Saturated Fatty Acids
The processes of fatty acid biosynthesis are well studied and are known to be catalysed by the enzyme fatty acid synthase. In animals, this is a multifunctional protein containing all of the catalytic activities required, whilst bacteria and plants utilize an assembly of separable enzymes. Acetyl-CoA and malonyl-CoA themselves are not involved in the condensation step they are converted into enzyme-bound thioesters, the malonyl ester by means of an acyl carrier protein ACP Figure 3.2 . The...
Decarboxylation Reactions
Many pathways to natural products involve steps which remove portions of the carbon skeleton. Although two or more carbon atoms may be cleaved off via the reverse aldol or reverse Claisen reactions mentioned above, by far the most common degradative modification is loss of one carbon atom by a decarboxylation reaction. Decarboxy-lation is a particular feature of the biosynthetic utilization of amino acids, and it has already been indicated that several of the basic building blocks, e.g. C6C2N,...
Coumarins
The hydroxylation of cinnamic acids ortho to the side-chain as seen in the biosynthesis of salicylic acid is a crucial step in the formation of a group of cinnamic acid lactone derivatives, the coumarins. Whilst the direct hydroxylation of the aromatic ring of the cinnamic acids is common, hydrox-ylation generally involves initially the 4-position para to the side-chain, and subsequent hydrox-ylations then proceed ortho to this substituent see page 132 . In contrast, for the coumarins,...
The Shikimate Pathway Aromatic Amino Acids And Phenylpropanoids
Shikimic acid and its role in the formation of aromatic amino acids, benzoic acids, and cinnamic acids is described, along with further modifications leading to lignans and lignin, phenylpropenes, and coumarins. Combinations of the shikimate pathway and the acetate pathway are responsible for the biosynthesis of styrylpyrones, flavonoids and stilbenes, flavonolignans, and isoflavonoids. Terpenoid quinones are formed by a combination of the shikimate pathway with the terpenoid pathway. Monograph...
Macrolide Antibiotics
The macrolide antibiotics are macrocyclic lactones with a ring size typically 12-16 atoms, and with extensive branching through methyl substituents. Two or more sugar units are attached through glycoside linkages, and these sugars tend to be unusual 6-deoxy structures often restricted to this class of compounds. Examples include L-cladinose, L-mycarose, D-mycinose, and L-oleandrose. At least one sugar is an amino sugar, e.g. D-desosamine, D-forosamine, and D-mycaminose. These antibiotics have a...
Kava
Aqueous extracts from the root and rhizome of Piper methysticum Piperaceae have long been consumed as an intoxicating beverage by the peoples of Pacific islands comprising Polynesia, Melanesia and Micronesia, and the name kava or kava-kava referred to this drink. In herbal medicine, the dried root and rhizome is now described as kava, and it is used for the treatment of anxiety, nervous tension, agitation and insomnia. The pharmacological activity is associated with a group of styrylpyrone...
Alkaloids Derived From Ornithine
L-Ornithine Figure 6.1 is a non-protein amino acid forming part of the urea cycle in animals, where it is produced from L-arginine in a reaction catalysed by the enzyme arginase. In plants it is formed mainly from L-glutamate Figure 6.2 . Ornithine contains both S- and a-amino groups, and it is the nitrogen from the former group which is incorporated into alkaloid structures along with the carbon chain, except for the carboxyl group. Thus ornithine supplies a C4N building block to the alkaloid,...
CAlkylation Reactions
A common feature of many natural products containing phenolic rings is the introduction of alkyl groups at nucleophilic sites. Obviously, the phenol groups themselves are nucleophilic, and with a suitable alkylating agent, O-alkyl derivatives may be formed see page 12 , e.g. the O -methylation of emodin to physcion Figure 3.30 . However, a phenol group also activates the ring carbons at the ortho and para positions, so that these positions similarly become susceptible to alkylation, leading to...
Artemisia annua and Artemisinin
Artemisia annua Compositae Asteraceae is known as qinghao in Chinese traditional medicine, where it has been used for centuries in the treatment of fevers and malaria. The plant is sometimes called annual or sweet wormwood, and is quite widespread, being found in Europe, North and South America, as well as China. Artemisinin qinghaosu Figure 5.34 was subsequently extracted and shown to be responsible for the antimalarial properties, being an effective blood schizontocide in humans infected with...
