Inositols

From simple myo-Inositol to complex antibiotics

General
Myo-inositol is a crystalline compound with a sweet taste which was first isolated by Scherer in 1849. While the complete structure was disclosed by Dangschat and Posternakt in the late 1930s, the first total synthesis was already published in 1915 by Wieland and Wishart [1].

structures
Fig. 1. Different representations of myo-inositol.


Structure
As shown in Figure 2, nine different stereoisomers of inositol are possible. However, only six have been found in nature. The allo-, cis-, and epi-inositols are synthetically prepared compounds.

inositol_isomers
Fig. 2. Stereoisomers of inositol


Inositols in Plants and Mammals
Members of naturally occurring inositol derivatives include the mono- and dimethyl esters that are found in a wide variety of plants. Examples for this class of compounds are 4-O-methyl-D-myo-inositol, 1,3-di-O-methyl-D-myo-inositol, D-Pinitol and L-Quebrachitol (Figure 3). D-Pinitol can be isolated from sugar pines and L-Quebrachitol is obtained from rubber trees. They are both readily available in large quantities and serve as versatile starting materials in synthetic organic chemistry.

natural_inositols
Fig. 3. Examples of naturally occurring inositol derivatives


Inositol and its derivatives also play an important role in animal and human metabolism. The human body is able to produce free inositol and the regulation of its level is of therapeutic relevance. An example of important inositol derivatives in mammals are phosphatidylinositols (Figure 4). One of these often constitutes a component of lecithin and acts as a lipotropic agent in the body, helping to emulsify fats. Furthermore, phosphatidylinositols play a key role in signal transduction in cells.

biologically_active_inositols
Fig. 4. Examples of biologically active inositol derivatives

Phosphatidylinositols
Myo-inositol triphosphate (IP-3) is a very prominent example of a phosphatidylinositol. It was discovered in 1983 by Irvine, Berridge, and co-workers to act as a second messenger and to be of central importance in the control of many cellular processes by regulating internal calcium signals. IP-3 is formed in two steps from membranous bound phosphatidylinositol (Figure 5). First, the phosphatidylinositol is cleaved by phospholipase-C to form diacetylglycerol (DAG) and inositol phosphate. (Both act as lipophilic second messenger molecules.) Subsequent enzymatic phosphorylation leads to IP-3 which now activates the inositol triphosphate receptor IP3R to form channels for Ca2+ ions.

phosphatidylinositol_pathway
Fig. 5. Biochemical pathway of phosphatidylinositols

The discovery of this phenomenon initiated extensive studies on inositol phosphates as biochemical and biological agents [2] and a number of other phosphatidyl derivatives have gained considerable attention. Many studies on the role of these compounds in basic cellular processes are still ongoing [3]. Several hormones and cellular growth factors mediate their effects by stimulating the hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP-2, see Figure 4). Other components of PIP-2 also act as second messengers; exerting control over processes such as calcium release and protein phosphorylation.

A different example for the importance phosphatidylinsoitols is DAG which is formed from phosphatidylinositols (Figure 5) and which serves as primary starting material in prostaglandin biosynthesis.

Inositols in Medical Treatment
The phosphatidylinositol pathways, as depicted in Figure 5, are of major importance in the context of physiological processes and disease conditions including arthritis pain, inflammation platelet aggregation, and, possibly, oncogenesis. Therefore, the inhibition of key enzymes along these biochemical pathways is of significant clinical interest and an important field of in today's research [4].

Also, it was found that diabetic patients should generally take extra free inositol. Even though the body is able to produce its own inositol from glucose, inositol is administered in the context of certain medical treatments. Some therapeutic success with inositol in improving the nerve function in diabetic patients with pain and numbness due to nerve degeneration has been achieved.

On the other hand, excessive caffeine consumption can lead to inositol deficiency. Some problems that are considered to be associated with low levels of inositol in the body are eczema, constipation, eye problems, hair loss, and elevation of cholesterol.

