Alkylation of Nucleic Acids by a Model Quinone Methide

Abstract

Quinone methides and related electrophiles represent a common class of intermediates that form during metabolism of drugs and xenobiotics and may lead to DNA alkylation. The intrinsic reactivity of these species has now been characterized using a stable model compound, O-(tert-butyldimethylsilyl)-2-bromomethylphenol, designed to generate an o-quinone methide in the presence of fluoride. The resulting deoxynucleoside adducts were assigned unambiguously through use of two-dimensional NMR and, in particular, heteronuclear multiple-bond connectivity (HMBC). Both purines, dG and dA, reacted at their exo-amino groups. In contrast, dC had previously been shown to react at its cyclic N3 position [Rokita, S. E.; Yang, J.; Pande, P.; Greenberg, W. A. J. Org. Chem. 1997, 62, 3010−3012], and the relatively nonnucleophilic T remained inert under all conditions examined. Surprisingly, the efficiency of cytosine modification exceeded that of adenine and guanine by more than 10-fold in competition studies with the deoxymononucleosides. Reaction of all residues was suppressed in duplex DNA, but none was affected more than cytosine (>3600-fold). Guanine consequently emerged as the predominant target in duplex DNA in accord with the selectivity of most natural products forming quinone methide-like species. These general observations may then in part reflect the ability of the exo-amino group of guanine to maintain its reactivity most effectively from nucleoside to helical DNA.

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

“…The potential barriers for migration of bisQM2 across DNA were pushed beyond a canonical or nicked duplex to include an analogue containing a bulge structure formed by two extrahelical Ts. Ts were chosen for their lack of reaction with the parent QM 61 and inserted into the sequence of OD6 resulting in a new strand OD7. This new strand was then used to displace OD4 from its crosslinked duplex with OD2.…”

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

“…Pande and colleagues have developed an experimental model to study the reactivity of o-QMs (2) generated in situ in the presence of synthetic DNA [86]. They have shown that, just as other alkylating agents, such as cisplatin, this particular QM binds with a great selectivity to particular bases.…”

“…11) (along with more recent duocarmycin derivatives) is among the most potent antitumor agents discovered to date [86][87][88][89][90][91]. Strictly speaking, CC-1065 is not a QM, but the cyclopropane moiety present on its structure is, from a reactivity point of view, a bioisosteric form of the methide found in QMs.…”

Substituents on Quinone Methides Strongly Modulate Formation and Stability of Their Nucleophilic Adducts

“…22 Initial model studies suggested a selectivity of QM for weak nucleophiles and an ability of some adducts to form reversibly. 19,[23][24][25][26] Further investigation revealed that this unusual selectivity was a function of QM adduct stability rather than initial product formation. [27][28][29] In contrast to earlier assumptions, the strongest nucleophiles of DNA reacted most quickly with a simple ortho-QM model to form kinetic products.…”