PYRROLO[2,3-H]QUINOLINONES: A NEW RING SYSTEM WITH POTENT PHOTOANTIPROLIFERATIVE ACTIVITY

A new class of compounds, the pyrrolo[2,3-h]quinolin-2-ones, nitrogen isosters of the angular furocoumarin Angelicin,was synthesized with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lowerundesired toxic effects than the lead compound. Two synthetic pathways were approached to allow the isolation both of the dihydroderivatives10–17 and of the aromatic ring system 23. Compounds 10–17 showed a remarkable phototoxicity and a great UVAdose dependence reaching IC50 values at submicromolar level. Intracellular localization of these compounds has been evaluated bymeans of fluorescence microscopy using tetramethylrhodamine methyl ester and acridine orange, which are specific fluorescentprobes for mitochondria and lysosomes, respectively. A weak co-staining was observed with mitochondrial stain, whereas a specificlocalization in lysosomes was observed. Studies directed to elucidate the mode of action of this series of compounds revealed thatthey do not intercalate with DNA and do not induce photodamage to the macromolecule. On the contrary, they induce significativephotodamage to lipids and proteins.