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Free EDTA Cooper- EDTA Figure 5: Desolvation/solvation barriers of protein folding/unfolding Figure 6: Crenulatin coordinated to Ca 2+ Figure 7: Equilibrated structures of PrP and bounded with Cu (II) Figure 9: Pullulan coordinated to Cu (II) Figure 8: Vitamin B12 structure with Co(III) SOME THOUGHTS: Considering that the activity of a drug is related to its conformation, able to activate the interaction with the receptor site. Consequently the activity of a drug contained in an extract must be related to its spatial conformation, originating by the above described interaction, which can lead to an effective interaction with the receptor site. This aspect could give a different view of the mechanism of action of active molecules present in natural products. Then in the case of synthetic product the spatial structure at the lowest internal energy is expected to be different to that of the same molecule present in the natural substrate. If the above hypothesis is correct in principle it would not exhibit any activity but, considering the phenomenon at molecular dynamics level, there is a non-zero probability that it assumes the right conformation for the interaction with the receptor site. This aspect could explain the maintenance of the biological activity and give account for its lowering with respect to that of the natural product. ON THE POSSIBLE STRUCTURAL DIFFERENCIES BETWEEN MOLECULES PRESENT IN NATURAL EXTRACTS AND SYNTHETIC ONES Luisa Mattoli 1 , Anna Maidecchi 1 , Valentino Mercati 1 , Ilena Isak 2 , Pietro Traldi 2 1 Research Area, Aboca S.p.A. Società Agricola, Loc. Aboca, Sansepolcro (AR), Italy - 2 CNR-ISTM, C.so Stati Uniti 4, Padova, Italy. INTRODUCTION Some discrepancies are sometimes observed in a different biological activity of the same molecule present in natural substrates and those extracted from phytocomplex or produced by synthesis. In the last two cases a lower activity is sometimes observed, as described for quercitin and hypericin in Hypericum perforatum, artemisin in Artemisia annua, Vitamin C and Flavonols in Citrus x limon. This behaviour has been usually ascribed to synergic effects with other molecular species present in the natural product, but a further hypotesis can be taken into account, i.e. that the different activity could originate from a different structure, at conformational level, of the active compound when present in the biological substrate, due to interactions with other molecular species and/or with oligoelements. If we consider a natural extract, it will be constituted of hundreds different organic and inorganic molecules, oligoelements and “ differently structured tissue ” of different chemical composition and physicochemical properties. Consequently a wide number of intermolecular interactions must be present and, among those above cited, the ion-dipole, dipole-dipole and dipole-induced dipole are reasonably the most relevant ones. A molecule interacting with another one or with an ion will have no more the same vibro-rotational freedom degrees originally present: the complexation will lead to a “frozen” structure, reasonably not the same of the original molecule in its fundamental state. This is particularly emphasized in the interaction molecule-inorganic ions. As a classical example the structure of EDTA and of its complex with Cu(II) are reported in Figure 2. In a recent study, quercitin was found to be effective in loading iron and permeating cell membranes, emphasizing its ability to shuttle labile iron from cell compartments followed by its transfer to transferrin 9 . 5. P. Mladĕnka et al. “In vitro analysis or iron chelating activity of flavonoids”, Journal of Inorganic Biochemistry, 2001, 105,693. 6. E. Hernandez et al. “ The metal cation chelating capacity of astaxanthin. Does this have any onfluence on antiradical activity? “, Molecules, 2012, 17, 1039. 7. G.S.Nikolić and M.D. Cakić “Analysis of bioactive olygosaccharide-metal complexes by modern FTIR spectroscopy: copper complexes.” 2009, Fourier Transforms - New Analytical Approaches and FTIR strategies, 15-44. 8. D. Malešev and V. Kuntić “Investigation of metal-flavonoid chelates and the determination of flavonoids via metal-flavonoid complexing reactions.”, J. Serb Chem Soc., 2007, 72, 921. 9. M.M. Baccan er alt., “Quercitin as a shuttle for labile iron2, Journal of Inorganic Biochemistry, 2012, 107, 34-39. Intermolecular interactions occur between all types of molecules or ions in all states of matter. They range from the strong, long-distance electrical attractions and repulsions between ions to the relatively weak dispersion forces which have not yet been completely explained. The various types of interactions are classified as (in order of decreasing strenght of the interactions): Without these interactions, the condensed forms of matter (liquids and solids) would not exist except at extremely low temperatures. Just to give an idea of the strenght of the intermolecular forces, the dissociation energy of a dipole-dipole couples is in the range 0.5-2 kcal, while that of hydrogen bonds grow up to 12-16 kcal. Comparing these values with the dissociation energy of a covalent bond (in the order of magnitude of 400 kcal) these interactions appear to be relevant. THEN: SYNERGISM OF INTERMOLECULAR INTERACTIONS? ion-dipole ion-induced dipole dipole-induced dipole hydrogen bonding dispersion forces REFERENCES: 1. JM Gazave et al. “Direct and indirect action mechanism of the C2 factor on the blood capillaries”, Bibliotheca Anatomica, 1975, 13, 82. 2. D. Atmani et al. “Flavonoids in human health:from structure to biological activity “,Current Nutrition& Food Science, 2009, 5, 225. 3. C.G. Fraga and P.I. Oteiza “Dietary flavonoids: role of (-)-epicatechin and related procyanidins in cell signalling”, Free Radical Biology&medicine, 2011,51,813. 4. R. Brouillard et al.” The visible flavonoids or anthocyanins: from research to applications”, Recent advances in pholyphenols, 2010, vol 2, Santos-Buelga. EXAMPLES OF ION-DIPOLE INTERACTION IN NATURAL PRODUCTS (Figure from 2 to 8): Complex formation with different ions 2-8 EXAMPLES OF DIPOLE-DIPOLE Interactions in natural products: Solvatation barrier (Figure 9) Vitamin C complex (C 1 + C 2 ) 1 Figure 1: Astaxanthin coordinated to Ca 2+ Figure 2: Free EDTA structure and coordinated to Cu(II) Figure 3: Clorophyll structure with Mg 2+ Figure 4: Pectin coordinated to Ca 2+ and Mg 2+ In conclusion we can propose the new concept of “SYNERGISM OF INTERMOLECULAR INTERACTIONS“among the molecules contained in an extract expression of a natural phytocomplex that can justify the behavior of all natural extract including herbal medicinal products.