Primary And Secondary Metabolism
All organisms need to transform and interconvert a vast number of organic compounds to enable them to live, grow, and reproduce. They need to provide themselves with energy in the form of ATP, and a supply of building blocks to construct their own tissues. An integrated network of enzymemediated and carefully regulated chemical reactions is used for this purpose, collectively referred to as intermediary metabolism, and the pathways involved are termed metabolic pathways. Some of the crucially...
Trichothecenes
The trichothecenes are a group of sesquiterpene toxins produced by several fungi of the genera Fusarium, Myrothecium, Trichothecium, and Trichoderma, which are parasitic on cereals such as maize, wheat, rye, barley, and rice. About 150 different structures have been identified, with some of these being isolated from plants of the genus Baccharis Compositae Asteraceae , where a symbiotic plant-fungus relationship may account for their production. Examples of trichothecene structures commonly...
Taxus brevifolia and Taxol Paclitaxel
A note on nomenclature the name taxol was given to a diterpene ester with anticancer properties when it was first isolated in 1971 from Taxus brevifolia. When the compound was subsequently exploited commercially as a drug, Taxol was registered as a trademark. Accordingly, the generic name paclitaxel has been assigned to the compound. The literature now contains an unhappy mixture of the two names, though the original name taxol is most often employed. The anticancer drug taxol Figure 5.43 is...
Folic Acid Vitamin B9
Folic acid vitamin B9 Figure 4.6 is a conjugate of a pteridine unit, p-aminobenzoic acid, and glutamic acid. It is found in yeast, liver, and green vegetables, though cooking may destroy up to 90 of the vitamin. Deficiency gives rise to anaemia, and supplementation is often necessary during pregnancy. Otherwise, deficiency is not normally encountered unless there is malabsorption, or chronic disease. Folic acid used for supplementation is usually synthetic, and it becomes sequentially reduced...
Statins
Cervoni P, Crandall DL and Chan PS 1993 Cardiovascular agents - atherosclerosis and antiathero-sclerosis agents. Kirk - Othmer Encyclopedia of Chemical Technology, 4th edn, Vol 5. Wiley, New York, 257 - 261. Endo A and Hasumi K 1993 HMG-CoA reductase inhibitors. Nat Prod Rep 10, 541 -550. Gopinath L 1996 Cholesterol drug dilemma. Chem Brit 32 11 , 38 -41. Laschat S 1996 Pericyclic reactions in biological systems - does nature know about the Diels-Alder reaction Angew Chem Int Ed Engl 35, 289...
Bile Acids
The bile acids are C24 steroidal acids that occur in salt form in bile, secreted into the gut to emulsify fats and encourage digestion. They act as detergents by virtue of their relatively non-polar steroid nucleus and the polar side-chain, which contains a carboxylic acid group, that is typically bound via an amide linkage to glycine or taurine. Thus, for example, cholic acid Figure 5.108 is found as sodium glycocholate and sodium tauro-cholate. Metabolism to bile acids is also the principal...
Androgens
The primary male sex hormone, or androgen, is testosterone Figure 5.139 . This is secreted by the testes and is responsible for development and maintenance of the male sex characteristics. Androgens also have a secondary physiological effect, an anabolic activity which stimulates growth of bone and muscle, and promotes storage of protein. The biosynthetic pathway to testosterone is outlined in Figure 5.133, where it can feature as an intermediate in the pathway to oestrogens. Low levels of...
Aromatic Amino Acids And Simple Benzoic Acids
The shikimate pathway begins with a coupling of phosphoenolpyruvate PEP and D-erythrose 4-phosphate to give the seven-carbon 3-deoxy-D-arabino-heptulosonic acid 7-phosphate DAHP Figure 4.1 . This reaction, shown here as an aldol-type condensation, is known to be mechanistically more complex in the enzyme-catalysed version several of the other transformations in the pathway have also been found to be surprisingly formally an elimination it actually involves oxidation of the hydroxyl adjacent to...