Furthermore, free inositol is part of the vitamin B-group (namely, vitamin Bh). Another member of the vitamin B-group, niacin or vitamin B3, is not only vital to cellular metabolism but is also gaining attention in the treatment of various diseases including several cardiovascular conditions. Particularly hyperlipidemias, and peripheral vascular disorders like Raynaud's disease and intermittent claudication have become interesting candidates. However, although niacin has numerous therapeutic benefits, it may also lead to a considerable number of side effects. Therefore, safer and perhaps even more effective forms of administration are needed. The most successful of these forms is the hexanicotinic acid ester of meso-inositol, inositol hexaniacinate (IHN); also called inositol hexanicotinate or inositol nicotinate (Figure 6). The compound consists of six nicotinic acid moieties and one inositol. It is slowly metabolized into its components, nicacin and inositol in the body. This slow metabolism results in a sustained increase in the level of free nicotinic acid in the blood and plasma. Therefore, by administering inositol hexaniacinate the undesired side effects of niacin can be reduced while maintaining its beneficial impact during the treatment of various diseases [5].

inositol_hexaniacinate
Fig. 6. Metabolism of inositol hexaniacinate

Another area of medical treatment in which inositols play an important role is some antibiotics. Streptomycin and Kanamycin contain diamino and diaminodeoxy derivatives of scyllo-inositol (Figure 7).The discovery of these aminoglycoside antibiotics in the 1940s and 1950s, respectively, was the beginning of a new age of synthetic studies on complex carbohydrates [6].

2_Inositol_antibiotics
Fig. 7. Streptomycin and Kanamycin

In the 1970s, the chemical modification of inositols and inositol derivatives in order to develop more potent drugs was in full swing. Especially myo-inositols were extensively used for this purpose. Recently, novel antioxidant and anticancer functions of inositol hexaphosphate (IP-6, see Figure 4), a naturally occurring component of plant fiber, have been discovered [7]. Its action both in vitro as well as in vivo has been investigated extensively by a large number of research groups. IP-6 is considered to have a promising future as an anticancer agent and may have other beneficial properties. Animal studies revealed that large amounts of IP-6 provide substantial protection against colon cancer [8] and possibly also breast cancer [9]. Unfortunately, tests with patients could not demonstrate any association between higher dietary levels of IP-6 in the colon and reduced indicators of colon cancer risk so far [10]. However, studies with mice injected with IP-6 to treat cancerous tumors have shown to cause partial regression of these tumors [11].



References

1. Ogawa, S. Anticancer Research 1999, 19, 3635.
2. Divecha, N.; Irvine, R.F. Cell 1995, 80, 269.
3. (a) Michell, M. Biochem. Biophys. Acta 1975, 415, 81. (b) Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315. (c) Beasdale, J. E.; Eichberg, J.; Hanser, G.; Eds., Inositols Phosphoinosities. Humana Press, Clifton, N.J. (1985).
4. Rahman, A. U.; Dahot, M. U. Sci. Int. (Lahore) 2004, 16, 95.
5. Head, K. A. Altern. Med. Rev. 1996, 1, 176.
6. Umezawa S. Adv. Carbohydr. Chem. Biochem. 1974, 30, 111.
7. Shamsuddin, M.; Vucenik, I.; Cole, K. E. Life Sci. 1997, 61, 343.
8. Graf, E.; Eaton, J. W. Nutr. Cancer 1993, 19, 11.
9. (a) Vucenik, I.; Sakamoto, K.; Bansel, M. Cancer Lett. 1993, 75, 95. (b) Vucenik, I.; Yang, G.; Shamsuddin, A. M. Nutr. Cancer 1997,28, 7.
10. Owen, R. W.; Weisgerber, U. M.; Spiegelhalder, B. Gut 1996, 38, 591.
11. Vucenik, I.; Zhang, Z. S.; Shamsuddin, A. M. Anticancer Res. 1988, 18, 4091.


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