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

Abstract

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 .

Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (−)-Bilobalide

“…The oxetane acetal motif is rare and represented by only a handful of examples in the literature. For example, the human derived platelet aggregation factor thromboxane A2 (TXA 2 ) contains a cyclic oxetane acetal but degrades with a half-life of 32 s at 37 °C in pH 7.4 Krebs media. Its instability complicates isolation and requires storage in basic methanol or as the alkali metal salt; the free acid decomposes within hours via oxetane ring opening.…”

Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde

“…[32] We have utilized this key intermediate in the total synthesis of a wide range of medicinally relevant prostaglandins, and in almost half the number of steps previously reported. [21,32,34,38] We have also been able to demonstrate the versatility of enal 6 by successfully applying it to the total synthesis of stable prostacyclin and thromboxane analogues, [42] again in considerably fewer steps. Like the Corey lactone, our enal 6 possesses the functionality and stereochemistry required to access a broad range of prostanoid-based natural products.…”

The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry

“…187 Most recently, Aggarwal et al prepared F-thromboxane A 2 (86) as a closer analogue of 84 and established the stereoelectronic origin of the improvement on the stability of fluorinated thromboxane A 2 analogues. 188 F-thromboxane A 2 displayed biological properties resembling 83 and 85, including a greater platelet aggregation efficacy than 85 as determined by integrin α IIb β 3 activation. Importantly, the stability of 86 is only slightly lower than 85 (t 1/2 = 20 days, 10fold) but much improved (10 5 -fold) when compared with thromboxane A 2 (Fig.…”