Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation
[Display omitted] The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (16), p.2286-2289 |
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| creator | Radhakrishnan, Sridhar Syed, Riyaz Takei, Hisashi Kobayashi, Ikei S. Nakamura, Eugene Sultana, Farheen Kamal, Ahmed Tenen, Daniel G. Kobayashi, Susumu S. |
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The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring. |
| doi_str_mv | 10.1016/j.bmcl.2019.06.024 |
| format | Article |
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The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2019.06.024</identifier><identifier>PMID: 31278031</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alkynes - chemistry ; Alkynes - pharmacology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; CCAAT-Enhancer-Binding Protein-alpha - antagonists & inhibitors ; CCAAT-Enhancer-Binding Protein-alpha - genetics ; CCAAT-Enhancer-Binding Protein-alpha - metabolism ; CCAAT/enhancer binding protein ; Cell Differentiation - drug effects ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - metabolism ; Molecular Structure ; Myeloid differentiation ; Quinazolinones - chemical synthesis ; Quinazolinones - chemistry ; Quinazolinones - pharmacology ; Structure-Activity Relationship ; Styryl quinazolinones ; Thienopyrimidinone</subject><ispartof>Bioorganic & medicinal chemistry letters, 2019-08, Vol.29 (16), p.2286-2289</ispartof><rights>2019</rights><rights>Copyright © 2019. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-ee34e4b39f3df28a7d23aeaf2c0a07bddb110ac7df7e74a0c3f9492fa9d3e8b63</citedby><cites>FETCH-LOGICAL-c455t-ee34e4b39f3df28a7d23aeaf2c0a07bddb110ac7df7e74a0c3f9492fa9d3e8b63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2019.06.024$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31278031$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Radhakrishnan, Sridhar</creatorcontrib><creatorcontrib>Syed, Riyaz</creatorcontrib><creatorcontrib>Takei, Hisashi</creatorcontrib><creatorcontrib>Kobayashi, Ikei S.</creatorcontrib><creatorcontrib>Nakamura, Eugene</creatorcontrib><creatorcontrib>Sultana, Farheen</creatorcontrib><creatorcontrib>Kamal, Ahmed</creatorcontrib><creatorcontrib>Tenen, Daniel G.</creatorcontrib><creatorcontrib>Kobayashi, Susumu S.</creatorcontrib><title>Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring.</description><subject>Alkynes - chemistry</subject><subject>Alkynes - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>CCAAT-Enhancer-Binding Protein-alpha - antagonists & inhibitors</subject><subject>CCAAT-Enhancer-Binding Protein-alpha - genetics</subject><subject>CCAAT-Enhancer-Binding Protein-alpha - metabolism</subject><subject>CCAAT/enhancer binding protein</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Molecular Structure</subject><subject>Myeloid differentiation</subject><subject>Quinazolinones - chemical synthesis</subject><subject>Quinazolinones - chemistry</subject><subject>Quinazolinones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Styryl quinazolinones</subject><subject>Thienopyrimidinone</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kNtKxDAQhoMo7np4AS-kL9A6OWwPIIKIJxAUVPAupMlEs3RTTbuF-vRmWV30xqu5-A8z8xFyRCGjQPOTeVYvdJMxoFUGeQZMbJEpFblIuYDZNplClUNaVuJlQva6bg5ABQixSyacsqIETqfk4bEfw9gkH0vn1WfbON967BLlTeL6LsH-bfRRNhjcoHo3RM15s9SYLEZsWmcS46zFgL53UW_9Admxqunw8Hvuk-ery6eLm_Tu_vr24vwu1WI261NELlDUvLLcWFaqwjCuUFmmQUFRG1NTCkoXxhZYCAWa20pUzKrKcCzrnO-Ts3Xv-7JeoNHxgKAa-R7cQoVRtsrJv4p3b_K1HWTJeM5yGgvYukCHtusC2k2WglzxlXO54itXfCXkMvKNoePfWzeRH6DRcLo2YPx9cBhkpx16jcYF1L00rfuv_wuzYpEo</recordid><startdate>20190815</startdate><enddate>20190815</enddate><creator>Radhakrishnan, Sridhar</creator><creator>Syed, Riyaz</creator><creator>Takei, Hisashi</creator><creator>Kobayashi, Ikei S.</creator><creator>Nakamura, Eugene</creator><creator>Sultana, Farheen</creator><creator>Kamal, Ahmed</creator><creator>Tenen, Daniel G.</creator><creator>Kobayashi, Susumu S.