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ndltd-NEU--neu-m044c450h2021-05-27T05:12:02ZDe novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.Abstract of Dissertation The p90 ribosomal S6 kinase (RSK) is a family of serine kinase that have been shown to be potential targets for anticancer therapy. Of the four known RSK isoforms, RSK1 and RSK2 are most closely linked to cancer cell growth. In a natural product extract screening effort aimed at finding selective inhibitors of RSK1 and RSK2, the natural product: SL0101 (a kaempferol glycoside) was discovered. In collaboration with Prof. Lannigan's group at Vanderbilt University, the O'Doherty group has found analogues of SL0101 that have improved potency, in vivo stability and solubility. In this regard, we have developed a synthesis route to cyclitol (5a-carbasugar) analogues of SL0101 that mimic the 3D structure of the O-glycoside analogues, yet should have improved in vivo activity due to the non-hydrolyzable glycosidic bond. The synthesis is able to prepare about half a gram quantities per batch of final product, C-5 n-Pr carbasugar analogue of SL0101, with 0.3% overall yield in 23 total steps. Concurrently, a series of analogues were also made with modified aglycon B-rings to further explore the RSK inhibition activity and bio-stability. The approach included a regio- and stereo-selective Pd-cyclitolization, cuprate addition and a regioselective acylation/carbamate formation with the use of Taylor's catalyst to install the desired product with excellent control of stereochemistry and regiochemistry. A related methyl substituted Pd-cyclitol-donor was also made for the purpose of synthesizing the natural product Epoxydine A and its analogues. Epoxydine A was isolated from the fungal endophyte Phoma sp. It has antibacterial and antialgal activities. Efforts towards the synthesis of Epoxydine A has been successful. The synthesis of stereo-isomeric analogues is and its analogues are ongoing and the latest efforts are described.http://hdl.handle.net/2047/D20316341
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Abstract of Dissertation The p90 ribosomal S6 kinase (RSK) is a family of serine kinase that have been shown to be potential targets for anticancer therapy. Of the four known RSK isoforms, RSK1 and RSK2 are most closely linked to cancer cell growth. In a natural product extract screening effort aimed at finding selective inhibitors of RSK1 and RSK2, the natural product: SL0101 (a kaempferol glycoside) was discovered. In collaboration with Prof. Lannigan's group at Vanderbilt
University, the O'Doherty group has found analogues of SL0101 that have improved potency, in vivo stability and solubility. In this regard, we have developed a synthesis route to cyclitol (5a-carbasugar) analogues of SL0101 that mimic the 3D structure of the O-glycoside analogues, yet should have improved in vivo activity due to the non-hydrolyzable glycosidic bond. The synthesis is able to prepare about half a gram quantities per batch of final product, C-5 n-Pr carbasugar analogue of
SL0101, with 0.3% overall yield in 23 total steps. Concurrently, a series of analogues were also made with modified aglycon B-rings to further explore the RSK inhibition activity and bio-stability. The approach included a regio- and stereo-selective Pd-cyclitolization, cuprate addition and a regioselective acylation/carbamate formation with the use of Taylor's catalyst to install the desired product with excellent control of stereochemistry and regiochemistry. A related methyl
substituted Pd-cyclitol-donor was also made for the purpose of synthesizing the natural product Epoxydine A and its analogues. Epoxydine A was isolated from the fungal endophyte Phoma sp. It has antibacterial and antialgal activities. Efforts towards the synthesis of Epoxydine A has been successful. The synthesis of stereo-isomeric analogues is and its analogues are ongoing and the latest efforts are described.
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De novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.
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| spellingShingle |
De novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.
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| title_short |
De novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.
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| title_full |
De novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.
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| title_fullStr |
De novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.
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| title_full_unstemmed |
De novo synthesis of RSK inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine A and its analogues.
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| title_sort |
de novo synthesis of rsk inhibitor analogues: carbasugar kaempferol glycosides; synthesis of epoxydine a and its analogues.
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http://hdl.handle.net/2047/D20316341
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1719407455060885504
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