Selective inhibition of prostaglandin synthetase by a bicyclo[2.2.1]heptene derivative

Abstract

The enzymatic conversion of 8,11,14-eicosatrienoic acid (1) into prostaglandin Ei (PGEi) (4) and PGFla (5) by the prostaglandin synthetase complex has been demonstrated to involve initial elimination of the pro-S hydrogen at C-13 and oxygenation at C-ll to give the peroxy acid 2, which is converted into endoperoxide 3. Removal of a hydrogen at C-9 in 3 with opening of the peroxide gives PGEi (4), whereas reduction of the endoperoxide affords PGFia (5); 3 can also be transformed into the Ci7-hydroxy acid 6 by elimination of malonaldehyde. It has also been shown that 2 can give rise to hydroxyeicosatrienoic acid 7 by reduction of the peroxy group.1•2 Reports on the inhibition of the overall conversion by various unsaturated fatty acids have appeared.3•4

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

“…16). 183,184 The former work is perhaps the best known and among the earliest examples of the power of a divergent synthetic strategy. This pioneering work was followed by the synthesis of U46619 ( 83) by Bundy as a stable ether analogue of PGH 2 with similarly potent smooth muscle-stimulation activity compared with PGH 2 185 and similar platelet aggregation activity compared with thromboxane A 2 (84), 186 and the synthesis of F 2 -thromboxane A 2 (85) by Fried et al which is a fluorinated analogue of 84 with much improved stability (t 1/2 = 46 weeks), and an increased platelet aggregation EC 50 , but a compromised platelet aggregation efficacy (Fig.…”