Abstract
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.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Circular Dichroism
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Coumarins / chemical synthesis*
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Coumarins / chemistry
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Coumarins / pharmacology
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Cross-Linking Reagents / chemical synthesis
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Cross-Linking Reagents / chemistry
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Cyclohexanes / chemical synthesis*
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology
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Cyclohexenes
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DNA Adducts / chemical synthesis
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Drug Screening Assays, Antitumor
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Furocoumarins / chemical synthesis*
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Furocoumarins / chemistry
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Furocoumarins / pharmacology
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Guinea Pigs
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Humans
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Intercalating Agents / chemical synthesis
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Intercalating Agents / chemistry
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Magnetic Resonance Spectroscopy
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Mass Spectrometry
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Models, Molecular
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PUVA Therapy
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Pyrones / chemical synthesis*
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Pyrones / chemistry
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Pyrones / pharmacology
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Skin / drug effects
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Skin / radiation effects
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Ultraviolet Rays
Substances
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3,4-cyclohexene-8-(3-dimethylaminopropoxy)-4'-methylfuro(3,2-g)coumarin
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3,4-cyclohexene-8-hydroxy-4'-methylfuro(3,2-g)coumarin
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Antineoplastic Agents
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Coumarins
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Cross-Linking Reagents
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Cyclohexanes
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Cyclohexenes
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DNA Adducts
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Furans
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Furocoumarins
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Intercalating Agents
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Pyrones