ADA-Bypass by lipophilic cycloSal-ddAMP pro-nucleotides. A second example of the efficiency of the cycloSal-concept

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 12, 1997, Pages 1577-1582

  Meier, Chris ^a,b   Knispel, Tina ^a   De Clercq, E ^c   Balzarini, Jan ^c  

^a GOETHE UNIVERSITY   (Germany)

^b UNIVERSITY OF WÜRZBURG   (Germany)

^c REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2',3' DIDEOXYADENOSINE; ADENOSINE DERIVATIVE; NUCLEOSIDE ANALOG;

ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG STABILITY; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 2; HYDROLYSIS; IN VITRO STUDY; LIPOPHILICITY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY;

EID: 0030927126     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00265-5     Document Type: Article

References (29)

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2. Shelton, M.J.; O'Donnell, M.; Morse, G.D.; Ann. Pharmacother. 1992, 26, 660-670.
3. Herdewijn, P.; Balzarini, J.; De Clercq, E.; in Advances in Antiviral Drug Design (Ed. DeClercq, E.); JAI Press Inc., London, Vol. 1; 1993, 233-318. In contrast to ddAMP, ddIMP is not further metabolized into ddIDP or ddITP: Ahluwalia, G.; Cooney, D.A.; Mitsuya, H.; Fridland, A.; Flora, K.P.; Hao, Z.; Dalal, M.; Broder, S.; Johns, D.G.; Biochem. Pharmacol. 1987, 36, 3797-3800.
4. Herdewijn, P.; Balzarini, J.; De Clercq, E.; in Advances in Antiviral Drug Design (Ed. DeClercq, E.); JAI Press Inc., London, Vol. 1; 1993, 233-318. In contrast to ddAMP, ddIMP is not further metabolized into ddIDP or ddITP: Ahluwalia, G.; Cooney, D.A.; Mitsuya, H.; Fridland, A.; Flora, K.P.; Hao, Z.; Dalal, M.; Broder, S.; Johns, D.G.; Biochem. Pharmacol. 1987, 36, 3797-3800.
5. Jones, R.J.; Bischofberger, N.; Antiviral Res. 1995, 27, 1-17 and cited literature; Farquhar, D.; Khan, S.; Srivastava, D.N.; Saunders, P.P.; J. Med. Chem. 1994, 37, 3902-3909; Lefebvre, I.; Périgaud, C.; Pompon, A.; Aubertin, A.-M.; Girardet, J.-L.; Kirn, A.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1995, 38, 3941-3950; Abraham, T.W.; Kalman, T.I.; McIntee, E.J.; Wagner, C.R.; J. Med. Chem. 1996, 39, 4569-4575; McGuigan, C.; Cahard, D.; Sheeka, H.M.; Balzarini, J.; De Clercq, E.; J. Med. Chem. 1996, 39, 1748-1753.
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7. Jones, R.J.; Bischofberger, N.; Antiviral Res. 1995, 27, 1-17 and cited literature; Farquhar, D.; Khan, S.; Srivastava, D.N.; Saunders, P.P.; J. Med. Chem. 1994, 37, 3902-3909; Lefebvre, I.; Périgaud, C.; Pompon, A.; Aubertin, A.-M.; Girardet, J.-L.; Kirn, A.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1995, 38, 3941-3950; Abraham, T.W.; Kalman, T.I.; McIntee, E.J.; Wagner, C.R.; J. Med. Chem. 1996, 39, 4569-4575; McGuigan, C.; Cahard, D.; Sheeka, H.M.; Balzarini, J.; De Clercq, E.; J. Med. Chem. 1996, 39, 1748-1753.
8. Jones, R.J.; Bischofberger, N.; Antiviral Res. 1995, 27, 1-17 and cited literature; Farquhar, D.; Khan, S.; Srivastava, D.N.; Saunders, P.P.; J. Med. Chem. 1994, 37, 3902-3909; Lefebvre, I.; Périgaud, C.; Pompon, A.; Aubertin, A.-M.; Girardet, J.-L.; Kirn, A.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1995, 38, 3941-3950; Abraham, T.W.; Kalman, T.I.; McIntee, E.J.; Wagner, C.R.; J. Med. Chem. 1996, 39, 4569-4575; McGuigan, C.; Cahard, D.; Sheeka, H.M.; Balzarini, J.; De Clercq, E.; J. Med. Chem. 1996, 39, 1748-1753.
