Development and Application of a Peroxyl Radical Clock Approach for Measuring Both Hydrogen-Atom Transfer and Peroxyl Radical Addition Rate Constants

Abstract

The rate-determining step in free radical lipid peroxidation is the propagation of the peroxyl radical, where generally two types of reactions occur: (a) hydrogen-atom transfer (HAT) from a donor to the peroxyl radical; (b) peroxyl radical addition (PRA) to a "CC" double bond. Peroxyl radical clocks have been used to determine the rate constants of HAT reactions (k H ), but no radical clock is available to measure the rate constants of PRA reactions (k add ). In this work, we modified the analytical approach on the linoleate-based peroxyl radical clock to enable the simultaneous measurement of both k H and k add . Compared to the original approach, this new approach involves the use of a strong reducing agent, LiAlH 4 , to completely reduce both HAT and PRAderived products and the relative quantitation of total linoleate oxidation products with or without reduction. The new approach was then applied to measuring the k H and k add values for several series of organic substrates, including para-and meta-substituted styrenes, substituted conjugated dienes, and cyclic alkenes. Furthermore, the k H and k add values for a variety of biologically important lipids were determined for the first time, including conjugated fatty acids, sterols, coenzyme Q10, and lipophilic vitamins, such as vitamins D 3 and A.

Punicic Acid Triggers Ferroptotic Cell Death in Carcinoma Cells

“…CLnAs have been reported to have a particularly high rate of peroxyl radical generation due to the triene structure of their double bonds [ 58 , 59 ]. Since ferroptosis relies on an extensive accumulation of PUFA-derived lipid peroxides [ 32 , 33 ], we assumed that PunA may trigger ferroptosis in carcinoma cells.…”

Dose–Response Effects of 7-Dehydrocholesterol Reductase Inhibitors on Sterol Profiles and Vesicular Stomatitis Virus Replication

“…There is reason to believe that 14-dehydrosterols like 14-dZym and 14-dZyme would also form reactive sterol electrophiles under peroxidation conditions, although the free radical chemistry of these sterols has not been explored in detail. Conjugated dienes like those present in these structures typically undergo peroxyl radical addition reactions, giving reactive allylic epoxide electrophiles, as shown in Figure B. , …”

Radical-Trapping Antioxidant Activity of Copper and Nickel Bis(Thiosemicarbazone) Complexes Underlies Their Potency as Inhibitors of Ferroptotic Cell Death

“…It is noteworthy that the magnitudes of the rate constants, which we have ascribed to peroxyl radical addition (10 5 –10 6 M –1 s –1 ), are even larger than those that have been reported for addition to highly conjugated species, such as the polyenes β-carotene ( cf. Figure D) and retinal (∼6 × 10 3 M –1 s –1 ) . The reactivity of the conjugated polyenes is confounded by the reversibility of the addition (and the O 2 addition which follows it), which generally leads to the measured rate constants being lower bounds of the true rate constants .…”

“…Figure 1D) and retinal (∼6 × 10 3 M −1 s −1 ). 44 The reactivity of the conjugated polyenes is confounded by the reversibility of the addition (and the O 2 addition which follows it), which generally leads to the measured rate constants being lower bounds of the true rate constants. 25 In the case of the metal bis(thiosemicarbazone)s, the subsequent HAT reaction from the weak N−H bond can drive the reaction forward.…”