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 lower undesired toxic effects than the lead compound. Two synthetic pathways were approached to allow the isolation both of the dihydroderivatives 10-17 and of the aromatic ring system 23. Compounds 10-17 showed a remarkable phototoxicity and a great UVA dose dependence reaching IC(50) values at submicromolar level. Intracellular localization of these compounds has been evaluated by means of fluorescence microscopy using tetramethylrhodamine methyl ester and acridine orange, which are specific fluorescent probes for mitochondria and lysosomes, respectively. A weak co-staining was observed with mitochondrial stain, whereas a specific localization in lysosomes was observed. Studies directed to elucidate the mode of action of this series of compounds revealed that they do not intercalate with DNA and do not induce photodamage to the macromolecule. On the contrary, they induce significative photodamage to lipids and proteins.
Barraja
Paola
P
Dipartimento Farmacochimico, Tossicologico e Biologico Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
Diana
Patrizia
P
Montalbano
Alessandra
A
Dattolo
Gaetano
G
Cirrincione
Girolamo
G
Viola
Giampietro
G
Vedaldi
Daniela
D
Dall'Acqua
Francesco
F
D000165:Acridine Orange; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005456:Fluorescent Dyes; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012235:Rhodamines / Q000378:metabolism; D014466:Ultraviolet Rays
D003432:Cross-Linking Reagents; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D017319:Photosensitizing Agents; D011506:Proteins; D015363:Quinolones; D012235:Rhodamines; C401833:tetramethylrhodamine methyl ester; D004247:DNA; D000165:Acridine Orange