Novel Pyrone Side Tetracyclic Psoralen Derivatives:  Synthesis and Photobiological Evaluation

This study reports the synthesis of tetrahydrobenzo- (4 − 6) and benzopsoralen (7 − 9) derivatives obtained by condensing the fourth ring to the pyrone side of the tricyclic psoralen moiety. The new compounds are characterized by having a methoxy, a hydroxy, or a dimethylaminopropoxy side chain inse...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-08, Vol.46 (18), p.3800-3810
Main Authors: Dalla Via, Lisa, Uriarte, Eugenio, Quezada, Elias, Dolmella, Alessandro, Ferlin, Maria Grazia, Gia, Ornella
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Circular Dichroism
Coumarins - chemical synthesis
Coumarins - chemistry
Coumarins - pharmacology
Cross-Linking Reagents - chemical synthesis
Cross-Linking Reagents - chemistry
Cyclohexanes - chemical synthesis
Cyclohexanes - chemistry
Cyclohexanes - pharmacology
Cyclohexenes
DNA Adducts - chemical synthesis
Drug Screening Assays, Antitumor
Furans - chemical synthesis
Furans - chemistry
Furans - pharmacology
Furocoumarins - chemical synthesis
Furocoumarins - chemistry
Furocoumarins - pharmacology
Guinea Pigs
Humans
Intercalating Agents - chemical synthesis
Intercalating Agents - chemistry
Magnetic Resonance Spectroscopy
Mass Spectrometry
Medical sciences
Models, Molecular
Photoradiation therapy and photosensitizing agent
PUVA Therapy
Pyrones - chemical synthesis
Pyrones - chemistry
Pyrones - pharmacology
Skin - drug effects
Skin - radiation effects
Structure-Activity Relationship
Treatment with physical agents
Treatment. General aspects
Tumor Cells, Cultured
Tumors
Ultraviolet Rays
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Summary:This study reports the synthesis of tetrahydrobenzo- (4 − 6) and benzopsoralen (7 − 9) derivatives obtained by condensing the fourth ring to the pyrone side of the tricyclic psoralen moiety. The new compounds are characterized by having a methoxy, a hydroxy, or a dimethylaminopropoxy side chain inserted at position 8 of the psoralen chromophore. The evaluation of the photoantiproliferative activity on human tumor cell lines along with skin phototoxicity on guinea pigs revealed an interesting photobiological pattern for the dimethylaminopropoxy derivatives 6 and 9:  they are in fact able to exert an antiproliferative effect up to 1 order of magnitude higher than that of the well-known drug 8-MOP, but they are devoid of skin phototoxicity. The ability of both 6 and 9 to photoadd to DNA is demonstrated by the isolation and characterization of the 4‘,5‘-monoadducts. AM1 calculations were also performed to gain further insight into the molecular basis of their photobiological behavior.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0210919