Chloramphenicol
Chloramphenicol chloromycetin Figure 4.14 was initially isolated from cultures of Streptomyces venezuelae, but is now obtained for drug use by chemical synthesis. It was one of the first broad spectrum antibiotics to be developed, and exerts its antibacterial action by inhibiting protein biosynthesis. It binds reversibly to the 50S subunit of the bacterial ribosome, and in so doing disrupts peptidyl transferase, the enzyme that catalyses peptide bond formation see page 408 . This reversible...
Phenolic Oxidative Coupling
Many natural products are produced by the coupling of two or more phenolic systems, in a process readily rationalized by means of free radical reactions. The reactions can be brought nucleophilic attack of peracid on to carbonyl carbonyl reforms alkyl group migrates from carbon to adjacent oxygen ortho-ortho coupling ortho-para coupling para-para coupling ortho-ortho coupling ortho-para coupling para-para coupling about by oxidase enzymes, including peroxidase and laccase systems, known to be...
Styrylpyrones
Cinnamic acids, as their coenzyme A esters, may also function as starter units for chain extension with malonyl-CoA units, thus combining elements of the shikimate and acetate pathways see page 80 . Most commonly, three C2 units are added via malonate giving rise to flavonoids and stilbenes, as described in the next section page 149 . However, there are several examples of products formed from a cinnamoyl-CoA starter plus one or two C2 units from malonyl-CoA. The short poly- -keto chain...
Taxol
Amos LA and Lowe J 1999 How Taxol stabilizes microtubule structure. Chem Biol 6, R65-R69. Appendino G 1995 The phytochemistry of the yew tree. Nat Prod Rep 12, 349 - 360. Appendino G 1996 Taxine. Alkaloids, Chemical and Biological Perspectives ed Pelletier SW Vol 11. Elsevier, Amsterdam, pp 237-268. Baloglu E and Kingston DGI 1999 The taxane diterpenoids. J Nat Prod 62, 1448-1472. Guenard D, Gueritte-Voegelein F and Potier P 1993 Taxol and taxotere discovery, chemistry, and structure-activity...
Lignans And Lignin
The cinnamic acids also feature in the pathways to other metabolites based on C6C3 building blocks. Pre-eminent amongst these, certainly as far as nature is concerned, is the plant polymer lignin, a strengthening material for the plant cell wall which acts as a matrix for cellulose microfibrils see page 473 . Lignin represents a vast reservoir of aromatic materials, mainly untapped because of the difficulties associated with release of these metabolites. The action of wood-rotting fungi offers...
Isoflavonoids
The isoflavonoids form a quite distinct subclass of flavonoid compound, being structural variants in which the shikimate-derived aromatic ring has migrated to the adjacent carbon of the heterocycle. This rearrangement process is brought about by a cytochrome P-450-dependent enzyme requiring NADPH and O2 cofactors, which transforms the flavanones liquiritigenin or naringenin into the isoflavones daidzein or genistein respectively via intermediate hydrox-yisoflavanones Figure 4.47 . A radical...
Carotenoids
Bartley GE and Scolnik PA 1995 Plant carotenoids pigments for photoprotection, visual attraction, and human health. Plant Cell 7, 1027-1038. Bramley PM 2000 Molecules of interest is lycopene beneficial to human health Phytochemistry 54, 233 - 236. Gordon MH 1996 Dietary antioxidants in disease prevention. Nat Prod Rep 13, 265-273. Krinsky NI 1994 The biological properties of carotenoids. Pure Appl Chem 66, 1003-1010. Sandmann G 1994 Carotenoid biosynthesis in microorganisms and plants. Eur J...
Gossypol
Gossypol occurs in the seeds of cotton Gossypium species, e.g. G. hirsutum, G. herbaceum, G. arboreum, G. barbadense Malvaceae in amounts of 0.1-0.6 . Its contraceptive effects were discovered when subnormal fertility in some Chinese rural communities was traced back to the presence of gossypol in dietary cottonseed oil. Gossypol acts as a male contraceptive, altering sperm maturation, spermatozoid motility, and inactivation of sperm enzymes necessary for fertilization. Extensive clinical...
