The Synthesis of [16,17-^14C]Geranylgeranyl Pyrophosphate as a Probe for The Biosynthesis of Taxol

Abstract

<P> Taxol, a highly functionalized and complex diterpene belonging to the taxane group, possesses strong antitumor activity against various cancers, especially in cases of advanced ovarian and breast cancers. Because of the unique mechanism of action and the unusual chemical structure, taxol may represent the prototype of a new class of chemotherapeutic agents. The non-clinical work up to date on taxol is described in this thesis, including natural resources, chemical synthesis and chemical manipulation of taxol. </p> <p> The biosynthesis of taxol has not yet been studied. The hypothesis proposed for the biosynthetic sequence involves cyclization of geranylgeranyl pyrophosphate (GGPP) into hydrocarbon intermediates, which are then further transformed into taxol. In order to study the biosynthesis of taxol, [^14C]-labelled GGPP was prepared. Through the use of this labelled precursor in incubations with cell-free extract of yew labelled biosynthetic intermediates which are formed can be isolated and identified, hence leading to further understanding of the biosynthesis of taxol. </p> <p> The synthesis of [16,17-^14C]geranylgeranyl pyrophosphate was achieved in eight steps starting from commercially available geranylgeraniol. The alcohol was protected as the acetate derivative and the terminal double bond selectively epoxidized. The epoxide was opened to the diol, which was then cleaved. The resulting aldehyde was coupled to [^14C] isopropyltriphenylphosphonium ylid in a Wittig reaction, giving [16,17-14C]geranylgeraniol after deprotection of the acetate group. The alcohol was converted into the chloride derivative and subsequently to [16,17-14C]geranylgeranyl pyrophosphate. </p>