Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation
The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blo...
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| Veröffentlicht in: | Journal of natural products (Washington, D.C.) D.C.), 2018-11, Vol.81 (11), p.2419-2428 |
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| creator | Rycek, Lukas Ticli, Vincenzo Pyszkowski, Jakob Latkolik, Simone Liu, Xin Atanasov, Atanas G Steinacher, Theresa Bauer, Rudolf Schuster, Daniela Dirsch, Verena M Schnürch, Michael Ernst, Margot Mihovilovic, Marko D |
| description | The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes. |
| doi_str_mv | 10.1021/acs.jnatprod.8b00439 |
| format | Article |
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The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.</description><identifier>ISSN: 0163-3864</identifier><identifier>ISSN: 1520-6025</identifier><identifier>EISSN: 1520-6025</identifier><identifier>DOI: 10.1021/acs.jnatprod.8b00439</identifier><identifier>PMID: 30362739</identifier><language>eng</language><publisher>United States: American Chemical Society and American Society of Pharmacognosy</publisher><subject>Allosteric Regulation ; anti-inflammatory activity ; Biological Products - chemistry ; Biological Products - pharmacology ; computer simulation ; gamma-aminobutyric acid ; HEK293 Cells ; Humans ; inflammation ; ion channels ; Molecular Docking Simulation ; Molecular Structure ; optical properties ; peroxisome proliferator-activated receptor gamma ; Polyynes - chemistry ; Polyynes - pharmacology ; PPAR gamma - metabolism ; Stereoisomerism ; stereoisomers ; stereoselective synthesis</subject><ispartof>Journal of natural products (Washington, D.C.), 2018-11, Vol.81 (11), p.2419-2428</ispartof><rights>Copyright © 2018 American Chemical Society and American Society of Pharmacognosy 2018 American Chemical Society and American Society of Pharmacognosy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a482t-49d6c51aa0b515d6510c863983944820d7968826233122a30b91391d8f6e076b3</citedby><cites>FETCH-LOGICAL-a482t-49d6c51aa0b515d6510c863983944820d7968826233122a30b91391d8f6e076b3</cites><orcidid>0000-0002-0057-5547 ; 0000-0002-5438-8368 ; 0000-0002-9261-5293 ; 0000-0003-2946-9294</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jnatprod.8b00439$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00439$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30362739$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rycek, Lukas</creatorcontrib><creatorcontrib>Ticli, Vincenzo</creatorcontrib><creatorcontrib>Pyszkowski, Jakob</creatorcontrib><creatorcontrib>Latkolik, Simone</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Atanasov, Atanas G</creatorcontrib><creatorcontrib>Steinacher, Theresa</creatorcontrib><creatorcontrib>Bauer, Rudolf</creatorcontrib><creatorcontrib>Schuster, Daniela</creatorcontrib><creatorcontrib>Dirsch, Verena M</creatorcontrib><creatorcontrib>Schnürch, Michael</creatorcontrib><creatorcontrib>Ernst, Margot</creatorcontrib><creatorcontrib>Mihovilovic, Marko D</creatorcontrib><title>Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation</title><title>Journal of natural products (Washington, D.C.)</title><addtitle>J. Nat. Prod</addtitle><description>The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.</description><subject>Allosteric Regulation</subject><subject>anti-inflammatory activity</subject><subject>Biological Products - chemistry</subject><subject>Biological Products - pharmacology</subject><subject>computer simulation</subject><subject>gamma-aminobutyric acid</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>inflammation</subject><subject>ion channels</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Structure</subject><subject>optical properties</subject><subject>peroxisome proliferator-activated receptor gamma</subject><subject>Polyynes - chemistry</subject><subject>Polyynes - pharmacology</subject><subject>PPAR gamma - metabolism</subject><subject>Stereoisomerism</subject><subject>stereoisomers</subject><subject>stereoselective synthesis</subject><issn>0163-3864</issn><issn>1520-6025</issn><issn>1520-6025</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkd9uFCEUxonR2LX6BsZw6c2sBxhY8MJku6napKkm1WvCMMyWZhZWYDbpe_jA4v5p9MZ4BZzz-76cw4fQawJzApS8MzbP74Mp2xT7uewAWqaeoBnhFBoBlD9FMyCCNUyK9gy9yPkeABgo_hydMWCCLpiaoZ-3xSUXsxudLX7n8O1DKHcu-4zjgOsNX-W4cWn_vIkl-mB9jiNevsfLnP1640I5ocuudqbi8CqGwa-nZIqP4dCthjem1NKIv9aJJ1uwCT2-8HGMa29r-XJnxmmveImeDWbM7tXxPEffP15-W31urr98ulotrxvTSlqaVvXCcmIMdJzwXnACVgqmJFNtBaBfKCElFZQxQqlh0CnCFOnlIBwsRMfO0YeD73bqNq63dZU6n94mvzHpQUfj9d-d4O_0Ou60oFwwTqrB26NBij8ml4ve-GzdOJrg4pQ1JVLVPFql_gOlQpGWy0VF2wNqU8w5ueFxIgL6d_a6Zq9P2etj9lX25s9tHkWnsCsAB2Avj1MK9XP_7fkLXUfAsw</recordid><startdate>20181126</startdate><enddate>20181126</enddate><creator>Rycek, Lukas</creator><creator>Ticli, Vincenzo</creator><creator>Pyszkowski, Jakob</creator><creator>Latkolik, Simone</creator><creator>Liu, Xin</creator><creator>Atanasov, Atanas