Syntheses and bioevaluation of novel tricyclic pyrone compounds and ovalicin and its analogues

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dc.contributor.author Battina, Srinivas K.
dc.date.accessioned 2007-05-04T19:25:20Z
dc.date.available 2007-05-04T19:25:20Z
dc.date.issued 2007-05-04T19:25:20Z
dc.identifier.uri http://hdl.handle.net/2097/310
dc.description.abstract The first part of this thesis deals with the syntheses of ovalicin and its analogues. Ovalicin inhibits the endothelial cell proliferation. Apart from being anti-angiogenic it also exhibits antibiotic, antitumor, and immunosuppressive properties. Unlike other syntheses, we started with an acyclic compound, ethyl propiolate (1.66). Our flexible route towards the synthesis used intramolecular Heck cyclization reaction to construct an appropriately functionalized 3-methylene-6-(tert-butyldimethylsilyloxy)cyclohexene (1.63) from 1.66 in four steps. A number of synthetic analogues were synthesized via this strategy. Upon selective epoxidation and dihydroxylation of 1.63, a mixture of diols (3S*,4R*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.107) and (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.108) were obtained. Subsequent functional group transformations of diols 1.107 and 1.108 gave ketones (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan-4-one (1.112) and (3S*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan -4-one (1.117). Addition of vinyl lithium to the ketones followed by functional group transformation gave ovalicin analogues. Several intermediates were subjected to biological activity test for inhibition of growth of T. brucei. Our synthetic efforts towards the synthesis of ovalicin are discussed. The second part of my thesis deals with the synthesis of different tricyclic pyrone (TP) analogues which inhibit the aggregation of Aβ peptides. Alzhemier’s disease (AD) is caused by accumulation of fibrillar amyloid deposits in the AD brain. We synthesized a series of tricyclic pyrone derivatives and evaluated their counteraction on amyloid toxicity. TP analogue, (5aS,7S)-7-[(1R) and (1S)-2-(N3-adenyl)-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3 -b] [1] benzopyran (CP2) is nontoxic, small and permeable molecule prevents the death of human neuroblastoma MC65 cells that conditionally expressed SβC gene. We further found that CP2 ameliorates the toxicity and inhibits the formation of Aβ oligomeric complexes. Binding studies using surface plasma resonance and atomic force microscopy studies suggest that CP2 permeates into the cells and interacts with Aβ peptides and inhibits the Aβ oligomerization. To understand the mechanism of Aβ aggregation and toxicity, CP2 and its derivatives are synthesized to evaluate their action. The key intermediate in the synthesis of CP2 is (5aS*,7S*)-7-[(1R*) and (1S*)-2-bromo-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3-b][1] benzopyran (2.9), which in turn can be prepared from our previously reported method. Our aim is to synthesize a series of compounds and investigate the biological activities of different TP analogues. en
dc.description.sponsorship Duy H Hua; Department of Chemistry en
dc.language.iso en_US en
dc.publisher Kansas State University en
dc.subject SYNTHESES en
dc.subject OVALICIN en
dc.subject TRICYCLIC PYRONE en
dc.subject ALZHEMIER'S en
dc.title Syntheses and bioevaluation of novel tricyclic pyrone compounds and ovalicin and its analogues en
dc.type Dissertation en
dc.description.degree Doctor of Philosophy en
dc.description.level Doctoral en
dc.description.department Department of Chemistry en
dc.description.advisor Duy H. Hua en
dc.subject.umi Chemistry, Organic (0490) en
dc.date.published 2007 en
dc.date.graduationmonth May en


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