20-O-acylcamptothecin derivatives: Evidence for lactone stabilization

Convincing UV and NMR spectrophotometric evidence is presented which demons trates that at physiological pH, 7.4, 20-O-acyl derivatives of camptothecin (CPT) are substantially more stable in the lactone form than the 20-OH par ent. Additionally, it was determined by HPLC analysis that the lactone ring of a 20-O-ether derivative of CPT underwent endocyclic ring opening at pR greater than or equal to 8.5, while the lactone ring of 20-O-acyl CPT deriv atives remained unaffected. PEG (and other smaller alkyl) 20-O-acyl-CPT der ivatives released native CPT at pH > 9.5, which arises from exocyclic cleav age, thus precluding isolation of any open CPT acyl PEG (or alkyl) carboxyl ate forms.