Abstract
In the present study the mould Penicillium-cyclopium was chosen as a model system, with a view to exploring the possibility of selectively inhibiting the interconversion of its metabolites, orsellinic acid and penicillic acid. This sequence necessitates a ring fission, involving cleavage of the bond linking carbon atoms 4 and 5 of orsellinic acid. This thesis is divided into three chapters: 1. A general introduction consisting of a survey of the background literature relating to the biosynthesis of penicillic acid. 2. This describes the syntheses of potential inhibitors including some derivatives of orsellinic acid. The established pathway for the preparation of orsellinic acid from ethyl acetoacetate and ethyl crotonate via bromination, hydrolysis and debromination is also evaluated, and the existing confusion in the literature concerning the bromination stage of this procedure is discussed. 3. This chapter is divided into two parts: Part one concerns an investigation of various aspects of the course of the fermentation of P. cyclopium and its relationship to the biosynthesis of penicillic acid. In addition, the recovery of the culture filtrate metabolites 3-methoxy-2,5-toluquinol and the corresponding quinone is described. Part two is devoted to a study of the feasibility of selectively inhibiting penicillic acid biosynthesis, using strategically-designed derivatives of advanced intermediates such 5-chloroorsellinic acid. The inhibitory effect of low concentrations of this inhibitor was demonstrated through a series of feeding and autoradiographic experiments, which also led to the observation of the concomitant accumulation of other metabolites, two of which were shown to be precursors of penicillic acid.