Facilitated catecholamine transport through bulk and polymer-supported liquid membranes

Journal of the American Chemical Society

Volumn 118, Issue 41, 1996, Pages 9820-9825

  Paugam, Marie France ^a   Bien, Jeffrey T ^a   Smith, Bradley D ^a   Chrisstoffels, Lysander A J ^b   De Jong, Feike ^b   Reinhoudt, David N ^b  

^a UNIVERSITY OF NOTRE DAME   (United States)

^b UNIVERSITY OF TWENTE   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ADRENALIN; CATECHOLAMINE; CROWN ETHER DERIVATIVE; DOPAMINE; DRUG CARRIER; NORADRENALIN; ORGANOBORON DERIVATIVE;

ARTICLE; DRUG BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; IN VITRO STUDY; LIPOPHILICITY; MASS SPECTROMETRY; MEMBRANE TRANSPORT; NUCLEAR MAGNETIC RESONANCE;

EID: 0029973914     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja9615076     Document Type: Article

References (36)

1. Whitley, R. J.; Meikle, A. W.; Watts, N. B. In Tietz Textbook of Clinical Chemistry, 2nd ed.; Burtis, C. A., Ashwood, E. R., Eds.; Saunders: Philadelphia. 1994; pp 1739-1764.
2. Neumeyer, J. L.; Booth, R. G. In Principles of Medicinal Chemistry, 4th ed.; Foye, W. O., Lemke, T. L., Williams, D. A., Eds.; Lea and Febiger: Philadelphia, 1995; Chapter 13.
3. (a) Rosano, T. G.; Swift, T. A.; Hayes, L. W. Clin. Chem. 1991, 37, 1854-1867.
4. (b) Quantitative Analysis of Catecholamines and Related Compounds; Krstulovic, A. M., Ed.; Ellis Horwood: Chichester, 1986.
5. Paugam, M.-F.; Valencia, L. S.; Boggess, B.; Smith, B. D. J. Am. Chem. Soc. 1994, 116, 11203-11204.
6. (a) Visser, H. C.; Reinhoudt, D. N.; de Jong, F. Chem. Rev. 1994, 23, 75-82.
7. (b) Liquid membranes: Chemical Applications; Araki, T., Tsukube, H., Eds.; CRC Press: Boca Raton, FL, 1990.
8. (c) Fyles, T. M. In Inclusion Aspects of Membrane Chemistry; Osa, T., Atwood, J. L., Eds.; Kluwer: Boston, 1991.
9. Torsell, K. In Progress in Boron Chemistry; Steinberg, H., McCloskey, A. L., Eds.; Pergamon: New York, 1964; p 385.
10. Lamb, J. D.; Christensen, J. J.; Izatt, S. R.; Bedke, K.; Astin, M. S.; Izatt, R. M. J. Am. Chem. Soc. 1980, 102, 3399-3403.
11. (a) Smith, B. D. Supramol. Chem. 1996, 7, 55-60.
12. (b) James, T. D.; Samankumara Sandanayake, K. R. A.; Shinkai, S. Supramol. Chem. 1995, 6, 141-157.
13. London, R. E.; Gabel, S. A. J. Am. Chem. Soc. 1994, 116, 2562-2569.
14. Other examples of synthetic ditopic receptors for catecholamines include: (a) Imada, T.; Kijima, H.; Takeuchi, M.; Shinkai, S. Tetrahedron 1996, 52, 2817-2826. (b) Kimura, E.; Fujioka, H.; Kodama, M. J. Chem. Soc., Chem. Commun. 1986, 1158-1159. (c) Saigo, K.; Kihara, N.; Hashimoto, Y.; Lin, R.; Fujimura, H.; Suzuki, Y.; Hasegawa, M. J. Am. Chem. Soc. 1990, 112, 1144-1150. (d) Dumont, B.; Schmitt, M-F.; Joly, J.-P. Tetrahedron Lett. 1994, 35, 4773-4776. (e) Sutherland, I. O. In Advances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwhich, CT, 1990; Vol. 1.
15. Other examples of synthetic ditopic receptors for catecholamines include: (a) Imada, T.; Kijima, H.; Takeuchi, M.; Shinkai, S. Tetrahedron 1996, 52, 2817-2826. (b) Kimura, E.; Fujioka, H.; Kodama, M. J. Chem. Soc., Chem. Commun. 1986, 1158-1159. (c) Saigo, K.; Kihara, N.; Hashimoto, Y.; Lin, R.; Fujimura, H.; Suzuki, Y.; Hasegawa, M. J. Am. Chem. Soc. 1990, 112, 1144-1150. (d) Dumont, B.; Schmitt, M-F.; Joly, J.-P. Tetrahedron Lett. 1994, 35, 4773-4776. (e) Sutherland, I. O. In Advances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwhich, CT, 1990; Vol. 1.
16. Other examples of synthetic ditopic receptors for catecholamines include: (a) Imada, T.; Kijima, H.; Takeuchi, M.; Shinkai, S. Tetrahedron 1996, 52, 2817-2826. (b) Kimura, E.; Fujioka, H.; Kodama, M. J. Chem. Soc., Chem. Commun. 1986, 1158-1159. (c) Saigo, K.; Kihara, N.; Hashimoto, Y.; Lin, R.; Fujimura, H.; Suzuki, Y.; Hasegawa, M. J. Am. Chem. Soc. 1990, 112, 1144-1150. (d) Dumont, B.; Schmitt, M-F.; Joly, J.-P. Tetrahedron Lett. 1994, 35, 4773-4776. (e) Sutherland, I. O. In Advances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwhich, CT, 1990; Vol. 1.
17. Other examples of synthetic ditopic receptors for catecholamines include: (a) Imada, T.; Kijima, H.; Takeuchi, M.; Shinkai, S. Tetrahedron 1996, 52, 2817-2826. (b) Kimura, E.; Fujioka, H.; Kodama, M. J. Chem. Soc., Chem. Commun. 1986, 1158-1159. (c) Saigo, K.; Kihara, N.; Hashimoto, Y.; Lin, R.; Fujimura, H.; Suzuki, Y.; Hasegawa, M. J. Am. Chem. Soc. 1990, 112, 1144-1150. (d) Dumont, B.; Schmitt, M-F.; Joly, J.-P. Tetrahedron Lett. 1994, 35, 4773-4776. (e) Sutherland, I. O. In Advances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwhich, CT, 1990; Vol. 1.
