title: Photogeneration and reactivity of naphthoquinone methides as purine selective DNA alkylating agents.
abstract: A one-step protecting-group-free synthesis of both 6-hydroxy-naphthalene-2-carbaldehyde and the bifunctional binaphthalenyl derivative afforded 6-hydroxymethylnaphthalen-2-ol, 6-methylaminomethyl-naphthalen-2-ol, [(2-hydroxy-3-naphthyl)methyl]trimethyl ammonium iodide, and a small library of bifunctional binol analogues in good yields. Irradiation of naphthol quaternary ammonium salt and binol-derivatives (X = OH, NHR, NMe(3)(+), OCOCH(3), and L-proline) at 310 and 360 nm resulted in the photogeneration of the 2,6-naphthoquinone-6-methide (NQM) and binol quinone methide analogues (BQMs) by a water-mediated excited-state proton transfer (ESPT). The hydration, the mono- and bis-alkylation reactions of morpholine and 2-ethanethiol, as N and S prototype nucleophiles, by the transient NQM (λ(max) 310, 330 nm) and BQMs (λ(max) 360 nm) were investigated in water by product distribution analysis and laser flash photolysis (LFP). Both the photogeneration and the reactivity of NQM and BQMs exhibited striking differences. BQMs were at least 2 orders of magnitude more reactive than NQM, and they were generated much more efficiently from a greater variety of photoprecursors including the hydroxymethyl, quaternary ammonium salt and several binol-amino acids. On the contrary, the only efficient precursor of NQM was the quaternary ammonium salt. All water-soluble BQM precursors were further investigated for their ability to alkylate and cross-link plasmid DNA and oligonucleotides by gel electrophoresis: the BQMs were more efficient than the isomeric o-BQM (binol quinone methide analogue of 2,3-naphthoquinone-3-methide). Sequence analysis by gel electrophoresis, HPLC, and MS showed that the alkylation occurred at purines, with a preference for guanine. In particular, a BQM was able to alkylate N7 of guanines resulting in depurination at the oligonucleotide level, and ribose loss at the nucleotide level. The photoreactivity of BQM precursors translated into photocytotoxic and cytotoxic effects on two human cancer cell lines: in particular, one compound showed promising selectivity index on both cell lines.
authors.affiliation: Dipartimento di Chimica Organica, Università di Pavia, V. le Taramelli 10, 27100 Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Verga
authors.forename: Matteo
authors.initials: M
authors.lastname: Nadai
authors.forename: Filippo
authors.initials: F
authors.lastname: Doria
authors.forename: Claudia
authors.initials: C
authors.lastname: Percivalle
authors.forename: Marco
authors.initials: M
authors.lastname: Di Antonio
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D009285:Naphthoquinones / Q000737:chemistry*; D010777:Photochemistry; D011687:Purines / Q000737:chemistry*
chemical_list: D000477:Alkylating Agents; D009285:Naphthoquinones; D011687:Purines; D004247:DNA