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1 November 2005 Mechanism of Action of 4-Hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one, a Very Active Angular Furocoumarin-like Sensitizer
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Abstract

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 (DPCL>0) was replaced by an efficient production of DNA–protein cross-links at zero length (DPCL=0), probably via guanine damage. Because of its angular molecular structure, HOFQ does not form interstrand cross-links (ISC): therefore, DPCL=0 and MA represent the main lesions induced by HOFQ in DNA. In comparison with FQ (which induces MA and DPCL>0) and 8-methoxypsoralen (8-MOP) (MA, ISC, DPCL>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.

Cristina Marzano, Frazia Bettio, Adriana Chilin, Sergio Caffieri, Elena Reddi, and Franco Bordin "Mechanism of Action of 4-Hydroxymethyl-1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one, a Very Active Angular Furocoumarin-like Sensitizer," Photochemistry and Photobiology 81(6), 1371-1379, (1 November 2005). https://doi.org/10.1562/2005-01-13-RA-413
Received: 13 January 2005; Accepted: 1 July 2005; Published: 1 November 2005
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