Prostaglandins 1
Prostaglandins occur in nearly all mammalian tissues, but only at very low concentrations. PGEt and PGFia were initially isolated from sheep seminal plasma, but these compounds and PGD2, PGE2, and PGF2a are widely distributed. Animal sources cannot supply sufficient amounts for drug usage. The soft coral Plexaura homomalla sea whip from the Caribbean has been identified as having very high 2-3 levels of prostaglandin esters, predominantly the C-15 epimerof PGA2 1 -2 with related structures....
Tannins
Ferreira D, Brandt EV, Coetzee J and Malan E 1999 Condensed tannins. Prog Chem Org Nat Prod 77, 21 -67. Ferreira D and Li X-C 2000 Oligomeric proantho-cyanidins naturally occurring O -heterocycles. Nat Prod Rep 17, 193 -212. Earlier review Ferreira D and Bekker R 1996 13, 411 -433. Ferreira D, Nel RJJ and Bekker R 1999 Condensed tannins. Comprehensive Natural Products Chemistry, Vol 3. Elsevier, Amsterdam, pp 747-797. Gross GG 1999 Biosynthesis of hydrolyzable tannins. Comprehensive Natural...
Flavonoids
Das A, Wang JH and Lien EJ 1994 Carcinogenicity, mutagenicity and cancer preventing activities of flavonoids a structure - system - activity relationship SSAR analysis. Prog Drug Res 42, 133-166. Forkmann G and Heller W 1999 Biosynthesis of flavonoids. Comprehensive Natural Products Chemistry , Vol 1. Elsevier, Amsterdam, pp 713-748. Gordon MH 1996 Dietary antioxidants in disease prevention. Nat Prod Rep 13, 265-273. Harborne JB and Williams CA 1998 Anthocyanins and other flavonoids. Nat Prod...
Terpenoid Quinones
Quinones are potentially derivable by oxidation of suitable phenolic compounds, cat-echols 1,2-dihydroxybenzenes giving rise to ortho-quinones and quinols 1,4-dihydroxyben-zenes yielding para-quinones see page 25 . Accordingly, quinones can be formed from phenolic systems generated by either the acetate or shikimate pathways, provided a catechol or quinol phylloquinone vitamin Kf, phytomenadione R1 R2 Me, a-tocopherol R1 H, R2 Me, P-tocopherol R1 Me, R2 H, Y-tocopherol R1 R2 H, 5 -tocopherol...
Griseofulvin
Griseofulvin is an antifungal agent produced by cultures of Penicillium griseofulvum and a number of other Penicillium species, including P. janczewski, P. nigrum, and P. patulum. Griseofulvin is the drug of choice for widespread or intractable dermatophyte infections, but is ineffective when applied topically. However, it is well absorbed from the gut and selectively concentrated into keratin, so may be used orally to control dermatophytes such as Epidermophyton, Microsporium, and...
Hemiterpenes C5
IPP and DMAPP are reactive hemiterpene intermediates in the pathways leading to more complex terpenoid structures. They are also used as alky-lating agents in the formation of meroterpenoids as indicated above, but examples of these structures are discussed under the section appropriate to the major substructure, e.g. alkaloids, shiki-mate, acetate. Relatively few true hemiterpenes are produced in nature, with isoprene, a volatile compound which is released by many species of plants, especially...
Diterpenes C20
The diterpenes arise from geranylgeranyl diphos-phate GGPP , which is formed by addition of a further IPP molecule to farnesyl diphosphate in the same manner as described for the lower terpenoids Figure 5.41 . One of the simplest and most important of the diterpenes is phytol Figure 5.42 , a reduced form of geranylgeran-iol, which forms the lipophilic side-chain of the chlorophylls, e.g. chlorophyll a Figure 5.42 . Related haem molecules, porphyrin components electrophilic addition gives...
Mycophenolic Acid
Mycophenolic acid Figure 3.36 is produced by fermentation cultures of the fungus P nicillium brevicompactum. It has been known for many years to have antibacterial, antifungal, antiviral, and antitumour properties. It has recently been introduced into medicine as an immunosuppressant drug, to reduce the incidence of rejection of transplanted organs, particularly kidney and heart transplants. It is formulated as the N-morpholinoethyl ester mycophenolate mofetil Figure 3.37 , which is metabolized...