G</creator><creator>Steinacher, Theresa</creator><creator>Bauer, Rudolf</creator><creator>Schuster, Daniela</creator><creator>Dirsch, Verena M</creator><creator>Schnürch, Michael</creator><creator>Ernst, Margot</creator><creator>Mihovilovic, Marko D</creator><general>American Chemical Society and American Society of Pharmacognosy</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>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0057-5547</orcidid><orcidid>https://orcid.org/0000-0002-5438-8368</orcidid><orcidid>https://orcid.org/0000-0002-9261-5293</orcidid><orcidid>https://orcid.org/0000-0003-2946-9294</orcidid></search><sort><creationdate>20181126</creationdate><title>Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation</title><author>Rycek, Lukas ; Ticli, Vincenzo ; Pyszkowski, Jakob ; Latkolik, Simone ; Liu, Xin ; Atanasov, Atanas G ; Steinacher, Theresa ; Bauer, Rudolf ; Schuster, Daniela ; Dirsch, Verena M ; Schnürch, Michael ; Ernst, Margot ; Mihovilovic, Marko D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a482t-49d6c51aa0b515d6510c863983944820d7968826233122a30b91391d8f6e076b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Allosteric Regulation</topic><topic>anti-inflammatory activity</topic><topic>Biological Products - chemistry</topic><topic>Biological Products - pharmacology</topic><topic>computer simulation</topic><topic>gamma-aminobutyric acid</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>inflammation</topic><topic>ion channels</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Structure</topic><topic>optical properties</topic><topic>peroxisome proliferator-activated receptor gamma</topic><topic>Polyynes - chemistry</topic><topic>Polyynes - pharmacology</topic><topic>PPAR gamma - metabolism</topic><topic>Stereoisomerism</topic><topic>stereoisomers</topic><topic>stereoselective synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rycek, Lukas</creatorcontrib><creatorcontrib>Ticli, Vincenzo</creatorcontrib><creatorcontrib>Pyszkowski, Jakob</creatorcontrib><creatorcontrib>Latkolik, Simone</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Atanasov, Atanas G</creatorcontrib><creatorcontrib>Steinacher, Theresa</creatorcontrib><creatorcontrib>Bauer, Rudolf</creatorcontrib><creatorcontrib>Schuster, Daniela</creatorcontrib><creatorcontrib>Dirsch, Verena M</creatorcontrib><creatorcontrib>Schnürch, Michael</creatorcontrib><creatorcontrib>Ernst, Margot</creatorcontrib><creatorcontrib>Mihovilovic, Marko D</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>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of natural products (Washington, D.C.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rycek, Lukas</au><au>Ticli, Vincenzo</au><au>Pyszkowski, Jakob</au><au>Latkolik, Simone</au><au>Liu, Xin</au><au>Atanasov, Atanas G</au><au>Steinacher, Theresa</au><au>Bauer, Rudolf</au><au>Schuster, Daniela</au><au>Dirsch, Verena M</au><au>Schnürch, Michael</au><au>Ernst, Margot</au><au>Mihovilovic, Marko D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation</atitle><jtitle>Journal of natural products (Washington, D.C.)</jtitle><addtitle>J. Nat. Prod</addtitle><date>2018-11-26</date><risdate>2018</risdate><volume>81</volume><issue>11</issue><spage>2419</spage><epage>2428</epage><pages>2419-2428</pages><issn>0163-3864</issn><issn>1520-6025</issn><eissn>1520-6025</eissn><abstract>The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.</abstract><cop>United States</cop><pub>American Chemical Society and American Society of Pharmacognosy</pub><pmid>30362739</pmid><doi>10.1021/acs.jnatprod.8b00439</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-0057-5547</orcidid><orcidid>https://orcid.org/0000-0002-5438-8368</orcidid><orcidid>https://orcid.org/0000-0002-9261-5293</orcidid><orcidid>https://orcid.org/0000-0003-2946-9294</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0163-3864 |
| ispartof | Journal of natural products (Washington, D.C.), 2018-11, Vol.81 (11), p.2419-2428 |
| issn | 0163-3864 1520-6025 1520-6025 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Allosteric Regulation anti-inflammatory activity Biological Products - chemistry Biological Products - pharmacology computer simulation gamma-aminobutyric acid HEK293 Cells Humans inflammation ion channels Molecular Docking Simulation Molecular Structure optical properties peroxisome proliferator-activated receptor gamma Polyynes - chemistry Polyynes - pharmacology PPAR gamma - metabolism Stereoisomerism stereoisomers stereoselective synthesis |
| title | Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation |
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