Design and Synthesis of Simplified Polyketide Analogs: New Modalities beyond the Rule of 5

Natural products provide important lead structures for development of pharmaceutical agents or present attractive tools for medicinal chemistry. However, structurally complex and thus less accessible metabolites defying conventional drug-like properties, as expressed by Pfizer's rule of five, have received less attention as medicinal leads. Traditionally, research focus has been on realizing total syntheses rather than developing more readily available analogs to resolve the critical supply issue. However, very recent studies with complex myxobacterial polyketides have demonstrated that considerable structural simplification may be realized with retention of biological potencies. The context, underlying rationale and importance of tailored synthetic strategies of three such case studies are presented, which may inspire further related activities and may eventually help exploiting the largely untapped biological potential of complex metabolites in general.