A Review of Advances in the Synthesis of Analogues of the Delphinium ­Alkaloid Methyllycaconitine

Abstract

Neuronal nicotinic acetylcholine receptors of the α7 sub-type are potential targets for drug development in the treatment of Alzheimer’s disease. The Delphinium alkaloid methyllycaconitine is a potent and selective α7 sub-type selective nicotinic acetylcholine receptor antagonist. The total synthesis of this pharmacologically active alkaloid has not yet been achieved. A summary of semi-synthetic methods to prepare methyllycaconitine is presented. ­Existing synthetic strategies used to prepare E, AE, AEF, ABE, ­ABDE, ABEF ring analogues of methyllycaconitine are reviewed for the first time.

• 1 Introduction

• 1.1 Alzheimer’s Disease and α7 Nicotinic Acetylcholine ­Receptors

• 1.2 Methyllycaconitine - An α7 Subtype Selective Nicotinic Acetylcholine Receptor Antagonist

• 1.3 Structure-Activity Relationships of Delphinium Alkaloids

• 2 Semi-Syntheses of Delphinium Alkaloids

• 3 Synthesis of Analogues of Methyllycaconitine

• 3.1 Synthesis of E Ring Analogues of Methyllycaconitine

• 3.2 Synthesis of AE Ring Bicyclic Analogues of Methyl­lycaconitine

• 3.3 Synthesis of AEF Ring Tricyclic Analogues of Methyl­lycaconitine

• 3.4 Synthesis of ABE Ring Tricyclic Analogues of Methyl­lycaconitine

• 3.5 Synthesis of ABDE Ring Tetracyclic Analogues of Methyllycaconitine

• 3.6 Synthesis of ABEF Ring Tetracyclic Analogues of Methyllycaconitine

• 4 Conclusion

semi-synthesis - Delphinium alkaloids - nicotinic acetylcholine receptor α7 sub-type selective antagonists

References

1 Cooper JR. Bloom FE. Roth RH. The Biochemical Basis of Neuropharmacology   8th ed.:  Oxford University Press; Oxford: 2003. 

2 Levin ED. Rezvani AH. Eur. J. Pharmacol.  2000,  393:  141 

3 Hellstrom-Lindahl E. Eur. J. Pharmacol.  2000,  393:  255 

4 Marx J. Science  1996,  273:  50 

5 Papke RL. Meyer E. Nutter T. Uteshev VV. Eur. J. Pharmacol.  2000,  393:  179 

6 Pereira EFR. Hilmas C. Santos MD. Alkondon M. Maelicke A. Albuquerque EX. J. Neurobiol.  2002,  53:  479 

7 Levin ED. Bradley A. Addy N. Sigurani N. Neuroscience  2002,  109:  757 

8 Clementi F. Fornasari D. Gotti C. Eur. J. Pharmacol.  2000,  393:  3 

9 Holladay MW. Dart MJ. Lynch JK. J. Med. Chem.  1997,  40:  4169 

10 Martin-Ruiz CM. Court JA. Molnar E. Lee M. Gotti C. Mamalaki A. Tsouloufis T. Tzartos S. Ballard C. Perry RH. Perry EK. J. Neurochem.  1999,  73:  1635 

11 Addy NA. Nakijama A. Levin ED. Cogn. Brain Res.  2003,  16:  51 

12 Wang H. Lee DHS. Davis CB. Shank RP. J. Neurochem.  2000,  75:  1155 

13 Perry E. Martin-Ruiz C. Lee M. Griffiths M. Johnson M. Piggot M. Haroutunian V. Buxbaum JD. Nasland J. Davis K. Gotti C. Clementi F. Tzartos S. Cohen O. Soreq H. Jaros E. Perry R. Ballard C. McKeith I. Court J. Eur. J. Pharmacol.  2000,  393:  215 