Adrenocortical HormonesCorticosteroids
A large number of steroid hormones have been isolated and characterized from the adrenal glands. Since they are produced by the adrenal cortex, the outer part of the adrenal glands near the kidneys, they are termed adrenocortical hormones or corticosteroids . They contain a pregnane C21 skeleton and fall into two main activity groups, the glucocorticoids and the mineralocorticoids, although it is difficult to separate entirely the two types of activity in one molecule. Glucocor-ticoids are...
Tacrolimus and Sirolimus
Tacrolimus FK-506 Figure 3.69 is a macrolide immunosuppressant isolated from cultures of Streptomyces tsukubaensis. It is used in liver and kidney transplant surgery. Despite the significant structural differences between tacrolimus and the cyclic peptide cyclosporin A ciclosporin see page 429 , these two agents have a similar mode of action. They both inhibit T-cell activation in the immunosuppressive mechanism by binding first to a receptor protein giving a complex, which then inhibits a...
Senna
Senna leaf and fruit are obtained from Cassia angustifolia Leguminosae Fabaceae , known as Tinnevelly senna, or less commonly from Cassia senna syn C. acutifolia , which is described as Alexandrian senna. The plants are low, branching shrubs, C. angustifolia being cultivated in India and Pakistan, and C. senna being produced in the Sudan, much of it from wild plants. Tinnevelly senna is cultivated in wetter conditions than Alexandrian senna, which gives more luxuriant growth. Early harvests...
Modified Triterpenoids
The triterpenoid skeletons may be subjected to a variety of structural modifications as already illustrated. However, the particular modifications considered in this section are those that lead to loss of several skeletal carbon atoms. Preeminent amongst such degraded triterpenoids are the steroids, and these are so important that they are considered separately. Other degraded triterpenoids include the limonoids tetranortriter-penoids , in which four terminal carbons from the side-chain are...
Flavonolignans
An interesting combination of flavonoid and lig-nan structures is found in a group of compounds called flavonolignans. They arise by oxidative coupling processes between a flavonoid and a phenylpropanoid, usually coniferyl alcohol. Thus, the dihydroflavonol taxifolin through one-electron oxidation may provide a free radical, which may combine with the free radical generated from coniferyl alcohol Figure 4.44 . This would lead to an adduct, which could cyclize by attack of the phenol nucleophile...
Cardioactive Glycosides
Many of the plants known to contain cardiac or cardiotonic glycosides have long been used as arrow poisons e.g. Strophanthus or as heart drugs e.g. Digitalis . They are used to strengthen a weakened heart and allow it to function more efficiently, though the dosage must be controlled very Sarsaparilla consists of the dried roots of various Smilax species Liliaceae Smilacaceae , including S. aristolochiaefolia, S. regelii, and S. febr fuga, known respectively as Mexican, Honduran, and Ecuadorian...
STEROIDS Stereochemistry
The steroids are modified triterpenoids containing the tetracyclic ring system of lanos-terol Figure 5.55 , but lacking the three methyl groups at C-4 and C-14. Cholesterol Figure 5.76 typifies the fundamental structure, but further modifications, especially to the side-chain, help to create a wide range of biologically important natural products, e.g. sterols, steroidal saponins, cardioactive glycosides, bile acids, corticosteroids, and mammalian sex hormones. Because of the profound...
Ginseng
The roots of the herbaceous plants Panax ginseng Araliaceae from China, Korea, and Russia, and related Panax species, e.g. P. quinquefolium American ginseng from the USA and Canada, and P. notoginseng Sanchi-ginseng from China, have been widely used in China and Russia for the treatment of a number of diseases including anaemia, diabetes, gastritis, insomnia, sexual impotence, and as a general restorative. Interest in the drug has increased considerably in recent years and ginseng is widely...
Irregular Monoterpenes
A number of natural monoterpene structures contain carbon skeletons which, although obviously derived from isoprene C5 units, do not seem to regular monoterpene skeleton irregular monoterpene skeletons fit the regular head-to-tail coupling mechanism, e.g. those in Figure 5.17. These structures are termed irregular monoterpenes and seem to be limited almost exclusively to members of the plant family the Compositae Asteraceae. Allowing for possible rearrangements, the two isoprene units appear to...
