A nuclear Overhauser effect difference study of the solution conformation of (6 R )-prostaglandin I 1

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HELMUT BEIERBECK, GEORGE KOTOVYCH, and MAKIKO SUGIURA. Can. J. Chem. 63, 1 143 (1985). The conformations of prostacyclin, PG12, and three of its analogues, 6R-and 6s-PGII and carbacyclin, were studied by high field 'H nmr spectroscopy. The cis-bicyclo-and cis-oxabicyclo[3.3.O]octane ring conformations were completely assigned. The minima for the pseudorotational conformations are observed at 7~/ l z~ for PGI?, :,T/:~T for 6R-PGI,, and 6 E / 1 '~ for 6s-PGI, and carbacyclin. The data indicate that each molecule adopts a narrow pseudolibrational range, if not a single conformation. The a-and w-side chain conformations were characterized, but not unambiguously. Vicinal coupling constants --and nuclear Overhauser enhancements proved to be the most useful spectroscopic parameters in this study.HELMUT BEIERBECK, GEORGE KOTOVYCH et MAKIKO SUGIURA. Can. J. Chem. 63, 1143Chem. 63, (1985. In a recent series of articles (1-4) we reported ' H nmr chemical shifts and coupling constants for prostacyclin and three of its derivatives, compounds of considerable pharmacological interest. Prostacyclin or PG12, first isolated in 1976, is a potent vasodilator and inhibitor of platelet aggregation (5, 6). It is rather unstable, however, and a number of biologically active analogues were developed ( 3 , among them the isomeric 5,6-dihydroprostacyclins, 6R-PGII and 6s-PGII, and carbacyclin, in which the ether oxygen is replaced by a methylene group. In the present study we have undertaken a detailed conformational analysis, based on ' H nmr coupling constants and nuclear Overhauser effects, of this important group of prostaglandins. ExperimentalThe samples of PGI?, 6s-PGI,, 6R-PGI,, and carbacyclin used in this study were gifts from Drs. R. A. Johnson, J. E. Pike, and D. R. IMorton of Upjohn, Kalamazoo. For the measurements of coupling 'Paper No. 10 in a series of high-field nmr studies on the prostaglandins and leukotrienes.2Author to whom correspondence should be addressed.constants in chloroform solution, CD,OD was distilled into nmr tubes containing PGI? methyl ester or 6s-PGII, respectively, to exchange labile protons; the methanol was then evaporated and CDCI, added. The prostaglandin concentrations were -0.005 M. The samples were sealed after four freeze-pump-thaw cycles. PGIz samples were prepared in glycine/D20 buffer solutions at pH 2 10. Solutions were 0.005 M PGIz in a 0.20 M and 0.015 M buffer and 0.017 M in 0.02 M buffer to check for the effect of concentration on the T , data. The high pH was necessary to prevent PGI? hydrolysis. For 6s-and 6R-PGI,, a 0.10 M phosphate/D20 buffer of pH = 7.0 was used. The samples were weighed into nmr tubes, buffer solution added, the solvent evaporated, fresh 100% D 2 0 added, and oxygen removed in four freeze-pump-thaw cycles. 6s-PGI, concentrations were 0.005 M, 0.008 M, and 0.013 M while the 6R-PGI, solutions were 0.005 M. All glassware was cleaned extensively, including a nitric acid wash, to eliminate paramagnetic impurities.All nmr measurements were carried out on a Bruker WH-40...

Section: Resultsmentioning

confidence: 99%

The conformations of prostacyclin and related prostaglandins

Beierbeck¹,

Kotovych²,

Sugiura³

1985

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“…2. Only the The one-dimensional n o e difference experiments were per-high-field region is shown as it illustrates the formed following standard procedures (23,24). The two-dimen-manner in which multiplets can be readily observed sional nmr measurements were carried out using the Bruker in regions ofthe spectrum where there is extensive software package (25).…”

Section: Resultsmentioning

confidence: 99%

“…For the 2D nOe experiment, r, equals 0.35 s. 32 transients were accumulated and the delay time between pulse sequences was 7.5 s. The FID's were multiplied by a sine bell function before Fourier transformation. The normal Fourier transform ID spectrum obtained for 6-keto-PGE, is shown in C. The line assignments are indicated in the figure. (6R)-prostaglandin I, (23), prostaglandin E, (29), (6s)-prostaglandin I, (30), and carboprostacyclin (31). These studies have now been extended to the 2D nOe experiment.…”

