Mechanism of action of 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one, a very active angular furocoumarin-like sensitizer.
The molecular structure of 1,4,6,8-tetramethylfuro[2,3-h]quinolin-2(1H)-one (FQ), a recent furocoumarin-like photosensitizer, has been modified with the aim of reducing its strong genotoxicity, by replacing the methyl group at 4 position with a hydroxymethyl one, and so obtaining 4-hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ). This modification gave rise to a strong reduction of lipophilicity and dark interaction with DNA. The formation of monoadducts (MA) was deeply affected, whereas the induction of bifunctional adducts between DNA and proteins (DPC(L>0)) was replaced by an efficient production of DNA-protein cross-links at zero length (DPC(L=0)), probably via guanine damage. Because of its angular molecular structure, HOFQ does not form interstrand cross-links (ISC): therefore, DPC(L=0) and MA represent the main lesions induced by HOFQ in DNA. In comparison with FQ (which induces MA and DPC(L>0)) and 8-methoxypsoralen (8-MOP) (MA, ISC, DPC(L>0)), HOFQ seems to be a more selective agent. In fact, contrary to FQ and 8-MOP, HOFQ, together with a noticeable antiproliferative activity, shows low levels of point mutations in bacteria and of clastogenic effects in mammalian cells. HOFQ is also an efficient apoptosis inducer, especially in comparison with 8-MOP, when tested at equitoxic experimental conditions; this property might be correlated with the complete HOFQ inability of inducing skin erythemas, a well-known side effect of classic furocoumarin photosensitization.
Marzano
Cristina
C
Department of Pharmaceutical Science, Padova University, Padova, Italy.
Bettio
Frazia
F
Chilin
Adriana
A
Caffieri
Sergio
S
Reddi
Elena
E
Bordin
Franco
F
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D011564:Furocoumarins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008027:Light; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014466:Ultraviolet Rays
C450158:4-hydroxymethyl-1,6,8-trimethylfuro(2,3-h)quinolin-2(1H)-one; D004268:DNA-Binding Proteins; D005663:Furans; D011564:Furocoumarins; D017319:Photosensitizing Agents; D015363:Quinolones; D017382:Reactive Oxygen Species; D004247:DNA