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

Research output: Contribution to journalArticle (Academic Journal)peer-review

34 Downloads (Pure)

Abstract

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 (t1/2 = 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 αIIbβ3.
Original languageEnglish
Pages (from-to)995–1000
JournalACS Central Science
Volume6
Issue number6
Early online date10 Jun 2020
DOIs
Publication statusPublished - 24 Jun 2020

Fingerprint Dive into the research topics of 'Synthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A2'. Together they form a unique fingerprint.

Cite this