Camptothecins and Key Lessons in Drug Design

The discovery and development of camptothecin and its various analogues illustrates a number of interesting points concerning the rational development of therapeutic drugs and the implementation of promising compounds into the therapeutic setting. The unique pentacyclic structure (rings A-E) of camptothecins is essential for anti-tumour activity. This basic structure contains an α-hydroxy-δ-lactone system in ring E and an unsaturated pyridone moiety in ring D. The lactone E-ring of camptothecins hydrolyses reversibly to the carboxylate form in aqueous solutions and this ring-opening is a critical determinant of activity. The spectacular early failure of camptothecin in the clinical setting, due to the use of the inactive carboxylate form, highlights the need for extensive studies on structure-activity relationships before drugs are tested in patient populations. Following the elucidation of the molecular target of camptothecins there was renewed interest in developing more water-soluble derivatives of camptothecin that still retained anti-tumour activity. Two of these derivatives, CPT-11 and topotecan, have shown promising activity against a wide range of tumours and are now being used in the clinical setting.