Camptothecin and Analogs

The drug camptothecin (1) is a natural product, first isolated and characterized from the plant Camptotheca acuminate1 The successful clinical introduction was substantially delayed, largely due to problems with insolubility and instability, particularly of the ring E lactone. This is absolutely required for activity, yet is unstable in aqueous solution, being in equilibrium with the corresponding, and possibly toxic, carboxylate at physiological pH. Following the clinical success of camptothecin,15 the major driving forces behind analog development were to increase water solubility and bioavailability, after extensive experimental structure-activity relationship (SAR) studies showed that only substitution at positions 9-11 of ring A, and position 7 of ring B were permitted. Of a large number of analogs evaluated, topotecan (2) and the carbamate-based prodrug irinotecan (3) have established themselves,16 but several others are in early clinical development.

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