Graduate Thesis Or Dissertation

 

Mandelalides as Potent Mitochondrial ATP Synthase Inhibitors : From Discovery of New Analogs to Function-Oriented Synthetic Studies Public Deposited

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  • Our quest for pharmaceutically important marine natural products led to re-isolation of known mandelalides A-D and identification of new congeners E-L from re-collected South African Lissoclinum tunicate specimens. Mandelalides A, B, and L were characterized as selective cancer cell toxins, with an unusual activity profile influenced by their glycosylation / acylation status and assay cell density. Real-time measurement of the respiratory capacity of living mammalian cells indicated that mandelalides A and B are inhibitors of mitochondrial function acting in a manner similar to the known mitochondrial ATP synthase inhibitor oligomycin A. Based on our current results we concluded that sensitivity of cancer cell lines to mandelalides A and B is more likely related to the oxidative phenotype and compromised adaptive survival response of the cell lines. After evaluation of the structure-activity profile of all natural and synthetic mandelalides, we hypothesized that the southern hemisphere of mandelalide A is more likely to be important for transport to the intracellular site of action, and perhaps binding to its molecular target, while the C₁₆-C₂₄ segment of the macrocycle may serve mainly as a spacer domain which remotely controls the conformational stability of the southern hemisphere. As part of our recent ongoing studies and to test our hypothesis we initiated the function-oriented stereoselective synthesis of simplified analogs of mandelalide A that retain the biological activity of the natural product. The highlight of our synthetic strategy is a catalytic asymmetric hetero Diels-Alder (HDA) cycloaddition to construct the tetrahydropyran moiety of the southern hemisphere.
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  • description.provenance : Submitted by Mohamad Nazari Alikorzani (nazarimo@oregonstate.edu) on 2017-03-30T21:43:12ZNo. of bitstreams: 2license_rdf: 1089 bytes, checksum: 0a703d871bf062c5fdc7850b1496693b (MD5)NazariMohamad2017.pdf: 44726326 bytes, checksum: 59010c03ad7f37722283116adf67b883 (MD5)
  • description.provenance : Made available in DSpace on 2017-04-13T18:00:30Z (GMT). No. of bitstreams: 2license_rdf: 1089 bytes, checksum: 0a703d871bf062c5fdc7850b1496693b (MD5)NazariMohamad2017.pdf: 44726326 bytes, checksum: 59010c03ad7f37722283116adf67b883 (MD5) Previous issue date: 2017-03-23
  • description.provenance : Approved for entry into archive by Julie Kurtz(julie.kurtz@oregonstate.edu) on 2017-04-13T17:34:42Z (GMT) No. of bitstreams: 2license_rdf: 1089 bytes, checksum: 0a703d871bf062c5fdc7850b1496693b (MD5)NazariMohamad2017.pdf: 44726326 bytes, checksum: 59010c03ad7f37722283116adf67b883 (MD5)
  • description.provenance : Approved for entry into archive by Laura Wilson(laura.wilson@oregonstate.edu) on 2017-04-13T18:00:30Z (GMT) No. of bitstreams: 2license_rdf: 1089 bytes, checksum: 0a703d871bf062c5fdc7850b1496693b (MD5)NazariMohamad2017.pdf: 44726326 bytes, checksum: 59010c03ad7f37722283116adf67b883 (MD5)
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  • 2017-08-10 to 2019-04-13

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