Terpenoids Dr. Amol Kharat Objectives • To study the Terpenoids in the form of Meaning, Different types Properties, occurrences, uses Isolation Method General Biogenetic Pathway Pharmacognostic account of different drug con taining important constituents Terpenoids. INTRODUCTION Terpenoids are the secondary metabolites synthesized by plants, marine organisms and fungi by head to tail joining of isoprene units . They are also found to occur in rocks, fossils and animal kingdom. Isoprene The terpenoids , sometimes referred to as isoprenoids , are a large and diverse class of naturally-occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in functional groups but also in their basic carbon skeletons . These lipids can be found in all classes of living things, and are the largest group of natural products. CALASSFICATION TYPE OF NUMBER OF ISOPRENE TERPENOIDS CARBON ATOMS UNITS hemiterpene C5 one monoterpenoid C10 two sesquiterpenoid C15 three diterpenoid C20 four sesterterpenoid C25 five triterpenoid C30 six tetraterpenoid C40 eight NOTE hemi = half di = two : sesqui = one and a half tri = three tetra = four Mnonoterpenoids Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C 10 H16 . Monoterpenes may be linear (acyclic) or contain rings. Biochemical modifications such as oxidation or rearrange- ment produce the related monoterpenoids. Mnonoterpenoids Acyclic monoterpenoid: Bicyclic monoterpenoid CHO CH 2 OH n e ro l g era n ia l ¦Â-m y r c e n e ¦Á ---ppp i nene Monocyclic monoterpenodi OH O OH O d-borneol l-menthol menthone cin eole Acyclic monoterpenoid Acyclic monoterpenoid Biosynthetically, isopentenyl pyrophosphate( 异戊烯 焦磷酸) and dimethylallyl pyrophosphate ( 二甲基丙烯焦 磷酸酯) are combined to form geranyl pyrophosphate (牻牛儿醇焦磷酸酯). Geranyl pyrophosphate Acyclic monoterpenoid Elimination of the pyrophosphate group leads to the formation of acyclic monoterpenes such as ocimene and the myrcenes . Myrcene ( 月桂烯) Acyclic monoterpenoid Hydrolysis of the phosphate groups leads to the prototypical acyclic monoterpenoid geraniol. geraniol （（香叶醇香叶醇） Acyclic monoterpenoid Additional rearrangements and oxidations provide compounds such as citral ( 柠檬醛), citronellal( 香茅醛), citronellol( 香茅醇), and many others. citral （柠檬醛） Acyclic monoterpenoid Many monoterpenes found in marine organisms are halogenated( 卤代的), such as halomon . Halomon is a polyhalogenated monoterpene first isolated from the marine red algae Portieria hornemannii . It has attracted research interest because of its promising profile of selective cytotoxicity ( 细胞毒) that Halomon suggests its potential use as an antitumor agent. Monocyclic monoterpenoid In addition to linear attachments, the isoprene units can make connections to form rings. The most common ring size in monoterpenes is a six-membered ring. A classic example is the cyclization of geranyl pyrophosphate to form limonene (柠檬烯）. Monocyclic monoterpenoid The terpinenes, phellandrenes( 水芹烯), and terpinolene (异松油烯) are formed similarly. Hydroxylation of any of these compounds followed by dehydration can lead to the aromatic p-cymene( 百里香素). Important terpenoids derived from monocyclic terpenes are menthol ( 薄荷醇), thymol( 麝香草酚,百里酚), carvacrol( 香芹酚,甲基异 丙基苯酚) and many others. β-phellandrene p-cymene menthol Menthol • waxy / crystalline substance • clear or white • solid at room temperature and melts slightly above. The main form of menthol occurring in nature is (-) - menthol, which is assigned the (1R, 2S, 5R) configuration. (-) dextro- (+) laeotro- a colourless liquid at room temperatures Limonene with an extremely strong smell of oranges. a chiral molecule (asymmetric carbon atoms) is common with such forms biological sources produce one enantiomer (对映体) Limonene is common in cosmetic products. As the main odor constituent of citrus, D - limonene is used in food manufacturing and some medicines, e.g., bitter alkaloids, as a flavoring; it is also used as botanical insecticide Be increasingly used as a solvent for cleaning Limonene purposes, such as the removal of oil from machine parts, as it is produced from a renewable source (citrus oil, as a byproduct of orange juice manu- facture). Combustible, be considered as a biofuel Limonene is common in cosmetic products. As the main odor constituent of citrus, D - limonene is used in food manufacturing and some medicines, e.g., bitter alkaloids, as a flavoring; it is also used a s botanical insecticide Limonene Chemistry relatively stable, can be distilled without decom- position oxidises easily in moist air to carveol and carvone Dehydration with sulfur gives to p-cymene, hydro gen sulfide, as well as some sulfides. Carvone ( 香芹酮) Limonene Safety limonene and its oxidation products are skin and respiratory irritants. Although once thought to cause renal ( 肾脏的) cancer in rats, limonene now is considered by some researchers to be a significant chemopreventive agent with potential value as a dietary anticanc er tool in humans. Bicyclic monoterpenoid Bicyclic monoterpenoid Geranyl pyrophosphate can also undergo two sequential cyclization reactions to form bicyclic monoterpenes, such as pinene( 蒎烯) which is the primary constituent of pine resin. Bicyclic monoterpenoid Other bicyclic monoterpenes include carene ( 蒈烯) and camphene ( 樟脑萜). Camphor( 樟脑), borneol( 龙脑) and eucalyptol( 桉叶素) a re examples of bicyclic monoterpenoids containing ketone, alcohol, and ether functional groups, respectively. carene ( 蒈烯) camphor( 樟脑) borneol( 龙脑) Bicyclic monoterpenoid Role in Climate Monoterpenes are emitted by forests and form aerosols (气溶胶) that can serve as cloud condensation nuclei (CCN). Such aerosols can increase the brightness of clouds and cool the climate. Pinene There are two structural isomers found in nature: α-pinene and β-pinene. As the name suggests, both forms are important constituents of pine resin; they are also found in the resins of many other conifers, and more widely in other plants. Both are also used by many insects in their chemical communication system. Pinene Usage Selective oxidation of pinene with some catalysts in chemical industry give many components for pharmacy, artificial odorants and so on. The prima ry oxidation product is verbenone( 马鞭草烯酮) . It can form by simple air oxidation but a synthetic method employs lead tetraacetate . Eucalyptol a natural colorless liquid has a variety of synonyms the dominant portion of "Eucalyptus oil“ comprises up to 90 percent of Eucalyptus oil Although it can be used internally as a flavoring and medi- cine ingredient at very low doses, typical of many essential oils (volatile oils), eucalyptol is toxic if ingested at high doses. Uses of eucalyptol flavorings, fragrances, and cosmetics. an ingredient of mouthwash and cough suppressant. Eucalyptol suppository( 栓栓栓剂), reducing inflammation and pain for the treatment of some respiratory ailments kill leukaemia cells in vitro In a 1994 report released by five top cigarette companies, eucalyptol was listed as one of the 599 additives ( 添加剂) to c igarettes. It is added to improve the flavor. Sesquiterpenoids Sesquiterpenoids Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C 15 H24 . Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations. Biochemical modifications such as oxida- tion or rearrangement produce the related sesquiterpenoids. Sesquiterpenoids • Acyclic sesquiterpenoids • Monocyclic sesquiterpenoids O 姜 黄 酮 姜 稀 ¦Á-farnesene ¦Â-farnesene • Bicyclic sesquiterpenoids H OH H ¦Á - eudesmol guaiazulene cadinene Acyclic Sesquiterpenoids When geranyl pyrophosphate reacts with isopentenyl pyro- phosphate, the result is the 15-carbon farnesyl pyrophosphate (焦磷酸法尼酯) , which is an intermediate in the biosynthesis of sesquiterpenes such as farnesene( 金合欢烯) . Oxidation can then provide sesquiterpenoids such as farnesol( 金合欢醇) . Sesquiterpenes are found naturally in plants as defensive agents. farnesene farnesyl pyrophosphate farnesol Monocyclic Sesquiterpenoids With the increased chain length and additional double bond, the number of possible ways that cyclization can occur is also in creased, and there exists a wide variety of cyclic sesquiterpenes. In addition to common six-membered ring systems such as is fo und in zingiberene( 姜烯), a consitituent of the oil from ginger, c yclization of one end of the chain to the other end can lead to m acrocyclic( 大环的)rings such as humulene( 葎草烯). zingiberene姜 稀 Bicyclic Sesquiterpenoids In addition to common six-membered rings such as in the cadinenes ( 杜松烯), one classic bicyclic sesquiterpene is caryophyllene( 丁香烯), from the oil of cloves( 丁香), which has a nine-membered ring and cyclobutane ( 环丁烷) ring. A dditional unsaturation provides aromatic bicyclic sesquiter - pe noids such as guaiazulene （（愈愈创木烷）. H H cadinene caryophyllene guaiazulene Tricyclic Sesquiterpenoids With the addition of a third ring, the possible structures become increasingly varied. Examples include longifolene (长松叶烯), copaene( 胡椒烯)and the alcohol patchoulol. isomers of longifolene copaene patchoulol Example of Sesquiterpenoids • Zingiberene • is a monocyclic sesquitepenoid which is the predominant constituent of the oil of ginger (Zingiber officinale ), from which it gets its name . • Zingiberene Chemical name 5-(1,5-di zingiberene姜 稀 m--ethyl-4-hexenyl)-2-methyl-1,3-cyclo