18. Other examples of synthetic ditopic receptors for catecholamines include: (a) Imada, T.; Kijima, H.; Takeuchi, M.; Shinkai, S. Tetrahedron 1996, 52, 2817-2826. (b) Kimura, E.; Fujioka, H.; Kodama, M. J. Chem. Soc., Chem. Commun. 1986, 1158-1159. (c) Saigo, K.; Kihara, N.; Hashimoto, Y.; Lin, R.; Fujimura, H.; Suzuki, Y.; Hasegawa, M. J. Am. Chem. Soc. 1990, 112, 1144-1150. (d) Dumont, B.; Schmitt, M-F.; Joly, J.-P. Tetrahedron Lett. 1994, 35, 4773-4776. (e) Sutherland, I. O. In Advances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwhich, CT, 1990; Vol. 1.
19. Visser, H. C.; Vink, R.; Snellink-Ruel, B. H. M.; Kokhuis, S. B. M.; Harkema, S.; de Jong, F.; Reinhoudt, D. N. Reel. Trav. Chim. Pays-Bas 1995, 114, 285-294.
20. Charewicz, W. A.; Heo, G. S.; Bartsch, R. A. Anal. Chem. 1982, 54, 2094-2097. Heo, G. S.; Bartsch, R. A.; Schlobohm, L. L.; Lee, J. G. J. Org. Chem. 1981, 46, 3575-3576.
21. Charewicz, W. A.; Heo, G. S.; Bartsch, R. A. Anal. Chem. 1982, 54, 2094-2097. Heo, G. S.; Bartsch, R. A.; Schlobohm, L. L.; Lee, J. G. J. Org. Chem. 1981, 46, 3575-3576.
22. 19F NMR studies was contaminated with 8% of the protiodeboronated analogue 10. This impurity was not expected to prejudice the outcome of the experiment and in fact was a benefit because it acted as an internal reference signal (see Supporting Information).
23. Stolwijk, T. B.; Sudhölter, E. J. R.; Reinhoudt, D. N. J. Am. Chem. Soc. 1987, 109, 7042-7047. van Straaten-Nijenhuis, W.; de Jong, F.; Reinhoudt, D. N. Reel. Trav. Chim. Pays-Bas 1993, 112, 317-324.
24. Stolwijk, T. B.; Sudhölter, E. J. R.; Reinhoudt, D. N. J. Am. Chem. Soc. 1987, 109, 7042-7047. van Straaten-Nijenhuis, W.; de Jong, F.; Reinhoudt, D. N. Reel. Trav. Chim. Pays-Bas 1993, 112, 317-324.
25. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
26. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
27. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
28. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
29. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
30. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
31. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
32. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
33. While there have been many studies of ditopic membrane carriers, surprisingly few have unambiguously demonstrated an increase in ditopic cooperativity due to covalent conjugation, i.e., the ditopic receptor is a more efficient transporter than an equimolar mixture of two appropriate monotopic half-receptors. See, for example: Rudkevich, D. M.; Mercer-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.; Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6125. Reetz, M. T.; Huff, J.; Rudolph, J.; Töllner, K.; Deege, A.; Goddard, R. J. Am. Chem. Soc. 1994, 116, 11588-11589. Mohler, L. K.; Czarnik, A. W. J. Am. Chem. Soc. 1993, 115, 2998-2999. Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, J.; Salmerón, A.; Usman, N. 1994. 116, 5501-5502. Král, V.; Andrievsky, A.; Sesslor, J. L. J. Chem. Soc., Chem. Commun. 1995, 2349-2351. Sesslor, J. L.; Furuta, H.; Král, V. Supramol. Chem. 1993, 1, 209-220. Schwabacher, A. W.; Lee, J.; Lei, H. J. Am. Chem. Soc. 1992, 114, 7597-7598. Seel, A.; Vögtle, F. Angew. Chem., Int. Ed. Engl. 1991, 30, 442-444. Aoyama, Y.; Asakawa, M.; Yamagishi, A.; Toi, H.; Ogoshi, H. J. Am. Chem. Soc. 1990, 112, 3145-3151.
34. Aldag, R.; Scröder, G. Liebigs Ann. Chem. 1984, 1036-1048.
35. The ditopic recognition sites in 1 are essentially identical to those in 4. Thus, it is reasonable to expect that 1 and 4 would have the same general transported structure, i.e., the 1:1 cyclic zwitterion 7. One important difference, however, is that the membrane concentration of 4 in the SLM study was 33 times higher than the concentration of 1 in the BLM study. Although there is strong evidence that 1 forms structure 7, it is possible that 4 may be form a larger oligomeric analogue(s), which may explain its propensity to precipitate from the membrane.
36. Morin, G. T.; Paugam, M.-F.; Hughes, M. P.; Smith, B. D. J. Org. Chem. 1994, 59, 2724-2728.