Searching for bioactive Lycopodium alkaloids derivatives

M.G. VALLEJO; M.G. ORTEGA; D.A. CIFUENTE; C. ARDANAZ; J.L. CABRERA; C.E. TONN; A.M. AGNESE

Ribeirao Preto, Brasil

Simposio; 4th International Symposium of Research and Posgraduation; 2010

Universidad de Sao Paulo

In previous works we has been studied the effects related to learning and memory produced by the alkaloids, sauroine and sauroxine, isolated from Huperzia saururus (Lam.) Trevis. Additionally, we had demonstrated that sauroine strongly enhances hippocampal Long Term Potentiation (LTP) and memory retention, but it has not effect on acethylcholinesterase enzyme. On the other hand sauroxine is an acetylcholinesterase inhibitor and has not effect on LTP. These results suggest that sauroine and sauroxine could act through different mechanisms. This fact could be explained due to the alkaloid structural types are different. In this sense, it would be interesting to explore about the basic chemical requirements to produce these biological effects. To reach this objective it is necessary to obtain new derivatives to develop the biological assays. With this aim, in the present work we assayed several chemical transformations on sauroine in order to elucidate later the pharmacophore structure. The new derivatives were obtained from acetylation, sililation, reduction, oxidation, acetonide-formation, imine, oxime, and phenylimine- formation of sauroine. Only acetylation (a), sililation (b) and reduction (c) lead effectively to products from this set of reactions. In order to obtain each derivative the following conditions were performed: acetic anhydride and pyridine for a; methyl chlorosilane and imidazol in pyridine for b; and NaBH4 in EtOH with an aliquot of 10 % NaOH, for c. The new sauroine derivatives were purified by preparative TLC. Unexpectedly, we obtained two products in a, A2 and A3, since both positions (C7 and C8) were acetylated in sauroine. It would be explained due to the C7-OH sterochemistry. One sauroine derivative was obtained when sililation and reduction reactions were conducted, S4 and R2, respectively. The purified products were identified by GLC-MS and 1H-RMN (selected signals): A2: m/z 206, m/z 321 (M+); ä (ppm);  0.90 (d), 2.09 (s), 4.64 (d); A3: m/z 206, m/z 248, m/z 321 (M+);  ä (ppm): 0.93 (d), 2.13 (s), 4.58 (d), S4: m/z 206, m/z 336, m/z 351 (M+); decomp; R2: m/z 207, m/z 281(M+);  ä (ppm): 1.00 (d), 2.41 (m), 2.57 (d), 2.94 (m). In conclusion new sauroine derivatives performed by chemical transformations, were achieved. After biological assays structure-activity relationship will be analyzed.