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Browsing by Author "Neidigh, Kurt Alan"

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    Chemical studies of the C-4 position of baccatin III and taxol
    Neidigh, Kurt Alan (Virginia Tech, 1995)
    Because of the efficacy of taxol against a wide variety of cancers, the demand for this drug has vastly increased during the last decade. Due to its limited natural supply, a number of alternative sources of taxol continue to be investigated. One approach toward alleviating the taxol supply problem is by the systematic investigation of the structure-activity relationships of the molecule, in order to establish the structural features and functionalities necessary for biological activity. Research efforts during the last decade have led to the establishment of the molecular domains and functionalilties which are crucial for biological activity, however at the inception of this work, the structure-activity relationships of the C-4 position of taxol were unknown. It was thus the major goal of this work to prepare 4-deacetyltaxol, in order to assess the importance of the C-4 acetate for overall activity, as well as to have a template molecule with which to begin studies aimed at determining the effect on activity rendered by replacement of the C-4 acetate with other acyl groups. Preliminary studies of the deacylation and reacylation of baccatin III were carried out in order to find conditions necessary for the preparation of 4-deacetylbaccatin III, and hence 4-deacetyltaxol. 4-Deacetyltaxol has now been prepared from baccatin III via two synthetic approaches and from taxol via one synthetic approach, and has been shown to be significantly less potent than taxol, suggesting that the C-4 acetate is necessary for biological activity. From the investigation of several potential synthetic approaches toward the formation of 4-acyltaxol analogs, one methodology has been developed which has allowed the preparation of 4-acyltaxol derivatives from baccatin III] or the more readily available 10- deacetylbaccatin III. This particular methodology can be extended to the preparation of other 4-acvitaxol or 4-acyltaxotere derivatives. Two C-5a halogenated oxetane ring-opened compounds have been prepared from a 4-deacetyltaxol derivative, offering the opportunity to investigate the potential effects on biological activity generated by modifications to the oxetane ring.
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    Studies on the biosynthesis of podophyllotoxin:synthesis of labelled yatein and matairesinol, two potential precursors of podophyllotoxin
    Neidigh, Kurt Alan (Virginia Tech, 1992)
    Podophyllotoxin, a naturally occurring lignan isolated from several species of Podophyllum, is used as a precursor to the clinical chemotherapeutic agents teniposide and etoposide. The biosynthesis of podophyllotoxin is not fully understood, but its optical activity, like that of most lignans, is suggestive of enzyme-mediated processes. It has been proposed that the formation of podophyllotoxin begins with stereo-controlled coupling of a hydroxy cinnamyl alcohol derivative and a substituted hydroxy Cinnamic acid, although no "coupling" enzyme has been isolated to date. Further biosynthetic modifications of the coupled compound could lead to matairesinol and/or yatein, which have been proposed as potential biological precursors of podophyllotoxin. Although no firm evidence has been obtained to date, conversion of matairesinol to yatein has been postulated. This conversion would, however, involve biosynthetic steps which, though common for hydroxycinnamates, are unprecedented at the dimeric level. Conversion of yatein to podophyllotoxin has been demonstrated, with the conversion involving a stereo-controlled cyclization and subsequent stereospecific hydroxylation. In order to investigate the biosynthesis of podophyllotoxin, leading from the postulated precursors matairesinol and yatein, a series of stereospecific deuterium-labelled matairesinol and yatein derivatives was proposed and the synthetic methodology for each compound developed. The methodology used to obtain deuterium-labelled compounds can be extended to generating tritium-labelled compounds as well. With sufficient quantities of a number of the deuterium-labelled compounds, feeding studies can now be carried out in Podophyllum plants. Isolation and analysis of podophyllotoxin, from plants fed with labelled yatein, will allow determination of the stereochemical nature of yatein cyclization. Isolation and analysis of yatein, from plants fed with labelled matairesinol, will indicate whether matairesinol is indeed a precursor to yatein (and, hence, podophyllotoxin). The information obtained from the synthesis and incorporation of such labelled compounds should then provide a clearer understanding of some interesting but, as yet, unestablished biotransformations.