320 Journal of Medicinal Chemistry, 1977, Vol. 20, No. 2
and weighed. Finally, uterine ratios were calculated as uterine weight (mg)/body weight (9) X 100.
One Of us (T- Qazi) gratefully acknowledges support by the National Research Development Corporation in the form of a postdoctoral research associateship.
Communications t o the Editor
References and Notes (1) D. J. Bailey, N. S. Doggett, L. Y.Ng, and T. Qazi, J . Med. Chem., 19, 438 (1976). (2) B. L. Rubin, A. S. Dorfman, L. Black, and R. I. Dorfman, Endocrinology, 49, 429 (1951). ( 3 ) A. Goldstein, Pharrnacol. Reu., 1, 102 (1949). (4) J. M. Van Rossum, Adu. Drug Res., 3, 189 (1966).
Communications to the Editor A Novel Prostaglandin Endoperoxide Mimic, Prostaglandin Fz,Acetal
Table I. Relative Potency of Prostaglandin F,, Acetal ( l a ) on Various Smooth Muscle Preparations
Sir: The prostaglandin endoperoxides PGG2 and PGH2 are known to be intermediates in the biosynthesis of PGE2, PGF2,, PGD2, and Thromboxane A2.1-4 The fact that PGG2 and PGH2 are extremely potent, but chemically labile, has prompted the synthesis of a number of stable analogues whose ring-system geometry approximates that of the e n d o p e r o ~ i d e . ~Several -~ of these analogues have been reported6s7z9to mimic the biological activity of PGG2 and PGH2. This communication describes the synthesis and biological properties of a novel endoperoxide mimic, PGF2, acetal ( l ) , whose ring geometry represents a departure from that found in the natural endoperoxides and their analogues.
Reference a Based on the mean molar potencies i SE. 18. Reference 1 9 . Reference 2 0 . e Data obtained from ref 1 0 .
spectively. The NMR spectrum of the isomer mixture indicates an approximately 60:40 ratio for 1a:lb in the mixture. Preliminary experiments indicate that la is fairly stable in aqueous medium, as it was observed that close to 100% of the biological activity was retained when a Krebs solution (pH 8.2) of la was maintained at 4 OC for l week. Moreover, a saline solution of 1 stored at 25 "C for 24 h was estimated to be approximately 5% hydrolyzed. Previous studies have indicated a spectrum of activities which are characteristic for the endoperoxide^.^^'^ Prostaglandins G2 and H2 are potent inducers of platelet aggregation and, relative to the classical prostaglandins, are potent stimulators of vascular smooth muscle contractility but are generally less or equipotent stimulators of gastrointestinal tract smooth muscle. This profile of activity has been employed in the present study to evaluate la. Epimer la was tested"," for its ability to induce platelet aggregation in human, citrated platelet-rich plasma. A t concentrations of 0.7-4 pg/ml PGFznacetal caused a small reversible wave of platelet aggregation which became complete and irreversible at concentrations of 5-10 pg/ml ( n = 4). By comparison, PGGz produces irreversible aggregation at 1W250 ng/ml. Thus, la has approximately 1/40-1/j0ththe potency of PGG2. The effect of la on platelets is uninhibited by 10 pg/ml of the PG synthetase inhibitor,I3 indomethacin, suggesting that its primary action is direct and is not due to stimulation of endogenous prostaglandin synthesis. Finally, transmission electron microscopy of platelets exposed to la shows that its effect on platelet ultrastr~cture'~is very similar to that of PGG2.I5-l7 Additional evidence suggesting that la is acting as an endoperoxide mimic was obtained from its pattern of activity on three different smooth muscle preparations: the isolated gerbil colon,l8 rabbit thoracic and canine lateral saphenous vein20 (Table I). Prostaglandin Fz, acetal la caused concentration-dependent contraction of all three preparations and the pattern of relative potencies was qualitatively similar to that of PGG2 (Table I). Epimer