14 Selkoe DJ. Trends Cell. Biol.  1998,  8:  447 

15 Pettit DL. Shao Z. Yakel JL. J. Neurosci.  2001,  21:  RC120 

16 Dougherty JJ. Wu J. Nichols RA. J. Neurosci.  2003,  23:  6740 

17 Sharples CGV. Wonnacott S. Tocris Reviews  2001,  19:  1 

18 Dinley KT. Westerman M. Bui D. Bell K. Ashe KH. Sweatt JD. J. Neurosci.  2001,  21:  4125 

19 Whiteaker P. Marks MJ. Grady SR. Lu Y. Picciotto MR. Changeux J. Collins AC. Eur. J. Pharmacol.  2000,  393:  123 

20 Romanelli MN. Gualtieri F. Med. Res. Rev.  2003,  24:  393 

21 Dwoskin LP. Crooks PA. J. Pharmacol. Exp. Ther.  2001,  298:  395 

22 Manske RHF. Can. J. Res.  1938,  16:  B, 57 

23 Wonnacott S. Albuquerque EX. Bertrand D. Methods Neurosci.  1993,  12:  263 

24 Goodson JA. J. Chem. Soc.  1943,  139 

25 Ulubelen A. Desai HK. Srivastava SK. Hart BP. Park J.-C. Joshi BS. Pelletier SW. Mericli AH. Mericli F. Ilarslan R. J. Nat. Prod.  1996,  59:  360 

26 Jennings KR. Brown DG. Wright DP. Experientia  1986,  42:  611 

27 Ward JM. Cockcroft VB. Lunt GG. Smillie FS. Wonnacott S. FEBS Lett.  1990,  270:  45 

28 Lind RJ. Hardick DJ. Blagbrough IS. Potter BVL. Wolstenholme AJ. Davies ARL. Clough MS. Earley FGP. Reynolds SE. Wonnacott S. Insect Biochem.  2001,  31:  533 

29 Panter KE. Manners GD. Stegelmeir BL. Lee S. Gardner DR. Ralphs MH. Pfister JA. James LF. Biochem. Syst. Ecol.  2002,  30:  113 

30 Hardick DJ. Blagbrough IS. Cooper G. Potter BVL. Critchley T. Wonnacott S. J. Med. Chem.  1996,  39:  4860 

31 Jacyno JM. Harwood JS. Lin N. Campbell JE. Sullivan JP. Holladay MW. J. Nat. Prod.  1996,  59:  707 

32 Kukel CF. Jennings KR. Can. J. Physiol. Pharmacol.  1994,  72:  104 

33 Manners GD. Panter KE. Pelletier SW. J. Nat. Prod.  1995,  58:  863 

34 Manners GD. Panter KE. Pfister JA. Ralphs MH. James LF. J. Nat. Prod.  1998,  61:  1086 

35 Gardner DR. Manners GD. Panter KE. Lee ST. Pfister JA. J. Nat. Prod.  2000,  63:  1127 

36 Blagbrough IS. Coates PA. Hardick DJ. Lewis T. Rowan MG. Wonnacott S. Potter BV. Tetrahedron Lett.  1994,  35:  8705 

37 Coates PA. Blagbrough IS. Hardick DJ. Rowan MG. Wonnacott S. Potter BV. Tetrahedron Lett.  1994,  35:  8701 

38 Blagbrough IS. Hardick DJ. Wonnacott S. Potter BVL. Tetrahedron Lett.  1994,  35:  3367 

39 Hardick DJ. Blagbrough IS. Wonnacott S. Potter BVL. Tetrahedron Lett.  1994,  35:  3371 

40 Pelletier SW. Ross SA. Heterocycles  1990,  31:  671 

41 Ross SA. Pelletier SW. Heterocycles  1991,  32:  1307 

42 Davies ARL. Hardick DJ. Blagbrough IS. Potter BVL. Wolstenholme AJ. Wonnacott S. Neuropharmacology  1999,  38:  679 

43 Hardick DJ. Blagbrough IS. Potter BVL. J. Am. Chem. Soc.  1996,  118:  5897 

44 Navarro HA. Zhong D. Abraham P. Xu H. Carroll FI. J. Med. Chem.  2000,  43:  142 

45 Bergmeier SC. Lapinsky DJ. Free RB. McKay DB. Bioorg. Med. Chem. Lett.  1999,  9:  2263 

46 Byant DL. Free RB. Thomasy SM. Lapinsky DJ. Ismail KA. McKay SB. Bergmeier SC. McKay DB. Neurosci. Res.  2002,  42:  57 