Section: Figmentioning

confidence: 97%

Homonuclear one- and two-dimensional nuclear Overhauser effect experiments and spin-echo correlated spectroscopy. Application to prostaglandin E₁ and 6-keto-prostaglandin E₁

Kotovych¹,

Aarts²

1982

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GEORGE KOTOVYCH and GERDY H. M. AARTS. Can. J. Chem. 60,2617Chem. 60, (1982 Nuclear Overhauser effect one-dimensional and two-dimensional nuclear magnetic resonance experiments are reported for prostaglandin E l . The two-dimensional nuclear Overhauser effect measurements are combined with spin-echo correlated spectroscopy in order to assign the complete high-field proton magnetic resonance spectrum of 6-keto-prostaglandin E,. The advantages of these two-dimensional techniques are illustrated in these studies. It is also observed that the 6-keto-prostaglandin E l H-loci proton is substituted more readily by deuterium than are the other protons a to the keto groups. Chem. 60,2617Chem. 60, (1982. On rapporte des experiences en rmn sur I'effet Overhauser nucleaire a une e t a deux dimensions pour la prostaglandine E l . Les mesures de l'effet Overhauser nucleaire sont combinees avec la spectroscopie spin-echo de correlation dans le but d'identifier le spectre complet de resonance magnetique du proton a haut champ de la ceto-6 prostaglandine E l . On illustre dans ces etudes les avantages de ces techniques a deux dimensions. On a Cgalement observe que le proton H-lOa de la prostaglandine E, est substitue plus facilement par le deuterium que les autres protons en a des groupes cetoniques.[Traduit par le journal]Prostacyclin (Prostaglandin I,, PGI,) is the most potent inhibitor of platelet aggregation and a potent vasodilator (1, 2). It is unstable and rapidly hydrolyses to 6-keto-prostaglandin F,,. The metabolism of PGI, or 6-keto-prostaglandin F,, by 9-hydroxyprostaglandin dehydrogenase in human platelets leads to a more stable substance, 6-keto-prostaglandin El (6-keto-PGE,) (3) with similar biological activity to PGI, (4, 5). In our continuing studies of the structure-activity relationships of PGI, and its derivatives, we found it very difficult to analyze the complete proton magnetic resonance spectrum of 6-keto-PGE,. Even at 400 MHz, due to the overlap of the multiplets in the high-field region, standard decoupling and one-dimensional nuclear Overhauser effect (nOe) measurements could not be used to assign all of the proton resonances. The complete assignment was possible by means of the combined two-dimensional nOe measurements and spin-echo correlated spectroscopy (SECSY).The selective proton-proton one-dimensional (ID) nOe experiments have been extensively applied in the study of molecular structure and conformation (6-9). This experiment requires the measurement of the intensity change of a proton resonance upon saturating another proton. Twodimensional nOe experiments have recently been developed for the investigation of cross-relaxation 'Paper No. 9 in a series of high-field nmr studies on the prostaglandins and vitamins. For paper No. 8, see ref. 31. and chemical exchange processes (10-15). The advantages of this technique over the one-dimensional nOe experiment are (a) the simultaneous measurement of all the nOe's between closelyspaced protons in a molecule, and (b) the elimination of problems assoc...

“…The structure contains a surements have proved to be invaluable in the nmr between C5 and C61 the studies of PGI, (18) and (6R)-PGI, (19). In the atom at C5 has the 5Z but the rest present study, these measurements, together with the molecule is identical to PGI,.…”

Section: Introductionmentioning

confidence: 83%

A nuclear Overhauser effect difference study and a two-dimensional J proton magnetic resonance study of (6S)-prostaglandin I₁

Kotovych¹,

Aarts²,

Nakashima³

1981

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High-field nuclear Overhauser effect difference measurements allowed the assignment of the proton resonances for (6S)-prostaglandin I1 in phosphate buffer solutions. The two-dimensional J proton magnetic resonance experiments complemented these studies, as they also allowed the structure of several multiplets to be obtained when these multiplets are hidden by nearby resonances in a normal spectrum. The chemical shifts and coupling constants are compared with the data obtained previously for (6R)-prostaglandin I1.