LycooH
Q---
I
la PGG,
Relative contractile effectsa Gerbil Rabbit Saphenous colonb aortaC veind (PGE, = 1) (PGF,, = 1) (PGF,, = 1) 0 . 1 2 1 0.01 ( n = 3 ) 1 9 i- 4 ( n = 3 ) 32 I 7 ( n = 6 ) 1.5e 80e
()---
P
PGG,, R = OOH PGH,, R = OH
OH
1
Prostaglandin FZawas allowed to react with neat acetaldehyde in the presence of 0.1% HC1 for 1.5 h at 25 "C. The reaction mixture was treated with aqueous sodium bicarbonate to quench catalyst and the product 1 was regenerated with pH 3 buffer. Purification by column chromatography on silica gel furnished the desired acetal 1 as a mixture of two epimers la and lb: yield 41%;two spots on TLC with R, 0.53 and 0.49 [silica gel, 100 pm, double development in CHC1,-EtOAc-HOAc (50:50:1)]. Anal. Calcd for C22H3605: C, 69.44; H, 9.54. Found: C, 69.40; H, 9.28. HPLC of the mixture using a 25 cm X 8 mm i.d. Micropak CN-10 column and 2% MeOH in CHC13 furnished purified la: IR (CHCl,) 3500-3300 (OH), 1710 (acid C=O), 1340 cm-' (OCHO, CH def); EIMS of the methyl ester m / e 394 (M'). The NMR spectrum (CDC13) of the epimeric mixture prior to HPLC separation of la exhibited readily observable acetal methyl and methine proton absorptions as doublets and quartets, respectively. The methyl and methine resonances for the acetal group of the pure isomer la appear at 6 1.25 and 5.10, respectively, and those of l b appear at 6 1.37 and 4.75, re-
Journal of Medicinal Chemistry, 1977, Vol. 20, No. 2
Book Reviews
la was a particularly potent venoconstrictor, threshold responses being obtained a t a concentration of 1ng/ml. By comparison, canine intrapulmonary veins have also been reportedz1to be very sensitive to PG endoperoxide analogues. The EDs0 (95% confidence interval) of la for contraction of the canine saphenous vein was 5.8 (5-6.7) ng/ml. Additional experiments showed that venoconstriction induced by la was not blocked by indomethacin and that la did not possess vasodilator activity.22 It should be noted that the 60:40 mixture of 1a:lb was tested on platelets and the isolated saphenous vein. The effects were not substantially different from that of la, thus suggesting that la and l b possess similar activities and potencies. The results of this study indicate that endoperoxide mimicry is not restricted to heterobicyclo[2.2.1]heptane analogues of PGHz and that other bicyclic systems may share similar biological properties. We are presently investigating the stereochemistry of the acetal chiral center in 1 and the biological properties of homologues of 1. Acknowledgment. This study was supported by NIH Grants HL 16 524, HL 11880, and HL 15 447. References and Notes M. Hamberg and B. Samuelsson, Proc. Natl. Acad. Sci. U.S.A., 70, 899 (1973). D. H. Nugteren and E. Hazelhof, Biochim. Biophys. Acta, 326, 448 (1973). M. Hamberg, J. Svensson, T. Wakabayashi, and B. Samuelsson, Proc. Natl. Acad. Sci. U.S.A., 71, 345 (1974). M. Hambere. J. Svensson. and B. Samuelsson. Proc. Natl. Acad. Sci. fi.S.A., 72, 2994 (1975). G. L. Bundy, Tetrahedron Lett., 1957 (1975). E. J. Corey, K. C. Nicolaou, Y. Machida, C. L. Malmsten, and B. Samuelsson, Proc. Natl. Acad. Sci. U.S.A., 72,3355 (1975). E. J. Corey, M. Shibasaki, K. C. Nicolaou, C. L. Malmsten, and B. Samuelsson, Tetrahedron Lett., 737 (1976). A. G. Abatjoglou and P. S.Portoghese, Tetrahedron Lett., 1457 (1976).
