
1
: 12 nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and
in vitro
excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X = H and X = F a fluorinated analogue (PNB-028 ), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer-(MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg kg
−1
by oral administration.
Hydroxy-pyrrolones, which were potent CCK1R antagonists, showed nanomolar
in vitro
activity and anticancer activity
in vivo
for colon and pancreatic cancer.</description><issn>2040-2503</issn><issn>2040-2511</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNpF0D1PwzAQBmALgUQFXdiRMiIkgz8Tmw2F8iEVscDEELmO3QZSO_hSifx7UorKdDc8d9L7InRGyRUlXF_bfF0TQiRzB2jCiCCYSUoP9zvhx2gK8DEawplSWkzQe7mKrbMD9PGzCU3ANEvOuq6PKTOhN8sYGujhJpN4NdQpfg9YYpOGFndDSrHFDMfgIDOw5Y01wbrxculCD6foyJsW3PRvnqC3-9lr-YjnLw9P5e0cW85Yj2tZmIWutdGiYFJ7LbmkuWJ-TGJFsbCGSl8vmPfMGVUIpxT3eeGFF3Vuqecn6GL3t0vxa-Ogr9YNWNe2Jri4gYoqonLOJKcjvdxRmyJAcr7qUrMe81SUVNsSqzJ_vvstcTbi8x1OYPfuv2T-Azu7bnQ</recordid><startdate>20160101</startdate><enddate>20160101</enddate><creator>Lattmann, E</creator><creator>Russell, S. T</creator><creator>Schwalbe, C. H</creator><creator>Shortt, A</creator><creator>Balaram, P. N</creator><creator>Theochari, E</creator><creator>Alharbi, M</creator><creator>Narayanan, R</creator><creator>Lattmann, P</creator><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160101</creationdate><title>Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents</title><author>Lattmann, E ; Russell, S. T ; Schwalbe, C. H ; Shortt, A ; Balaram, P. N ; Theochari, E ; Alharbi, M ; Narayanan, R ; Lattmann, P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c322t-d57ab9d9a947259f95351682f052c47bca15fdb2ff2ea874e883f67f4f4d6c1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lattmann, E</creatorcontrib><creatorcontrib>Russell, S. T</creatorcontrib><creatorcontrib>Schwalbe, C. H</creatorcontrib><creatorcontrib>Shortt, A</creatorcontrib><creatorcontrib>Balaram, P. N</creatorcontrib><creatorcontrib>Theochari, E</creatorcontrib><creatorcontrib>Alharbi, M</creatorcontrib><creatorcontrib>Narayanan, R</creatorcontrib><creatorcontrib>Lattmann, P</creatorcontrib><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>MedChemComm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lattmann, E</au><au>Russell, S. T</au><au>Schwalbe, C. H</au><au>Shortt, A</au><au>Balaram, P. N</au><au>Theochari, E</au><au>Alharbi, M</au><au>Narayanan, R</au><au>Lattmann, P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents</atitle><jtitle>MedChemComm</jtitle><date>2016-01-01</date><risdate>2016</risdate><volume>7</volume><issue>6</issue><spage>1138</spage><epage>1145</epage><pages>1138-1145</pages><issn>2040-2503</issn><eissn>2040-2511</eissn><abstract>A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by X-ray analysis. Using a radiolabelled binding assay, potent CCK
1
selective ligands were identified (CCK
1
: 12 nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and
in vitro
excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X = H and X = F a fluorinated analogue (PNB-028 ), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer-(MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg kg
−1
by oral administration.
Hydroxy-pyrrolones, which were potent CCK1R antagonists, showed nanomolar
in vitro
activity and anticancer activity
in vivo
for colon and pancreatic cancer.</abstract><doi>10.1039/c6md00052e</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | MedChemComm, 2016-01, Vol.7 (6), p.1138-1145 |
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| language | eng |
| recordid | cdi_rsc_primary_c6md00052e |
| source | Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection |
| title | Cholecystokinin-1 receptor antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents |
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