Synthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A₂

Platelet activation results in the generation of thromboxane A₂ (TxA₂), which promotes thrombus formation by further amplifying platelet function, as well as causing vasoconstriction. Due to its role in thrombus formation and cardiovascular disease, its production is the target of antiplatelet drugs such as aspirin. However, the study of TxA₂-stimulated cellular function has been limited by its instability (t _1/2 = 32 s, pH = 7.4). Although more stable analogues such as U46619 and difluorinated 10,10-F₂-TxA₂ have been prepared, we targeted a closer mimic to TxA₂ itself, monofluorinated 10-F-TxA₂, since the number of fluorine atoms can affect function. Key steps in the synthesis of F-TxA₂ included α-fluorination of a lactone bearing a β-alkoxy group, and a novel synthesis of the strained acetal. F-TxA₂ was found to be 10⁵ more stable than TxA₂, and surprisingly was only slightly less stable than F₂-TxA₂. Preliminary biological studies showed that F-TxA₂ has similar potency as TxA₂ toward inducing platelet aggregation but was superior to F₂-TxA₂ in activating integrin α_IIbβ₃.