</creator><general>Elsevier Ltd</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>5PM</scope></search><sort><creationdate>20190815</creationdate><title>Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation</title><author>Radhakrishnan, Sridhar ; Syed, Riyaz ; Takei, Hisashi ; Kobayashi, Ikei S. ; Nakamura, Eugene ; Sultana, Farheen ; Kamal, Ahmed ; Tenen, Daniel G. ; Kobayashi, Susumu S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-ee34e4b39f3df28a7d23aeaf2c0a07bddb110ac7df7e74a0c3f9492fa9d3e8b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Alkynes - chemistry</topic><topic>Alkynes - pharmacology</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>CCAAT-Enhancer-Binding Protein-alpha - antagonists & inhibitors</topic><topic>CCAAT-Enhancer-Binding Protein-alpha - genetics</topic><topic>CCAAT-Enhancer-Binding Protein-alpha - metabolism</topic><topic>CCAAT/enhancer binding protein</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - metabolism</topic><topic>Molecular Structure</topic><topic>Myeloid differentiation</topic><topic>Quinazolinones - chemical synthesis</topic><topic>Quinazolinones - chemistry</topic><topic>Quinazolinones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Styryl quinazolinones</topic><topic>Thienopyrimidinone</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Radhakrishnan, Sridhar</creatorcontrib><creatorcontrib>Syed, Riyaz</creatorcontrib><creatorcontrib>Takei, Hisashi</creatorcontrib><creatorcontrib>Kobayashi, Ikei S.</creatorcontrib><creatorcontrib>Nakamura, Eugene</creatorcontrib><creatorcontrib>Sultana, Farheen</creatorcontrib><creatorcontrib>Kamal, Ahmed</creatorcontrib><creatorcontrib>Tenen, Daniel G.</creatorcontrib><creatorcontrib>Kobayashi, Susumu S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Radhakrishnan, Sridhar</au><au>Syed, Riyaz</au><au>Takei, Hisashi</au><au>Kobayashi, Ikei S.</au><au>Nakamura, Eugene</au><au>Sultana, Farheen</au><au>Kamal, Ahmed</au><au>Tenen, Daniel G.</au><au>Kobayashi, Susumu S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2019-08-15</date><risdate>2019</risdate><volume>29</volume><issue>16</issue><spage>2286</spage><epage>2289</epage><pages>2286-2289</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The tumor suppressor transcription factor CCAAT enhancer-binding protein α (C/EBPα) expression is downregulated in myeloid leukemias and enhancement of C/EBPα expression induces granulocytic differentiation in leukemic cells. Previously we reported that Styryl quinazolinones induce myeloid differentiation in HL-60 cells by upregulating C/EBPα expression. To identify more potent molecule that can induce leukemic cell differentiation we synthesized and evaluated new series of styryl quinazolinones, ethynyl styryl quinazolinones, styryl quinolinones and thienopyrimidinones. Thienopyrimidinones were found toxic and styryl quinolinones were found inactive. Ethynyl styryl quinazolinone 39 and styryl quinazolinone 5 were found active on par with the earlier reported analogues 1 and 2 suggesting that the 5-nitro furan-2-yl styryl quinazolinones find a real promise in leukemic cell differentiation. The improved potency of 5 suggested that further modifications in the 5-nitro furan-2-yl styryl quinazolinones can be at the phenyl substitution at the 3-position of the quinazolinone ring apart from the 5-position of the heteroaryl ring.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31278031</pmid><doi>10.1016/j.bmcl.2019.06.024</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2019-08, Vol.29 (16), p.2286-2289 |
| issn | 0960-894X 1464-3405 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Alkynes - chemistry Alkynes - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects CCAAT-Enhancer-Binding Protein-alpha - antagonists & inhibitors CCAAT-Enhancer-Binding Protein-alpha - genetics CCAAT-Enhancer-Binding Protein-alpha - metabolism CCAAT/enhancer binding protein Cell Differentiation - drug effects Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Screening Assays, Antitumor HL-60 Cells Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Molecular Structure Myeloid differentiation Quinazolinones - chemical synthesis Quinazolinones - chemistry Quinazolinones - pharmacology Structure-Activity Relationship Styryl quinazolinones Thienopyrimidinone |
| title | Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation |
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