9. Jones, R.J.; Bischofberger, N.; Antiviral Res. 1995, 27, 1-17 and cited literature; Farquhar, D.; Khan, S.; Srivastava, D.N.; Saunders, P.P.; J. Med. Chem. 1994, 37, 3902-3909; Lefebvre, I.; Périgaud, C.; Pompon, A.; Aubertin, A.-M.; Girardet, J.-L.; Kirn, A.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1995, 38, 3941-3950; Abraham, T.W.; Kalman, T.I.; McIntee, E.J.; Wagner, C.R.; J. Med. Chem. 1996, 39, 4569-4575; McGuigan, C.; Cahard, D.; Sheeka, H.M.; Balzarini, J.; De Clercq, E.; J. Med. Chem. 1996, 39, 1748-1753.
10. Meier, C.; Angew. Chem. 1996, 108, 77-79; Angew. Chem. Int. Ed. Engl. 1996, 35, 70-72; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press; Lorey, M.; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press.
11. Meier, C.; Angew. Chem. 1996, 108, 77-79; Angew. Chem. Int. Ed. Engl. 1996, 35, 70-72; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press; Lorey, M.; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press.
12. Meier, C.; Angew. Chem. 1996, 108, 77-79; Angew. Chem. Int. Ed. Engl. 1996, 35, 70-72; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press; Lorey, M.; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press.
13. Meier, C.; Angew. Chem. 1996, 108, 77-79; Angew. Chem. Int. Ed. Engl. 1996, 35, 70-72; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press; Lorey, M.; Meier, C.; E. De Clercq, Baizarini, J.; Nucleosides & Nucleotides 1997, 16, in press.
14. Meier, C.; Lorey, M.; E. De Clercq, Balzarini, J.; Bioorg. Med. Chem. Letters 1997, 7, 99-104; Meier, C.; Lorey, M.; E. De Clercq, Balzarini, J.; Nucleosides & Nucleotides 1997, 16, in press.
15. Meier, C.; Lorey, M.; E. De Clercq, Balzarini, J.; Bioorg. Med. Chem. Letters 1997, 7, 99-104; Meier, C.; Lorey, M.; E. De Clercq, Balzarini, J.; Nucleosides & Nucleotides 1997, 16, in press.
16. Only one other phosphotriester prodrugs of ddAMP, which should be cleaved by enzymatic hydrolysis has been published recently: Périgaud, C.; Gosselin, G.; Benzaria, S.; Girardet, J.-L.; Maury, G.; Pelicano, H.; Aubertin, A.-M.; Kirn, A.; Imbach, J.-L.; Nucleosides & Nucleotides 1995, 14, 789-791 and Périgaud, C.; Aubertin, A.-M.; Benzaria, S.; Pelicano, H.; Girardet, J.-L.; Maury, G.; Gosselin, G.; Kirn, A.; Imbach, J.-L.; Biochem. Pharmacol. 1994, 48, 11-14.
17. Only one other phosphotriester prodrugs of ddAMP, which should be cleaved by enzymatic hydrolysis has been published recently: Périgaud, C.; Gosselin, G.; Benzaria, S.; Girardet, J.-L.; Maury, G.; Pelicano, H.; Aubertin, A.-M.; Kirn, A.; Imbach, J.-L.; Nucleosides & Nucleotides 1995, 14, 789-791 and Périgaud, C.; Aubertin, A.-M.; Benzaria, S.; Pelicano, H.; Girardet, J.-L.; Maury, G.; Gosselin, G.; Kirn, A.; Imbach, J.-L.; Biochem. Pharmacol. 1994, 48, 11-14.
18. It is well known in literature that phosphodiesters are extremely stable against chemical hydrolysis at physiological pH values: Bunton, C.A.; Mhala, M.M.; Oldham, K.G.; Vernon, C.A.; J. Chem. Soc. 1960, 3293-3301. Even the "reactive" diphenylphosphate showed a half live of 180 years(!) at pH 7.0 and 100°C: Kirby, A.J.; Younas, M.; J. Chem. Soc. (B) 1970, 510-513. Also enzymatically catalyzed approaches have already shown some limitations in the hydrolyses of non-natural products: Valette, G.; Pompon, A.; Girardet, J.-L.; Cappellacci, L.; Franchetti, P.; Grifantini, M.; La Colla, P.; Loi, A.G.; Périgaud, C.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1996, 39, 1981-1990.
