KINETICS OF LACTONE HYDROLYSIS IN ANTITUMOR DRUGS OF CAMPTOTHECIN SERIES AS STUDIED BY FLUORESCENCE SPECTROSCOPY

Potent antitumor activity exhibited by 20-S-camptothecin (CPT) and num erous derivatives is known to be lost upon opening of the alpha-hydrox y-lactone ring of these drugs, hydrolyzable at neutral and basic pH. T o quantify in 'real time' the lactone hydrolysis reaction in CPTs unde r physiological conditions, we have applied a non-perturbing approach by fluorescence spectroscopy. CPT and a set of its derivatives (21-lac tam-S-CPT, 10,11-(methylenedioxy)-CPT, CPT-11, SN-38, topotecan, tricy clic ketone-CPT) with antitumor activity varying from negligible to 10 times that of CPT have been studied, Prior to the kinetic measurement s, the effects of substitutions, pH, polarity of molecular environment , lactone ring opening (lactone-carboxylate transition) have been inve stigated in terms of the UV-visible absorption and fluorescence emissi on spectra of CPTs. Then the determined parameters of the fluorescence emission spectra corresponding to the respective lactone and carboxyl ate forms have been used to estimate the residual lactone percentage a s a function of time. The reproducibility of the obtained data demonst rates that the spectroscopic approach provides a satisfactory precisio n for this kind of measurements. For CPT at pH 7.3, the lactone half-l ife was 29.4 +/- 1.7 min and the lactone percentage at equilibrium was 20.9 +/- 0.3%, Within a series of derivatives with substitutions at q uinoline rings, the lactone half-life varied from 29 to 32 min and the equilibrium lactone content varied from 15% to 23%. For each compound , even slight increase of pH from 7.1 to 7.3 or from 7.3 to 7.6 logica lly leads to a remarkable decrease of both lactone half-life and equil ibrium lactone percentage. (C) 1998 Elsevier Science B.V.