Synthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A(2)

[Image: see text] Platelet activation results in the generation of thromboxane A(2) (TxA(2)), 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 TxA(2)-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-F(2)-TxA(2) have been prepared, we targeted a closer mimic to TxA(2) itself, monofluorinated 10-F-TxA(2), since the number of fluorine atoms can affect function. Key steps in the synthesis of F-TxA(2) included α-fluorination of a lactone bearing a β-alkoxy group, and a novel synthesis of the strained acetal. F-TxA(2) was found to be 10(5) more stable than TxA(2), and surprisingly was only slightly less stable than F(2)-TxA(2). Preliminary biological studies showed that F-TxA(2) has similar potency as TxA(2) toward inducing platelet aggregation but was superior to F(2)-TxA(2) in activating integrin α(IIb)β(3).