Current Organic Chemistry - Volume 18, Issue 1, 2014

Quinone methides (QMs) are important intermediates in chemistry and biochemistry of phenols that are characterized by wide biological activity. Some classes of anticancer antibiotics exhibit their effect due to methabolic formation of QMs that alkylate DNA. Photochemical reactions provide mild and easy approach to QMs. Photoreactions that give QMs include cleavage of oxa-heterocycles, dehydrohalogenation, dehydration, deammination, excited state intramolecular proton transfer (ESIPT) and tautomerizations of phenols. This critical review (137 references) features different photochemical reactions giving QMs that are applicable in biology and medicine.

The following review analyzes the most effective activation protocols for the generation of transient electrophilic quinone methides, merged into the recent strategies to achieve recognition and alkylation of nucleic acids. The covalent targeting has to be specific for selected oligonucleotide sequences (sequence-specificity) or for those oligonucleotides capable to fold into supramolecular structures, such as G-quadruplexes (structure-specificity). The reversibility of the DNA alkylation process by QM is reviewed underlining the opportunities (in term of selectivity and delivery) and drawbacks (in term of product characterization of the covalent damage) in the DNA targeting.

In this review, we discuss the advances in understanding the reactivity of quinone methide (QM) intermediates and the reversibility of DNA alkylation by QMs in the past two decades. QMs react with strong nucleophiles of DNA under kinetic control but reversibly. The effective lifetime of QMs can be extended through repeated capture and release from DNA adducts. A QM-acridine conjugate DNA cross-linking agent remains dynamic and “migrates” among DNA strands through multiple strand exchange reactions until forming stable adducts irreversibly. Self-adducts of QM-biopolymer conjugates exhibit strong capability to alkylate complementary DNA strands in a sequence specific manner.

The formation of quinone methides (QMs) from either direct 2-electron oxidation of 2- or 4-alkylphenols, isomerization of oquinones, or elimination of a good leaving group could explain the cytotoxic/cytoprotective effects of several drugs, natural products, as well as endogenous compounds. For example, the antiretroviral drug nevirapine and the antidiabetic agent troglitazone both induce idiosyncratic hepatotoxicity through mechanisms involving quinone methide formation. The anesthetic phencyclidine induces psychological side effects potentially through quinone methide mediated covalent modification of crucial macromolecules in the brain. Selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene, and raloxifene are metabolized to quinone methides which could potentially contribute to endometrial carcinogenic properties and/or induce detoxification enzymes and enhance the chemopreventive effects of these SERMs. Endogenous estrogens and/or estrogens present in estrogen replacement formulations are also metabolized to catechols and further oxidized to o-quinones which can isomerize to quinone methides. Both estrogen quinoids could cause DNA damage which could enhance hormone dependent cancer risk. Natural products such as the food and flavor agent eugenol can be directly oxidized to a quinone methide which may explain the toxic effects of this natural compound. Oral toxicities associated with chewing areca quid could be the result of exposure to hydroxychavicol through initial oxidation to an o-quinone which isomerizes to a p-quinone methide. Similar o-quinone to p-quinone methide isomerization reactions have been reported for the ubiquitous flavonoid quercetin which needs to be taken into consideration when evaluating risk-benefit assessments of these natural products. The resulting reaction of these quinone methides with proteins, DNA, and/or resulting modulation of gene expression may explain the toxic and/or beneficial effects of the parent compounds.

Quinone methides (QMs) are naturally occurring reactive intermediates which play important roles in organic syntheses as well as in a large number of chemical and biological processes. QMs are also believed to be responsible for the ultimate cytotoxicity of many antitumor drugs, antibiotics, and DNA alkylators through enzyme inhibition or DNA alkylation. Many different chemical methods have been developed to synthesize QMs and their derivatives. This review highlights generation of QMs by exploiting cellular process and their biological applications.

Bioorthogonal ligations have found widespread use in biomedical research for site selective labeling of biomolecules in living systems. Discovering new reactions to expand the toolbox of bioorthogonal chemistry remains an important, yet challenging task as most reactions do not meet the stringent requirements of bioorthogonal reaction. As highly useful synthetic intermediates, ortho-quinone methides (oQMs) have been broadly utilized in the total synthesis of natural products but have rarely been applied to biological studies. The required harsh reaction condition to generate oQMs would be detrimental to the cell or living organism. In this highlight, we would like to describe our recent development of a new bioorthogonal ligation enabled by the “click” cycloaddition of ortho-quinolinone quinone methide (oQQM) and vinyl thioether (VT).

Homochirality and related problems have been reviewed. Relative probability of different versions of homochirality arising were estimated on the example of processes, synthesis of organic compounds in space, asymmetric photolysis under circularly polarized light, synthesis of optically active compounds as a result of parity violation, magnetochiral dichroism, chiral amplification, optical active amino acids synthesis and theirs isotope ratios in meteorites, and some other determinate and indeterminate processes. It has been estimated handedness of moving objects as source of chirality. Possible contributions of these processes in homochirality origin in nature have been evaluated. The view is justified that homochirality (and life) origin may be not an accidental event.

Pyrazoles are compounds of synthetic origin, and constitute a group of nitrogen heterocyclic compounds that have shown several biological activities. Their transformations into other biologically active molecules have been exploited since the early 1960s. This review describes the work on the environment-friendly synthesis of bioactive pyrazoles. The review covers mainly the data published over the last five years (2007–2012).

Conformationally rigid phosphoric acids derived from suitably substituted axially dissymmetric 1,1’-bi-2,2’-naphthol (BINOL) find wide application in organic synthesis. These chiral Brønsted acids are able to catalyze enantioselective transformations of electrophilic imines with both carbon-centered and other hetero nucleophiles to generate enantioenriched products of academic, industrial and biological significance. Selected examples of this transformation as well as catalytic action and stereochemical features of plausible transition state intermediates are discussed in the present review.