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Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression
(E)-13-(Aryl/heteroaryl)parthenolides (5a–i and 6a–i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminoph...
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Published in: | European journal of medicinal chemistry 2014-10, Vol.85, p.517-525 |
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container_title | European journal of medicinal chemistry |
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creator | Penthala, Narsimha R. Bommagani, Shobanbabu Janganati, Venumadhav MacNicol, Kenzie B. Cragle, Chad E. Madadi, Nikhil R. Hardy, Linda L. MacNicol, Angus M. Crooks, Peter A. |
description | (E)-13-(Aryl/heteroaryl)parthenolides (5a–i and 6a–i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminophenyl) parthenolide (5b) caused a significant inhibition of progesterone-stimulated oocyte maturation, and was determined to function downstream of MAP kinase signaling, but upstream of the activation of the universal G2/M regulator, M-phase promoting factor (MPF), cyclin B/Cyclin-dependent kinase (CDK). The compound (E)-13-(2-bromo-phenyl)parthenolide (5c) activates oocyte maturation independently of progesterone stimulation. Compounds 5b and 5c displayed modest growth inhibition on select cancer cell lines at 10 μM dose when tested on the panel of 60 cancer cell lines. By contrast, compounds (5f and 7) did not modulate oocyte maturation but did exhibit micromolar level growth inhibition against most of the human cancer cell lines over a range of doses. Together, our findings indicate that screening of compounds in the oocyte maturation assay may identify additional effective cell cycle regulatory compounds that do not necessarily exert overt cytotoxicity as assessed in traditional drug screening assays.
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•Developed a method for the synthesis of E-olefinic coupling products of PTL and MMB.•Compounds screened for anticancer activity and effects on cell cycle progression.•Two compounds showed good growth inhibitory effects on human cancer cell lines.•The two compounds caused significant effects in oocyte maturation assays.•Screening for effects on cell cycle progression complements cancer cell screening. |
doi_str_mv | 10.1016/j.ejmech.2014.08.022 |
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•Developed a method for the synthesis of E-olefinic coupling products of PTL and MMB.•Compounds screened for anticancer activity and effects on cell cycle progression.•Two compounds showed good growth inhibitory effects on human cancer cell lines.•The two compounds caused significant effects in oocyte maturation assays.•Screening for effects on cell cycle progression complements cancer cell screening.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.08.022</identifier><identifier>PMID: 25117652</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Anti-cancer activity ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Cycle - drug effects ; Cell Line, Tumor ; Heck reaction ; Humans ; Melampomagnolide B ; Oocyte maturation ; Oocytes - cytology ; Oocytes - drug effects ; Parthenolide ; Sesquiterpenes - chemistry ; Structure-Activity Relationship ; Xenopus</subject><ispartof>European journal of medicinal chemistry, 2014-10, Vol.85, p.517-525</ispartof><rights>2014 Elsevier Masson SAS</rights><rights>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</rights><rights>2014 Elsevier Masson SAS. All rights reserved. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-329363a7612bb656340f79e7966d4c930faaeda0ea0627643317694ff03c73323</citedby><cites>FETCH-LOGICAL-c463t-329363a7612bb656340f79e7966d4c930faaeda0ea0627643317694ff03c73323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25117652$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Penthala, Narsimha R.</creatorcontrib><creatorcontrib>Bommagani, Shobanbabu</creatorcontrib><creatorcontrib>Janganati, Venumadhav</creatorcontrib><creatorcontrib>MacNicol, Kenzie B.</creatorcontrib><creatorcontrib>Cragle, Chad E.</creatorcontrib><creatorcontrib>Madadi, Nikhil R.</creatorcontrib><creatorcontrib>Hardy, Linda L.</creatorcontrib><creatorcontrib>MacNicol, Angus M.</creatorcontrib><creatorcontrib>Crooks, Peter A.</creatorcontrib><title>Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>(E)-13-(Aryl/heteroaryl)parthenolides (5a–i and 6a–i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminophenyl) parthenolide (5b) caused a significant inhibition of progesterone-stimulated oocyte maturation, and was determined to function downstream of MAP kinase signaling, but upstream of the activation of the universal G2/M regulator, M-phase promoting factor (MPF), cyclin B/Cyclin-dependent kinase (CDK). The compound (E)-13-(2-bromo-phenyl)parthenolide (5c) activates oocyte maturation independently of progesterone stimulation. Compounds 5b and 5c displayed modest growth inhibition on select cancer cell lines at 10 μM dose when tested on the panel of 60 cancer cell lines. By contrast, compounds (5f and 7) did not modulate oocyte maturation but did exhibit micromolar level growth inhibition against most of the human cancer cell lines over a range of doses. Together, our findings indicate that screening of compounds in the oocyte maturation assay may identify additional effective cell cycle regulatory compounds that do not necessarily exert overt cytotoxicity as assessed in traditional drug screening assays.
