Quinone methide chemistry of prekinamycins: 13C- labeling, spectral global fitting and in vitro studies

Abstract

In this article, we address the presence of the prekinamycin quinone methide using the techniques of spectral global fitting and the 13C-labeling of the reactive centre. Two-electron reduction of a prekinamycin affords a long-lived quinone methide species that was characterised spectrally. A correlation was made between the calculated DeltaE (kcal/mol) values for quinone methide tautomerisation and cytostatic activity to support the postulate that the quinone methide plays a role in prekinamycin biological activity. We also prepared a stable quinone methide of prekinamycin and studied its solution chemistry directly.

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

“…Compound 51 is not toxic by itself, but it is metabolized in the liver by cleavage of the glycosidic bond, followed by the sulfonation of the OH in position 3. The resulting sulfate undergoes an elimination of HSO 4 -to produce QM 52. This latter molecule has been shown to react with DNA, thus, prompting carcinogenic effects [55] (see Table 3).…”

“…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. The QMs originating from binaphtols were 100-fold more reactive that the naphthyl QMs, and they were also produced from the water-soluble leaving group, trimethylammonium iodide; the QMs obtained were also able to alkylate DNA.…”

The cytotoxicity of (−)-lomaiviticin A arises from induction of double-strand breaks in DNA

“…Because (–)-lomaiviticin A ( 1 ) is not widely-available, these studies have employed the kinamycins or synthetic analogs. It has been proposed that redox cycling of the naphthoquinone to generate reactive oxygen species (ROS), 14,15 formation of covalent adducts ( 5 ) by nucleophilic addition, 16 production of vinyl radical intermediates ( 6 ), 15–21 and addition to ortho -quinone methide ( 7 ) 15,18–22 or acylfulvene ( 8 ) 23,24 electrophiles may contribute to cytotoxicity (Figure 1B). In principle, all of these intermediates and pathways are accessible to 1 , 2 , and 3 , and none sufficiently account for the superior cytotoxicity of 1 .…”

Chemical Biology: What is Its Role in Drug Discovery?

“…Iron(III)-salen complexes were used to demonstrate that, somewhat surprisingly, the less DNA cleavage activity these compounds showed in vitro, the more efficient they were at inducing apoptosis in MCF7 cells (Ansari et al, 2009). Further evidence has been gathered to support the proposal that it is the quinone methide, formed by two electron reduction of prekinamycin, that is responsible for its cytostatic activity (Khdour & Skibo, 2009). A series of substituted thienopyrimidines have been synthesised and shown to be cytotoxic to a number of cancer cell lines (Snegaroff et al, 2009) and substituted O-galactosyl aldoximes were prepared as selective galectin-3 inhibitors (Tejler et al, 2009).…”