Acetylenic Fatty Acids
Many unsaturated compounds found in nature contain one or more acetylenic bonds, and these are predominantly produced by further desaturation of olefinic systems in fatty acid-derived molecules. They are surprisingly widespread in nature, and are found in many organisms, but are especially common in plants of the Compositae Asteraceae, the Umbelliferae Apiaceae, and fungi of the group Basidiomycetes. These compounds tend to be highly unstable and some are even explosive if sufficient amounts...
Valerian
Valerian root consists of the dried underground parts of Valeriana officinalis Valerianaceae , a perennial herb found throughout Europe. Drug material comes from wild and cultivated plants, and is carefully dried at low temperature less than 40 C to minimize decomposition of constituents. Valerian preparations are widely used as herbal tranquillizers to relieve nervous tension, anxiety, and insomnia. Valerian was especially popular during the First World War, when it was used to treat...
Mevastatin and other Statins
Mevastatin formerly compactin Figure 3.83 is produced by cultures of Penicillium citrinum and P. brevicompactum, and was shown to be a reversible competitive inhibitor of HMG-CoA reductase, dramatically lowering sterol biosynthesis in mammalian cell cultures and animals, and reducing total and low density lipoprotein cholesterol levels see page 236 . Mevastatin in its ring-opened form Figure 3.84 mimics the half-reduced substrate mevaldate hemithioacetal during the two-stage reduction of...
Unsaturated Fatty Acids
Animal fats contain a high proportion of glyc-erides of saturated fatty acids and tend to be solids, whilst those from plants and fish contain predominantly unsaturated fatty acid esters and tend to be liquids. Some of the common naturally occurring unsaturated fatty acids are also included in Table 3.1. A convenient shorthand representation for fatty acids indicating chain length with number, position and stereochemistry of double bonds is also presented in Table 3.1. A less systematic...
Leukotrienes 1
The leukotrienes are involved in allergic responses and inflammatory processes. An antigen-antibody reaction can result in the release of compounds such as histamine see page 379 or materials termed slow reacting substance of anaphylaxis SRSA . These substances are then mediators of hypersensitive reactions such as hay fever and asthma. Structural studies have identified SRSA as a mixture of LTC4, LTD4 and LTE4. These cysteine-containing leukotrienes are powerful bronchoconstrictors and...
Coumarins 1
Bell WR 1992 Blood, coagulants and anticoagulants. Kirk - Othmer Encyclopedia of Chemical Technology, 4th edn, Vol 4. Wiley, New York, pp 333-360. Estevez-Braun A and Gonzalez AG 1997 Coumarins. Nat Prod Rep 14, 465 -475. Earlier review Murray RDH 1995 12, 477-505. Matern U, Luer P and Kreusch D 1999 Biosynthesis of coumarins. Comprehensive Natural Products Chemistry, Vol 1. Elsevier, Amsterdam, pp 623 - 637. Murray RDH 1997 Naturally occurring plant coumarins. Prog Chem Org Nat Prod 72, 1...
Pyrethrins
The pyrethrins are valuable insecticidal components of pyrethrum flowers, Chrysanthemum cinerariaefolium Tanacetum cinerariifolium Compositae Asteraceae . The flowers are harvested just before they are fully expanded, and usually processed to an extract. Pyrethrum cultivation is conducted in East Africa, especially Kenya, and more recently in Ecuador and Australia. The natural pyrethrins are used as a constituent of insect sprays for household use and as post-harvest insecticides, having a...
Phytosterols
The major sterol found in mammals is the C27 compound cholesterol, which acts as a precursor for other steroid structures such as sex hormones and corticosteroids. The main sterols in plants, fungi, and algae are characterized by extra one-carbon or two-carbon substituents on the side-chain, attached at C-24. These substituent carbons are numbered 241 and 242 Figure 5.77 some older publications may use 28 and 29. The widespread plant sterols campesterol and sitosterol Figure 5.100 are...