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.

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

“…This has also been demonstrated with "simpler" derivatives of naphthoquinones, produced by photochemical reactions (83 and 86, see Fig. 14) [99]. These species, although not closely related to standard QMs, as they undergo a [1][2][3][4][5][6][7][8] addition, can be generated in situ by irradiation between 310 and 360 nm.…”

Photochemical Generation of Benzyl Cations That Selectively Cross-Link Guanine and Cytosine in DNA

“…4,16–19,28,29 In this vein, Freccero and Zhou reported photochemical generation of bifunctional quinone methides (QMs) capable of cross-linking DNA. 8,9,12,14 In the present study, we describe a novel mechanism for photoinduced DNA ICL formation from several bifunctional aryl boronates ( 3a , b and 4a , b ) (Figure 1), which are activated by 350 nm irradiation to produce bifunctional benzyl cations that efficiently and selectively cross-link DNA at dG and dC sites.…”

Mannich base-connected syntheses mediated by ortho-quinone methides

“…Freccero et al examined the photogeneration by laser flash photolysis and reactivity of naphthoquinone methides as well as their activity as purine selective DNA alkylating agents [93]. Farrell et al studied the mechanism of the cytotoxic action of naphthoquinone–platinum(II) complexes [94].…”