47 Ismail KA. Bergmeier SC. Eur. J. Med. Chem.  2002,  469 

48 Doisy X. Blagbrough IS. Wonnacott S. Potter BVL. Pharm. Pharmacol. Commun.  1998,  4:  313 

49 Simoni D. Rossi M. Rondanin R. Baruchello R. Grisolia G. Eleopra M. Giovannini R. Bozzoli A. Davalli S. Di Fabio R. Donati D. Tetrahedron Lett.  2005,  46:  759 

50 Coates PA. Blagbrough IS. Rowan MG. Potter BVL. Pearson DPJ. Lewis T. Tetrahedron Lett.  1994,  35:  8709 

51 Coates PA. Blagbrough IS. Rowan MG. Pearson DPJ. Lewis T. Potter BVL. J. Pharm. Pharmacol.  1996,  48:  210 

52 Grangier G. Trigg WJ. Lewis T. Rowan MG. Potter BVL. Blagbrough IS. Tetrahedron Lett.  1998,  39:  889 

53 Trigg WJ. Grangier G. Lewis T. Rowan MG. Potter BVL. Blagbrough IS. Tetrahedron Lett.  1998,  39:  893 

54 Callis DJ. Thomas NF. Pearson DPJ. Potter BVL. J. Org. Chem.  1996,  61:  4634 

55 Baillie LC. Bearder JR. Whiting DA. J. Chem. Soc., Chem. Commun.  1994,  2487 

56 Baillie LC. Batsanov A. Bearder JR. Whiting DA. J. Chem. Soc., Perkin Trans. 1  1998,  3471 

57 Baillie LC. Bearder JR. Sherringham JA. Whiting DA. J. Chem. Soc., Perkin Trans. 1  1997,  2687 

58 Baillie LC. Bearder JR. Li W.-S. Sherringham JA. Whiting DA. J. Chem. Soc., Perkin Trans. 1  1998,  4047 

59 Kraus GA. Dneprovskaia E. Tetrahedron Lett.  1998,  39:  2451 

60 Kumar P. Dinesh CU. Pandey B. Tetrahedron Lett.  1994,  35:  9229 

61 Barker D. Brimble MA. McLeod MD. Synthesis  2003,  656 

62 Barker D. Brimble MA. McLeod MD. Savage GP. Wong DJ. J. Chem. Soc., Perkin Trans. 1  2002,  924 

63 Barker D. McLeod MD. Brimble MA. Savage GP. Tetrahedron Lett.  2001,  42:  1785 

64 Barker D. Brimble MA. McLeod MD. Savage GP. Tetrahedron  2004,  60:  5953 

65 Barker D. McLeod MD. Brimble MA. Savage GP. Tetrahedron Lett.  2002,  43:  6019 

66 Barker D. Brimble MA. McLeod MD. Savage GP. Org. Biomol. Chem.  2004,  2:  1659 

67 Brocke C. Brimble MA. Lin DS.-H. McLeod MD. Synlett  2004,  2359 

68 Davies ARL. Hardick DJ. Blagbrough IS. Potter BVL. Wolstenholme AJ. Wonnacott S. Biochem. Soc. Trans.  1997,  25:  5455 

69 Kraus GA. Andersh B. Su Q. Shi J. Tetrahedron Lett.  1993,  34:  1741 

70 Kraus GA. Shi J. J. Org. Chem.  1991,  56:  4147 

71 Kraus GA. Shi J. J. Org. Chem.  1990,  55:  5423 

72 Kraus GA. Kesavan S. Tetrahedron Lett.  2005,  46:  1111