321
(9) C. Malmsten, Life Sci., 18, 169 (1976). (10) M. Hamberg, P. Hedqvist, K. Strandberg, J. Svensson, and B. Samuelsson, Life Sci., 16, 451 (1975). (11) G. V. R. Born, Nature (London), 194, 927 (1962). (12) J. M. Gerrard, J. G. White, and W. Krivit, J.Lab. Clin. Med., 87, 73 (1976). (13) R. J. Flower, Pharrnacol. Rev., 26, 33 (1974). (14) J. G. White, Blood, 31, 604 (1968). (15) J. M. Gerrard, D. Townsend, S. Stoddard, C. T. Witkop, Jr., and J. G. White, Am. J. Pathol., in press. (16) J. M. Gerrard and J. G. White, Am. J.Pathol., 80,189 (1975). (17) The acetal la initiates an internal contractile response of the platelet, with the granules being squeezed into the center of the platelet surrounded closely by microtubules and by contractile microfilaments. (18) E. W. Dunham and B. G. Zimmerman, Am. Physiol., 219, 1279 (1970). (19) R. F. Furchgott and S.Bhadrakom, J. Pharmacol. Erp. Ther., 108, 129 (1953). (20) E. W. Dunham, M. K. Haddox, and N. D. Goldberg, Proc. Natl. Acad. Sci. U.S.A., 71, 815 (1974). (21) D. B. McNamara. C. A. Gruetter. A. L. Hvman. and P. J. Kadowitz, Pharmacologist, 18, 604 (1976;. (22) Most isolated vascular smooth muscles contract in response to prostaglandins known to be vasodilators in vivo (e.g., PGEp). The isolated vein preparation describedm can show the effect of potential vasodilators if it is precontracted. la showed no vasodilator activity on the precontracted (phenylephrine) saphenous vein. ~~~I
Philip S. Portoghese,’ Dennis L. Larson Anthony G . Abatjoglou Department of Medicinal Chemistry, College of Pharmacy
Earl W. Dunham Department of Pharmacology, Medical School
Jonathan M. Gerrard, James G . White Department of Pediatrics, Medical School University of Minnesota, Minneapolis, Minnesota 55455 Received November 5 , 1976
Book Reviews Advances in Carbohydrate Chemistry and Biochemistry. Volume 31. Edited by R. Stuart Tipson and Derek Horton. Academic Press, New York, N.Y. 1975. xii 23.5 cm. $18.50.
+ 416 pp.
15
X
“Advances in Carbohydrate Chemistry and Biochemistry”, Volume 31, consists of seven chapters and is a welcome addition to this series. The chapter on deamination of carbohydrate amines offers a comprehensive survey of the current status of nitrosation as a means of effecting deamination of carbohydrate and cyclitol amines. The reaction is certainly the most widely used one for deaminating carbohydrate amines and its usefulness as well as its limitations are adequately presented. The section dealing with the application of the reaction to synthetic and structural problems is an important one and serves to illustrate the most fruitful use of the reaction, namely, in degradation studies during the structural elucidation of carbohydrate amines. The formation of rearrangement products, depending on the stereochemistry of the substrate amines, imposes severe limitations on the synthetic utility of the nitrosation deamination reaction. Consequently, it would have been valuable if the author had included a short section on new methods for carrying out deaminations. Even though these reactions have not been used in the carbohydrate
field to date, it might have served to stimulate carbohydrate chemists to use them in the future. The chapter on the reaction of ammonia with acyl esters of carbohydrates by Gelpi and Cadenas deals with this interesting but complex reaction in a clear and concise way. It also summarizes the application of this reaction for the preparation of nitrogenated derivatives of carbohydrates and nitrogen-containing heterocyclic compounds. A description of the influence of the solvent, and the structure and configuration of the starting material, is included. At the end of the chapter there are two very useful tables which give a list of acylated monosaccharides and disaccharides and their reaction products with ammonia. The yield, physical constants of the final products (melting points, [a]D,etc.), and references are included in the tables. The chapter on chemistry and biochemistry of apiose by Watson and Orenstein is unnecessarily lengthy and contains too many historical details which may be interesting to read but are of little consequence to investigators in this area of research. Isolation, characterization, chemical synthesis, and biosynthesis of apiose have been discussed in this chapter and it also contains many useful references. In recent years many branched chain sugars have been isolated from antibiotics. The possible role of these branch-chained sugars and apiose containing polysaccharides in resisting microbiological degradations has been discussed.
