Crystal structure and biological properties of (±)-3,6-di-o-(2-propylpentanoyl)-1,2:4,5-di-o-isopropylidene-myo-inositol

G. E. ECHEVERRÍA; G. PUNTE; J. A. ELLENA; S. C. MOON; L. E. BRUNO-BLANCH

Arica, Primera Región, Chile

Congreso; X Seminario Latinoamericano de Análisis por Técnicas de Rayos X; 2006

Selectively protected myo-inositol chemistry has achieved intense interest since the recognition of the many biological implications of inositol. After the discovery, in 1983, that inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) is a Ca2+-mobilizing second messenger,[1] a great effort was dedicated during the eighties to the synthesis of inositol phosphates, some of them have shown to be components of cells. It followed, during the 1990s an interest on the lipid phase and this century has witnessed a renewed interest in the phosphates derivatives.[2] Diketals of myo-inositol are very important intermediates to prepare the different inositol phosphate derivatives.[3] One of diketals more utilized is the regioisomer (±)-1,2:4,5-di-O-isopropylidene-myo-inositol (1) and in our experience the best preparation technique of 1 was that described by Gigg,[4] but this reaction proceeds to give a mixture of the diketals which cannot easily be separated. However, the functionalization of this mixture by O-acylation permits to obtain a pure crystalline (±)-1,2:4,5-diketal derivative by a simple crystallization from the reaction medium. With the main purpose to get VPA derivatives with more efficient therapeutic action, taking into account their anticonvulsant activity as well as their effectiveness in the localization of the SNC, the synthesis of the title compound has been performed, by a procedure previously reported by us,[5] from 1 and 2-propylpentanoyl anhydride. The compound (±)-3,6-Di-O-(2-propylpentanoyl)-1,2:4,5-di-O-isopropylidene-myo-inositol (2) was the major reaction product which could be relatively easily isolated from the other derivatives. It proves to have anticonvulsant action, but its profile differs from that of VPA. Therefore, to get insight into the factors influencing the title compound biological activity its crystal structure has been characterized by single crystal X-ray diffraction. The results show that the myo-inositol ring adopts a distorted chair conformation, the valproate groups are equatorially bonded to opposite position of the myo-inositol ring through the hydroxylic oxygen. The O-C=O carboxylic plane locates approximately perpendicular to the mean myo-inositol and 2-propylpentanoyl plane with the carbonyl group pointing outwards in opposite directions. Due to this molecular conformation, the carbonyl and hydroxyl oxygens are not sterically hindered by any molecular fragment. Thus, they are available to establish hydrogen bonds with any proton donor group of surrounding molecules and the pendant 2-propylpentanoyl groups adopt an almost plane conformation with one end somewhat displaced from the mentioned  plane, causing that chains length reach almost its maximum possible value. According to MES and PZT test results it can be concluded that the mechanism of action of 2 differs from that of VPA. The influence of molecular conformation on this finding is discussed. [1] Streb, H., Irvine, R. F., Berridge, M. J. & Schulz, I. Nature, 1983, 306, 67–69. [2] Robin F. Irvine and Michael J. Schell. Nature Reviews Molecular Cell Biology, 2001, 2, 327-338 [3] Chung, S-K.; Chang, Y-T.; Sohn, K-H. Chem. Commun., 1996, 163-164 [4] Gigg, J.; Gigg, R.; Payne, S.; Conant, R. Carbohydr. Res. 1985, 142, 132-134. [5] Bodor, N.; Moon, S. C.& Bruno-Blanch, L. Pharmazie. 2000, 55, 184-186.