Kigen Kondo

Role of prostaglandin endoperoxides in the serum thiobarbituric acid reaction

Abstract In the presence of heme and reduced glutathione, prostaglandin (PG) endoperoxides underwent rapid conversion to malondialdehyde and 12 l -hydroxy-5,8,10-heptadecatrienoic acid. In addition, PG endoperoxides as well as lipid peroxides produced malondialdehyde to yield a red pigment during the thiobarbituric acid reaction with different efficiencies. The relative rates of the reaction were: 1,1,3,3-tetraethoxypropane, 100; PGG 2 , 55; PGH 2 , 32; and 15-hydroperoxyarachidonic acid, 6. The thiobarbituric acid reactive materials in rabbit serum decreased by 25–60%, after intravenous administration of aspirin (a cyclo-oxygenase inhibitor) and with a concomitant decline of serum PG levels. These results, taken together, suggested that serum thiobarbituric acid values, considered to be an indicator of lipid peroxide levels, were to a significant extent due to PG endoperoxides and their derivatives.

Design and synthesis of a highly selective EP2-receptor agonist

EP2-receptor selective agonist 3 was identified by the structural hybridization of butaprost 1a and PGE(2) 2a. Based on this information, a chemically more stabilized 4 was discovered as another highly selective EP2-receptor agonist, iv administration of which to anesthetized rats suppressed uterine motility, while PGE(2) 2a stimulated uterine motility.

Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE1 and 9-β-halo derivatives with improved stability

To identify a new selective EP4-agonist with improved chemical stability, further chemical modification of those reported previously was continued. We focused our attention on chemical modification of the alpha chain of 3,7-dithiaPGE(1) and selected 5-thiaPGE(1) as a new chemical lead. Introduction of an optimized omega chain to the 5-thiaPG skeleton afforded m-methoxymethyl derivative 33a, which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9beta-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the beta-hydroxyketone moiety. Among these series, and 39b showed potent agonist activity and good subtype-selectivity. Structure-activity relationships (SARs) are also discussed.

Effects of prostaglandin D2 on membrane potential in neuroblastoma X glioma hybrid cells as determined with a cyanine dye

Abstract A cyanine dye, diS-C3-(5) was used to determine the effects of prostaglandins on the membrane potential in neuroblastoma X glioma cells (NG 108-15). The largest depolarization was seen with prostaglandin D2 (ED50 = 1.5 μM), and relative potencies of various prostaglandins (3 μM) were: D2, 100; I2, 41; E1, 17; E2, 7; and F2α, 7. 5-Hydroxytryptamine in a dose over 100 μM also depolarized the membrane. The effect of prostaglandin D2 was observed in a Na+-free medium or when Ca2+ was replaced by Sr2+. The addition of 3 mM ethylene-glycol-bis (β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid or 5 mM Co2+ partially inhibited the effects. These observations suggest that the depolarization of membrane by prostaglandin D2 may primarily be related to alteration of Ca2+ permeability in the cell membrane.

Design and synthesis of a highly selective EP4-receptor agonist. Part 1: 3,7-dithiaPG derivatives with high selectivity.

To identify new highly selective EP4-agonists, further modification of the 16-phenyl moiety of 1 was continued. 16-(3-methoxymethyl)phenyl derivatives 13-(6q) and 16-(3-ethoxymethyl)phenyl derivatives 13-(7e) showed more selectivity and potent agonist activity than 1. 16-(3-methyl-4-hydroxy)phenyl derivative 18-(14e) demonstrated excellent subtype selectivity, while both its receptor affinity and agonist activity were less potent than those of 13-(6q). Structure-activity relationships (SARs) are also discussed.

Design and synthesis of a selective EP4-receptor agonist. Part 4: practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist

A practical method of synthesizing a highly selective EP4-receptor agonist 1 using Corey lactone 2 as a key intermediate was developed. Selective methanesulfonylation of the primary alcohol of the diol 8 under the newly devised conditions followed by the protection of the remaining secondary alcohol are key reactions in this new method. Further biological evaluation of 1a-b is also reported.

Development of a highly selective EP2-receptor agonist. Part 1: identification of 16-hydroxy-17,17-trimethylene PGE2 derivatives.

Design and synthesis of an EP2-receptor selective agonist began with the chemical modification of alpha- and omega-chains of butaprost 1a, which exhibits an affinity for the IP-receptor. Two series of prostaglandin (PG) analogues with a 16-hydroxy-17,17-trimethylene moiety as an omega-chain were identified. Among those tested, 4a,b,e,f,h and 6a,b,e,f,h were found to be highly selective EP2-receptor agonists. Structure-activity relationships are discussed.

Design and synthesis of a highly selective EP4-receptor agonist. Part 2: 5-thia and 9β-haloPG derivatives with improved stability

Further chemical modification to identify more chemically stabilized EP4-receptor selective agonists was continued. As a result, a further two EP4-receptor selective agonists 5-thiaPGE(1) 2a, 10 and 9beta-chloroPGF(2) analogue 11 were discovered.

Design and synthesis of a selective EP4-Receptor agonist. Part 1: discovery of 3,7-DithiaPGE1 derivatives and identification of Their ω chains

Abstract Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the α chain of PGE 1 was investigated. Among the compounds tested, 3,7-dithiaPGE 1 4a exhibited good EP4-receptor selectivity and agonist activity. Further modification of the ω chain of 3,7-dithiaPGE 1 was performed to improve EP4-receptor selectivity and agonist activity. Of the compounds produced, 16-phenyl-ω-tetranor-3,7-dithiaPGE 1 4p possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety.

A practical synthesis and biological evaluation of 9-halogenated PGF analogues.

A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.