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•Developed a method for the synthesis of E-olefinic coupling products of PTL and MMB.•Compounds screened for anticancer activity and effects on cell cycle progression.•Two compounds showed good growth inhibitory effects on human cancer cell lines.•The two compounds caused significant effects in oocyte maturation assays.•Screening for effects on cell cycle progression complements cancer cell screening.</description><subject>Animals</subject><subject>Anti-cancer activity</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Heck reaction</subject><subject>Humans</subject><subject>Melampomagnolide B</subject><subject>Oocyte maturation</subject><subject>Oocytes - cytology</subject><subject>Oocytes - drug effects</subject><subject>Parthenolide</subject><subject>Sesquiterpenes - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>Xenopus</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNp9UU1v1DAQtRAVXVr-AUI-ckkYf8TZXJCgoi1SpV7o2Zp1JrtekjjY3kr770nYUuDCyfLMm_fmzWPsrYBSgDAf9iXtB3K7UoLQJaxLkPIFW4narAslK_2SreaKKiqp9Dl7ndIeACoD8Iqdy0rMuEqu2HRL7jufYmgPLiceOj5hzDsaQ-9b4ji2fKAehykMuD0Vi88c09zJ3uHoKPJhHu4xh5h43mFe_r47ckd9z93R9bTwbyOl5MN4yc467BO9eXov2MP1l29Xt8Xd_c3Xq093hdNG5dlBo4zC2gi52ZjKKA1d3VDdGNNq1yjoEKlFIAQja6OVmg01uutAuVopqS7YxxPvdNgM1Doac8TeTtEPGI82oLf_dka_s9vwaLUwtZELwfsnghh-HChlO_i0eMKRwiFZURnRmBqa9QzVJ6iLIaVI3bOMALuEZff2FJZdwrKwtvBL4d3fKz4P_U7njweaD_XoKdrkPM03b30kl20b_P8VfgKYeam7</recordid><startdate>20141006</startdate><enddate>20141006</enddate><creator>Penthala, Narsimha R.</creator><creator>Bommagani, Shobanbabu</creator><creator>Janganati, Venumadhav</creator><creator>MacNicol, Kenzie B.</creator><creator>Cragle, Chad E.</creator><creator>Madadi, Nikhil R.</creator><creator>Hardy, Linda L.</creator><creator>MacNicol, Angus M.</creator><creator>Crooks, Peter A.</creator><general>Elsevier Masson SAS</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141006</creationdate><title>Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression</title><author>Penthala, Narsimha R. ; Bommagani, Shobanbabu ; Janganati, Venumadhav ; MacNicol, Kenzie B. ; Cragle, Chad E. ; Madadi, Nikhil R. ; Hardy, Linda L. ; MacNicol, Angus M. ; Crooks, Peter A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-329363a7612bb656340f79e7966d4c930faaeda0ea0627643317694ff03c73323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Anti-cancer activity</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Heck reaction</topic><topic>Humans</topic><topic>Melampomagnolide B</topic><topic>Oocyte maturation</topic><topic>Oocytes - cytology</topic><topic>Oocytes - drug effects</topic><topic>Parthenolide</topic><topic>Sesquiterpenes - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>Xenopus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Penthala, Narsimha R.</creatorcontrib><creatorcontrib>Bommagani, Shobanbabu</creatorcontrib><creatorcontrib>Janganati, Venumadhav</creatorcontrib><creatorcontrib>MacNicol, Kenzie B.</creatorcontrib><creatorcontrib>Cragle, Chad E.</creatorcontrib><creatorcontrib>Madadi, Nikhil R.</creatorcontrib><creatorcontrib>Hardy, Linda L.</creatorcontrib><creatorcontrib>MacNicol, Angus M.</creatorcontrib><creatorcontrib>Crooks, Peter A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Penthala, Narsimha R.</au><au>Bommagani, Shobanbabu</au><au>Janganati, Venumadhav</au><au>MacNicol, Kenzie B.</au><au>Cragle, Chad E.</au><au>Madadi, Nikhil R.</au><au>Hardy, Linda L.</au><au>MacNicol, Angus M.</au><au>Crooks, Peter A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2014-10-06</date><risdate>2014</risdate><volume>85</volume><spage>517</spage><epage>525</epage><pages>517-525</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>(E)-13-(Aryl/heteroaryl)parthenolides (5a–i and 6a–i) were synthesized and evaluated for their ability to modify cell cycle progression during progesterone-stimulated Xenopus oocyte maturation and screened for their anticancer activity against a panel of 60 human cancer cell lines. (E)-13-(4-aminophenyl) parthenolide (5b) caused a significant inhibition of progesterone-stimulated oocyte maturation, and was determined to function downstream of MAP kinase signaling, but upstream of the activation of the universal G2/M regulator, M-phase promoting factor (MPF), cyclin B/Cyclin-dependent kinase (CDK). The compound (E)-13-(2-bromo-phenyl)parthenolide (5c) activates oocyte maturation independently of progesterone stimulation. Compounds 5b and 5c displayed modest growth inhibition on select cancer cell lines at 10 μM dose when tested on the panel of 60 cancer cell lines. By contrast, compounds (5f and 7) did not modulate oocyte maturation but did exhibit micromolar level growth inhibition against most of the human cancer cell lines over a range of doses. Together, our findings indicate that screening of compounds in the oocyte maturation assay may identify additional effective cell cycle regulatory compounds that do not necessarily exert overt cytotoxicity as assessed in traditional drug screening assays.
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•Developed a method for the synthesis of E-olefinic coupling products of PTL and MMB.•Compounds screened for anticancer activity and effects on cell cycle progression.•Two compounds showed good growth inhibitory effects on human cancer cell lines.•The two compounds caused significant effects in oocyte maturation assays.•Screening for effects on cell cycle progression complements cancer cell screening.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>25117652</pmid><doi>10.1016/j.ejmech.2014.08.022</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Anti-cancer activity Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Cycle - drug effects Cell Line, Tumor Heck reaction Humans Melampomagnolide B Oocyte maturation Oocytes - cytology Oocytes - drug effects Parthenolide Sesquiterpenes - chemistry Structure-Activity Relationship Xenopus |
title | Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression |
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