Synthesis and conformational investigations of bioactive natural products and fluorinated analogues

(-)-Balanol, a fungal metabolite from Verticillium balanoides, is a potent protein kinase C(PKC) inhibitor and has potential as an antitumor agent. However, it competitively inhibits other AGC protein kinases and lacks PKC isozyme specificity. The success from the first kinase drug, Gleevec, suggests that conformationally biased small molecules can lead to selective inhibition of tyrosine protein kinases. Fluorination has recently been utilized as a tool to conformationally tune the shape of molecules. The aim was to synthesize conformationally biased fluorinated balanol analogues and examine their PKA/PKC affinity and selectivity profiles (Figure 1). The structure activity relationship from this study may help understand conformational control in molecular recognition in general. The synthesis of mono-, di- and trifluoroazepanes was accomplished with unusual stereochemical outcomes due to neighbouring group participation. The conformational preferences of the mono-, di- and trifluoro azepanes were investigated using computational methods and J based analysis after detailed 2D NMR structure elucidations. The parent (-)-balanol and fluorinated balanol analogues were synthesized, and the analogues were subjected to binding affinity measurements with selected PKC isozymes and PKA.