Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities
We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t‐butyldimethylsilyl (TBS) group at the hy...
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| Veröffentlicht in: | ChemMedChem 2022-06, Vol.17 (12), p.e202200176-n/a |
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| creator | Oikawa, Tsuyoshi Fujii, Shinya Mori, Shuichi Masuno, Hiroyuki Kawachi, Emiko Kagechika, Hiroyuki |
| description | We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t‐butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription‐promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα‐selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype‐selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.
The detailed structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids was investigated using silyl functionalities. 3‐tert‐Butyldimethylsilyl derivative 24 c exhibited potent HL‐60 cell differentiation‐inducing activity. Compound 24 c exhibited agonistic activity towards all three subtypes of retinoic acid receptor (RAR), with the highest activity towards RARγ. |
| doi_str_mv | 10.1002/cmdc.202200176 |
| format | Article |
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The detailed structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids was investigated using silyl functionalities. 3‐tert‐Butyldimethylsilyl derivative 24 c exhibited potent HL‐60 cell differentiation‐inducing activity. Compound 24 c exhibited agonistic activity towards all three subtypes of retinoic acid receptor (RAR), with the highest activity towards RARγ.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.202200176</identifier><identifier>PMID: 35451569</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Hydrophobic pharmacophore ; Hydrophobicity ; Lead compounds ; Retinoic acid ; Retinoic acid receptor ; Retinoic acid receptors ; Retinoid ; Retinoids ; Selectivity ; Silicon ; Structure-activity relationship ; Synthesis</subject><ispartof>ChemMedChem, 2022-06, Vol.17 (12), p.e202200176-n/a</ispartof><rights>2022 Wiley‐VCH GmbH</rights><rights>2022 Wiley-VCH GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4396-e8833e239dd9faf3ee671254a4f2a3034ec55341c41df2f0d6e7e3703e2602693</citedby><cites>FETCH-LOGICAL-c4396-e8833e239dd9faf3ee671254a4f2a3034ec55341c41df2f0d6e7e3703e2602693</cites><orcidid>0000-0002-6747-1013</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.202200176$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.202200176$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35451569$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oikawa, Tsuyoshi</creatorcontrib><creatorcontrib>Fujii, Shinya</creatorcontrib><creatorcontrib>Mori, Shuichi</creatorcontrib><creatorcontrib>Masuno, Hiroyuki</creatorcontrib><creatorcontrib>Kawachi, Emiko</creatorcontrib><creatorcontrib>Kagechika, Hiroyuki</creatorcontrib><title>Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t‐butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription‐promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα‐selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype‐selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.
The detailed structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids was investigated using silyl functionalities. 3‐tert‐Butyldimethylsilyl derivative 24 c exhibited potent HL‐60 cell differentiation‐inducing activity. Compound 24 c exhibited agonistic activity towards all three subtypes of retinoic acid receptor (RAR), with the highest activity towards RARγ.</description><subject>Hydrophobic pharmacophore</subject><subject>Hydrophobicity</subject><subject>Lead compounds</subject><subject>Retinoic acid</subject><subject>Retinoic acid receptor</subject><subject>Retinoic acid receptors</subject><subject>Retinoid</subject><subject>Retinoids</subject><subject>Selectivity</subject><subject>Silicon</subject><subject>Structure-activity relationship</subject><subject>Synthesis</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqFkc1u1DAUhS0EomVgyxJZYsNmBv_lj90obSlSEYjSdeRxbhhXjh1spyhd9RGQeJa-UJ-kjqYdJDYsLNu63zn3SAeh15SsKCHsvepbtWKEMUJokT9Bh7TMybKgZfF0_y6qA_QihEtChChp-Rwd8ExkNMurQ3R7Hv2o4uilwUdwBcYNPdiIXYfPtdHK2bub37WzUWqr7Q_8DaK2TrfhA35Uwt3Nn7WK-krHKc2NjNrZsNVDIsZ2mq3iFvDp1Ho3bN1GK_x1K30v1fz1MAM72w3Ya5fGa5UW4IswL0wpJoNPRqtmW2l01BBeomedNAFePdwLdHFy_L0-XZ59-fipXp8tleBVvoSy5BwYr9q26mTHAfKCskxI0THJCRegsowLqgRtO9aRNocCeEGSJicsr_gCvdv5Dt79HCHEptdBgTHSghtDw_JMsGo-CX37D3rpRp8Cz1SRcmQipVmg1Y5S3oXgoWsGr3vpp4aSZi60mQtt9oUmwZsH23HTQ7vHHxtMQLUDfmkD03_smvrzUf3X_B5SA7Lb</recordid><startdate>20220620</startdate><enddate>20220620</enddate><creator>Oikawa, Tsuyoshi</creator><creator>Fujii, Shinya</creator><creator>Mori, Shuichi</creator><creator>Masuno, Hiroyuki</creator><creator>Kawachi, Emiko</creator><creator>Kagechika, Hiroyuki</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-6747-1013</orcidid></search><sort><creationdate>20220620</creationdate><title>Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities</title><author>Oikawa, Tsuyoshi ; Fujii, Shinya ; Mori, Shuichi ; Masuno, Hiroyuki ; Kawachi, Emiko ; Kagechika, Hiroyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4396-e8833e239dd9faf3ee671254a4f2a3034ec55341c41df2f0d6e7e3703e2602693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Hydrophobic pharmacophore</topic><topic>Hydrophobicity</topic><topic>Lead compounds</topic><topic>Retinoic acid</topic><topic>Retinoic acid receptor</topic><topic>Retinoic acid receptors</topic><topic>Retinoid</topic><topic>Retinoids</topic><topic>Selectivity</topic><topic>Silicon</topic><topic>Structure-activity relationship</topic><topic>Synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oikawa, Tsuyoshi</creatorcontrib><creatorcontrib>Fujii, Shinya</creatorcontrib><creatorcontrib>Mori, Shuichi</creatorcontrib><creatorcontrib>Masuno, Hiroyuki</creatorcontrib><creatorcontrib>Kawachi, Emiko</creatorcontrib><creatorcontrib>Kagechika, Hiroyuki</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oikawa, Tsuyoshi</au><au>Fujii, Shinya</au><au>Mori, Shuichi</au><au>Masuno, Hiroyuki</au><au>Kawachi, Emiko</au><au>Kagechika, Hiroyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2022-06-20</date><risdate>2022</risdate><volume>17</volume><issue>12</issue><spage>e202200176</spage><epage>n/a</epage><pages>e202200176-n/a</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t‐butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription‐promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα‐selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype‐selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.
The detailed structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids was investigated using silyl functionalities. 3‐tert‐Butyldimethylsilyl derivative 24 c exhibited potent HL‐60 cell differentiation‐inducing activity. Compound 24 c exhibited agonistic activity towards all three subtypes of retinoic acid receptor (RAR), with the highest activity towards RARγ.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>35451569</pmid><doi>10.1002/cmdc.202200176</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-6747-1013</orcidid></addata></record> |
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| subjects | Hydrophobic pharmacophore Hydrophobicity Lead compounds Retinoic acid Retinoic acid receptor Retinoic acid receptors Retinoid Retinoids Selectivity Silicon Structure-activity relationship Synthesis |
| title | Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities |
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