19. It is well known in literature that phosphodiesters are extremely stable against chemical hydrolysis at physiological pH values: Bunton, C.A.; Mhala, M.M.; Oldham, K.G.; Vernon, C.A.; J. Chem. Soc. 1960, 3293-3301. Even the "reactive" diphenylphosphate showed a half live of 180 years(!) at pH 7.0 and 100°C: Kirby, A.J.; Younas, M.; J. Chem. Soc. (B) 1970, 510-513. Also enzymatically catalyzed approaches have already shown some limitations in the hydrolyses of non-natural products: Valette, G.; Pompon, A.; Girardet, J.-L.; Cappellacci, L.; Franchetti, P.; Grifantini, M.; La Colla, P.; Loi, A.G.; Périgaud, C.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1996, 39, 1981-1990.
20. It is well known in literature that phosphodiesters are extremely stable against chemical hydrolysis at physiological pH values: Bunton, C.A.; Mhala, M.M.; Oldham, K.G.; Vernon, C.A.; J. Chem. Soc. 1960, 3293-3301. Even the "reactive" diphenylphosphate showed a half live of 180 years(!) at pH 7.0 and 100°C: Kirby, A.J.; Younas, M.; J. Chem. Soc. (B) 1970, 510-513. Also enzymatically catalyzed approaches have already shown some limitations in the hydrolyses of non-natural products: Valette, G.; Pompon, A.; Girardet, J.-L.; Cappellacci, L.; Franchetti, P.; Grifantini, M.; La Colla, P.; Loi, A.G.; Périgaud, C.; Gosselin, G.; Imbach, J.-L.; J. Med. Chem. 1996, 39, 1981-1990.
21. Westheimer, F.H.; Acc. Chem. Res. 1968, 1, 70-78.
22. Buchwald, S.L.; Pliura, D.H.; Knowles, J.R.; J. Am. Chem. Soc. 1984, 106, 4916-4922.
23. ddA 1 was synthesized by the following procedure: regioselective 5′-O benzoylation of deoxyadenosine with benzoic acid catalyzed by N,N′-bis-(2-oxo-oxazolidin-3-yl)phosphorodiamidic chloride (BOPDC; Liguori, A.; Perri, E.; Sindona, G.; Uccella, N.; Tetrahedron 1988, 44, 229-234) in pyridine (65% yield), regioselective 3′-O esterification with thiocarbonyldiimidazole and subsequent reaction with methanol (77% yield; note: esterification using phenoxythiocarbonylchloride was not sufficiently regio-selective), subsequent Barton desoxygenation (88% yield) followed by a 12 hour treatment of the intermediate with ammonia in methanol to yield ddA (94% yield).
24. 31P NMR spectra: 3a (H; δ = -8.84 ppm/ -8.78 ppm); 3b (5-OMe; δ = -8.64 ppm / 8.58 ppm); 3c (3-Me; δ = -8.24 ppm / -8.13 ppm).
25. Balzarini, J.; Cools, J.M.; De Clercq, E.; Biochem. Biophys. Res. Commun. 1989, 158, 413.
26. Further hydrolysis studies in culture medium, in plasma and in cell extracts are in progress in our laboratory and will be publish in due course.
27. The evaluation of these compounds in thymidine kinase-deficient cells is not useful because the metabolization of ddA 1 is not dependent on thymidine kinase.
28. Nair, V.; Sells, T.B.; Biochim. Biophys. Acta 1992, 1119, 201-204.
29. The need of a free 5′-hydroxyl group for the ADA reaction has been shown by Bloch, A.; Robins, M.J.; McCarthy, J.R.; J. Med. Chem. 1967, 10, 908-912.