Controlled Tetradeuteration of Straight‐Chain Fatty Acids: Synthesis, Application, and Insight into the Metabolism of Oxidized Linoleic Acid

Abstract

We describe a concise and reliable protocol for the precisely controlled tetradeuteration of straightchain fatty acids (FAs) at the α-and β-positions that is generally applicable to a variety of FAs, including trans-FAs, polyunsaturated FAs (PUFAs), and their oxidized derivatives. The precisely controlled introduction of four deuterium atoms into the FAs enables their persistent and quantitative tracking by LC-MS/MS analysis based on their molecular structures. In addition, the phosphatidylcholine (PC) species prepared from the tetradeuterated FAs thus obtained give a diagnostic peak, namely, a phosphocholine fragment that contains deuterium, in the LC-MS/MS analysis. With these features, the metabolism of a representative oxidized linoleic acid, that is, hydroxyoctadecadienoic acid (HODE), was investigated, leading to the identification of acyltransferases that transfer the acyl moiety derived from HODE to lysophosphatidylcholine.

Chemoenzymatic β-specific methylene C(sp3)–H deuteration of carboxylic acids

“…α,α,β,β-Tetradeuterated palmitic acid ( 16b ) was as a tracer for metabolic analysis and its previous synthesis involved a five-pot route with an overall yield of less than 40%. 6 Using a combination of the Ohshima's α-deuteration 9 and the current β-deuteration method, we were able to prepare it in a two-pot route. The yield was 67% and the deuteration rate was 96% (Table 5, entry 1).…”

“…, Ni-catalyzed esterification followed by hydrolysis using a D 2 O solution of sodium deuteroxide. 6 The two-step process was necessary because the conventional harsh hydrolytic conditions would lead to dedeuteration. Despite the above advances to prepare β-deuterated carboxylic acids, significant limitations have remained, including tedious multi-step operations, strong acids/bases and stoichiometric condensation reagents, high catalyst loading, and insufficient deuteration rate.…”

Ferroptosis: Underlying mechanism and the crosstalk with other modes of neuronal death after intracerebral hemorrhage

“…15-LOX-1 has been regarded as a potent target for stroke treatment. Among the six LOXs isoforms (15-LOX-1, 15-LOX-2, 12S-LOX, 12R-LOX, eLOX3, and 5-LOX), 15-LOX-1 levels increase under pathological conditions in both human and mice following stroke ( Yigitkanli et al, 2013 ; Watanabe et al, 2022 ). Moreover, 15-LOX-1-KO mice exhibited a protective ability against ischemic injury in several experimental stroke models ( Shen et al, 2020a ), highlighting the benefits of inhibiting 15-LOX-1 during stroke treatment.…”

K2CO3/18-Crown-6-Catalyzed Selective H/D Exchange of Heteroarenes with Bromide as a Removable Directing Group

“…7 Recently, Takita's group reported H/D exchange of acidic protons in a variety of fatty acids using K 2 CO 3 /D 2 O solutions without isomerization of double bonds. 8 Unlike H/D exchange at acidic C(sp 3 )−H bonds, base-catalyzed H/D exchange at C(sp 2 )−H bonds is more challenging, in which strong base and harsh conditions are always needed. For example, Chen's group reported that deuteration of phenols can be achieved with NaOH as the base at 180 °C.…”

“…For example, the use of K 2 CO 3 enables late-stage deuteration of many biomolecules and drug molecules containing terminal alkynes . Recently, Takita’s group reported H/D exchange of acidic protons in a variety of fatty acids using K 2 CO 3 /D 2 O solutions without isomerization of double bonds . Unlike H/D exchange at acidic C­(sp 3 )–H bonds, base-catalyzed H/D exchange at C­(sp 2 )–H bonds is more challenging, in which strong base and harsh conditions are always needed.…”