Abstract
A new method for the synthesis of tertiary and quaternary aminoesters of N-substituted α,β-dehydroamino acids is described. Aseries of 16 dehydroamino acids esterified to choline or to its tertiary analog have been synthesized by the proposed method with a yield of 84–93%, and their interactions with human erythrocyte acetylcholinesterase (ACE) and human plasma butyrylcholinesterase (BCE) has been studied. The half-inhibiting concentrations IC50 of the synthesized compounds (determined with respect to cholinesterase hydrolysis of a model substrate, 0.1 mM ATC) vary within a broad range (0.16–1840 µM). The values of traditional parameters of the wave functions of ligands estimated using the Hartree-Fock method do not explain the observed pattern of the anticholinesterase activity. The specific properties of the molecules, especially in their quaternary ammonium salt forms, are probably related to their structural features, in particular, to the ability of the inhibitors to form cyclic conformations (so-called crown structures). Such structures are probably stabilized as a result of the formation of intramolecuar hydrogen bonds between protons of the choline residue and oxygen of the terminal peptide group.
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V. O. Topuzyan, G. P. Alebyan, O. L. Mndzhoyan, Khim.-Farm. Zh., 18(7), 798–802 (1984).
V. O. Topuzyan, A. S. Nesunts, R. G. Paronikyan, et al., Khim.-Farm. Zh., 31(1), 21–24 (1997).
G. P. Alebyan and V. O. Topuzyan, Abstracts of Papers, Armenian Chemistry at eh XXI Century Threshold, Erevean (2000), p. 112.
V. O. Topuzyan, J. A. Gerasimyan, A. S. Édilyan, et al., Khim.-Farm. Zh., 20(6), 675–679 (1986).
V. O. Topuzyan and G. Yu. Khachvankyan, Arm. Khim. Zh., 49(1–3), 138–141 (1996).
G. Fairbanks, T. L. Steck, and D. F. Wallach, Biochemistry, 10(13), 2606–2617 (1971).
B. N. La Du, C. F. Bartels, C. P. Nogueria, et al., Clin. Biochem., 23, 423–431 (1990).
G. L. Ellman, K. D. Coutney, V. Jr. Andres and R. M. Feather-Stone, Biochem. Pharmacol., 7, 88–95 (1961).
P. W. Riddles, R. L. Blakeley, and B. Zerner, Anal. Biochem., 94(1), 75–81 (1979).
W. Xie, C. V. Altamirano, O. Lockridge, et al., Mol. Pharmacol., 55, 83–91 (1999).
A. Cornish-Bowden, Principles of Enzyme Kinetics, Butterworth & Co., London (1976).
Q. S. Yu, H. W. Holloway, J. L. Flippen-Anderson, et al., J. Med. Chem., 44, 4062–4072 (2001).
B. Wellenzohn, K. R. Liedle, and B. M. Rode, J. Med. Chem., 46, 5087–5090 (2003).
Z. Radic, R. Duran, D. C. Vellom, et al., J. Biol. Chem., 269, 11233–11239 (1994).
P. Masson, M.-T. Froment, C. F. Bartels, and O. Lockridge, Biochem. J., 325, 53–61 (1997).
P. Masson, P. Legrand, C. F. Barlets, et al., Biochemistry, 36(8), 2266–2277 (1997).
M. J. S. Dewar, E. G. Zoebisch, E. F. Healy and J. J. P. Stewart, J. Am. Chem. Soc., 107, 3902–3909 (1985).
PC Spartan Plus, Version 1.5 Wavefunction Inc., 18401 Von Karman, Suite 370, Irvine, California, 92612, USA (1998).
M. J. Frisch, G. W. Trucks, H. B. Schlegel, et al., GAUSSIAN 98, Revision A.11, Gaussian, Inc., Pittsburgh, PA (2001).
R. Asatryan, N. Mailyan, L. Khachatryan and B. Dellinger, Chemosphere, 48(2), 227–236 (2002).
M. S. Aleksanyan, A. A. Karapetyan, Yu. T. Struchkov, et al., Arm. Khim. Zh., 46(1–2), 70–74 (1993).
G. Vistoli, A. Pedretti, L. Villa, and B. Testa, J. Am. Chem. Soc., 124, 7472–7480 (2002).
P. Masson, B. N. Goldstein, J.-C. Debouzy, et al., Eur. J. Biochem., 271, 220–234 (2004).
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Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 3, pp. 18–23, March, 2006.
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Grigoryan, A.A., Ambartsumyan, A.A., Mkrtchyan, M.V. et al. Synthesis and anticholinesterase activity of 2-(dimethylamino)ethyl and choline esters of n-substituted α, β-dehydroamino acids. Pharm Chem J 40, 135–140 (2006). https://doi.org/10.1007/s11094-006-0077-8
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DOI: https://doi.org/10.1007/s11094-006-0077-8