Squalene chemical structure

Figure 6.1 Chemical structures of plant metabolites synthesized from squalene-2,3-epoxide.

In 1996, Norte and co-workers elucidated the structures of two new antitumor polyoxygenated squalene derivatives that were isolated from the acetone extracts of Laurencia viridis [9]. Isodehydrothyrsiferol [12, Fig. (3)] possesses an appended tetrahydropyran unit instead of the common tetrahydrofuran moiety observed in previous chemical structures. 

Barnard et al.20 presented a somewhat different picture of the involvement of sulfur compounds in oxidation inhibition involving olefinic hydrocarbons. They studied the oxidation of squalene (an olefin) in the presence of sulfur compounds and concluded by careful measurement of oxygen uptake that it was not the sulfide that inhibited oxidation but the initially formed sulfoxide, and that inhibition was very dependent on the chemical structure of the sulfide. However, they did not suggest any specific mechanism for the inhibition. 

Figure 2.7 Chemical structure of squalene [6E,10E,14E,18E)-2,6,10,15,19,23-Hexamethyl-2,6,10,14,18,22-tetracosahexaene], (Picture taken from Pherobase.)...

It turns out that they are chemically related to each other, as you can imagine from the chemical structures shown in Fig. 12.1. They are called terpenes and terpenoids. They can be regarded as derivatives from a five-carbon compound called isoprene (2-methyl butadiene). Two isoprene molecules combine to form mono-terpene (ten-carbon compound). The fragrant oils mentioned above are all the derivatives of mono-terpene. Terpenes are derived from a common metabolic intermediate of glucose, acetyl-CoA (coenzyme A). By the way, a tri-terpene (which three terpene molecules combine to form) called squalene leads to the formation of steroids, and if you connect a large number of isoprene in a linear fashion, you will get natural rubber (Chap. 5). 

A general type of chemical reaction between two compounds, A and B, such that there is a net reduction in bond multiplicity (e.g., addition of a compound across a carbon-carbon double bond such that the product has lost this 77-bond). An example is the hydration of a double bond, such as that observed in the conversion of fumarate to malate by fumarase. Addition reactions can also occur with strained ring structures that, in some respects, resemble double bonds (e.g., cyclopropyl derivatives or certain epoxides). A special case of a hydro-alkenyl addition is the conversion of 2,3-oxidosqualene to dammara-dienol or in the conversion of squalene to lanosterol. Reactions in which new moieties are linked to adjacent atoms (as is the case in the hydration of fumarate) are often referred to as 1,2-addition reactions. If the atoms that contain newly linked moieties are not adjacent (as is often the case with conjugated reactants), then the reaction is often referred to as a l,n-addition reaction in which n is the numbered atom distant from 1 (e.g., 1,4-addition reaction). In general, addition reactions can take place via electrophilic addition, nucleophilic addition, free-radical addition, or via simultaneous or pericycUc addition. 

The isoprenoids contribute most to the list of structural similarities in the sea and on land. They range from common classes in both ecosystems, such as drimane sesquiterpenes, to rare classes in the sea, such as the trichothecenes (Chart 8.3.11). The similarity in marine and terrestrial polyether triterpenes (Chart 8.3.12) may be seen as convergence toward chemically favored structures, starting from squalene as a biosynthetic precursor. Similar conclusions may apply to polycyclic triterpenes. 

Steroids are important lipids whose structures are based on a tetracyclic system. Most steroids function as hormone chemical messengers, and thus these molecules have been discussed in detail in chapter 5. Structurally, steroids are heavily modified triterpenes that are biosynthesized starting from the acyclic hydrocarbon squalene and progressing through cholesterol to the final steroid product Bloch and Cornforth, who were awarded Nobel Prizes in medicine (1964), contributed greatly to the elucidation of this remarkable biosynthetic transformation. 

Squalene is also an intermediate in the synthesis of cholesterol. Structurally, chemically, and biogenetically, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that trans-squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instability however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of lipid-soluble drugs. 

Other studies have shown biological actions from these kinds of structure and indicate interrelationships between the chemicals in terms of their potencies. Tomita [229] found that the substances, vitamin A, vitamin K, vitamin E, /1-carotene, ubiquinone (15), phytol and squalene (16), from green-yellow vegetables could suppress the growth of tumour cells and enhance T-cell cytotoxicity, but /1-carotene, which does have both ends of the chain substituted with a bulky / -ionone ring on each end-group did not. Hydrophobic chain... 

Yuzurimine C, a minor squalene-derived alkaloid from Daphniphyllum mac-ropodum,n has been assigned the structure (5). A search for further compounds to support the postulated biogenetic pathway from squalene to the Daphniphyllum alkaloids has resulted in the isolation of daphniteijsmanine (6) from D. teijsmanii.12 It is structurally very similar to secodaphniphylline. Treatment of the mesylate (8) of the sodium borohydride reduction product of N-acetylsecodaphniphylline (7) with acetic acid afforded N-acetyldaphniteijsmanine acetate (see Chapter 6, p. 214). Further chemical interrelations in this series have been described.13... 

In related work, a series of important studies have been devoted to enzymatic cyclization of unnatural lanosterol precursors. Thus both epoxides (23) and (29), despite being notably different in structure from squalene oxide (32), were transformed enzymatically into the pentanorlanosterol (33a) and dihydrolano-sterol (33b), respectively. These results lend support to the suggestion that the methyl-hydrogen migration sequence rests solidly on physico-chemical... 

The mechanism whereby farnesyl pyrophosphate (6 = 2) is converted into squalene (7) has aroused much chemical and biochemical interest. An intermediate isolated from yeast is the C30 pyrophosphate (9). Rilling et suggested the cyclopropanoid structure (9a) while the cyclic pyrophosphate diester (9b) was suggested by Popjak et The universal involvement of this intermediate is supported by the incorporation of radioactivity from the diester (9), prepared from yeast, into squalene (7) by a rat liver system. However, the suggested mechanism for the formation of the diester is difficult to reconcile with the observation that nerolidyl pyrophosphate is not incorporated. 

Robert Robinson postulated that cholesterol is derived from the triterpene squalene (see the structure above). The correct structure of cholesterol (see chapter 2) was finally proven in 1932 by independent chemical studies by Wieland and Windaus and crystallographic studies by John Desmond ( J. D. ) Bernal (1901-70), Dorothy Crowfoot (1910-94 after 1937 Dorothy Crowfoot Hodgkin) and Otto Rosenheim (1871-1955). 

Rilling discovered that, in the absence of NADPH, a C30 pyrophosphate-containing intermediate (presqualene pyrophosphate) may be isolated (372). Once the structure and stereochemistry of the derived alcohol were established as 113b-OH through both chemical degradation (J70, 171, 273) and total synthesis (374—376), the biogenesis of squalene, at least in general terms, became clear (170, 373, 376—378) (Scheme 27). As we have seen (Section B.l and C.4), the structure of presqualene... 

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