Quality analysis of medical drugs from terpenoids.
The terpenoids, sometimes called 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. Hemiterpenes consist of a single isoprene unit. Isoprene itself is considered the only hemiterpene, but oxygen-containing derivatives such as prenol and isovaleric acid are hemiterpenoids.
Terpenes are hydrocarbons resulting from the combination of several isoprene units. Terpenoids can be thought of as modified terpenes, wherein methyl groups have been moved or removed, or oxygen atoms added. (Some authors use the term “terpene” more broadly, to include the terpenoids.) Just like terpenes, the terpenoids can be classified according to the number of isoprene units used:
Hemiterpenoids, 1 isoprene unit (5 carbons)
Monoterpenoids, 2 isoprene units (10C)
Sesquiterpenoids, 3 isoprene units (15C)
Diterpenoids, 4 isoprene units (20C) (e.g. ginkgolides)
Sesterterpenoids, 5 isoprene units (25C)
Triterpenoids, 6 isoprene units (30C) (e.g. sterols)
Tetraterpenoids, 8 isoprene units (40C) (e.g. carotenoids)
Polyterpenoid with a larger number of isoprene units
Terpenoids (or isoprenoids), a subclass of the prenyllipids (terpenes, prenylquinones, and sterols), represent the oldest group of small molecular products synthesized by plants and are probably the most widespread group of natural products.
Terpenoids can be described as modified terpenes, where methyl groups are moved or removed, or oxygen atoms added. Inversely, some authors use the term “terpenes” more broadly, to include the terpenoids.
During the 19th century, chemical works on turpentine led to name “terpene” the hydrocarbons with the general formula C10H16 found in that complex plant product. These terpenes are frequently found in plant essential oils which contain the “Quinta essentia“, the plant fragrance.
They are universally present in small amounts in living organisms, where they play numerous vital roles in plant physiology as well as important functions in all cellular membranes. The various functions of terpene natural products in the natural world have been reviewed.. On the other hand, they are also accumulated in many cases, and it is shown that the extraordinary variety they then display can be due to ecological factors playing an evolutionary role
They may be defined as a group of molecules whose structure is based on a various but definite number of isoprene units (methylbuta-1,3-diene, named hemiterpene, with 5 carbon atoms).
Terpenoids are extraordinarily diverse but they all originate through the condensation of the universal phosphorylated derivative of hemiterpene, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) giving geranyl pyrophosphate (GPP).
In higher plants, IPP is derived from the classic mevalonic acid pathway in the cytosol but from the methylerythritol phosphate pathway in plastids. It is generally accepted that the cytosolic pool of IPP serves as a precursor of sesquiterpenes, triterpenes, sterols and polyterpenes whereas the plastid pool of IPP provides the precursors of mono-, di- and tetraterpenes.. Some exceptions have been described showing that interactions between the two biosynthetic pathways may exist
A metabolic map giving the products of isoprene metabolism and their pathways may be found at the Prof Nicholson web site
A rational classification of the terpenes has been established based upon the number of isoprene (or isopentane) units incorporated in the basic molecular skeleton:
|
|
Terpenes |
Isoprene |
Carbon |
|
1 |
Monoterpenes |
2 |
10 |
|
2 |
Sesquiterpenes |
3 |
15 |
|
3 |
Diterpenes |
4 |
20 |
|
4 |
Sesterterpenes |
5 |
25 |
|
5 |
Triterpenes |
6 |
30 |
|
6 |
Carotenoids |
8 |
40 |
|
7 |
Rubber |
> 100 |
> 500 |
Mono-, sesqui-, di-, and sesterterpenes contain the isoprene units linked in a head to tail fashion. The triterpenes and carotenoids (tetraterpenes) contain two C15 and C20 units respectively linked head to head.
Many terpenes are hydrocarbons, but oxygen-containing compounds such as alcohols, aldehydes or ketones are also found. These derivatives are frequently named terpenoids.
Mono- and sesquiterpenes are the chief constituents of the essential oils while the other terpenes are constituents of balsams, resins, waxes, and rubber.
Oleoresin is a roughly equal mixture of turpentine (85% C10-monoterpenes and 15% C15- sesquiterpenes) and rosin (C20-diterpene) that acts in many conifer species to seal wounds and is toxic to both invading insects and their pathogenic fungi. A number of inducible terpenoid defensive compounds (phytoalexins) from angiosperm species are well known. These include both sesquiterpenoid and diterpenoid types.
Isoprenoid units are also found within the framework of other natural molecules. Thus, indole alkaloids, several quinones (vitamin K), alcohols (vitamin E, vitamin A formed from b-carotene), phenols, isoprenoid alcohols (also known as terpenols or polyprenols) also contain terpenoid fragments. The origin of the ubiquitous isoprene unit and its conversion into various compound has been extensively studied.The biogenesis, molecular regulation and function of plant terpenoids has been extensively reviewed by Bouvier F et al.
Terpenes history spans various civilizations. As they are largely found in essential oils, they were used in the Ancient Egypt for various religions aims. Camphor was introduced in Europe from the East by the Arabs around the 11th century.
The process of obtaining plant essential oils by fatty extraction was known by the early Middle Ages. In the 12th century, Arnaud de Villanosa described distillation of oils from rosemary and sage. He made an “oleum mirabile” from oils of turpentine and rosemary. It is noticeable that some 60 oils were described in the Nuremberg edition of “Dispensatorium valerii cordi” written in 1592.
Analyses of oils of turpentine were made in 1818 by JJ Houston de la Billardiиre. Dumas proposed in 1866 the name “terpene”, derived from turpentine, instead of camphor for crystalline oxygenated substances extracted from essential oils. In 1887, Wallach O proposed that one isoprenic unit of 5 carbon atoms (C5H8) is always present in the molecule of terpenes).
The structure of camphor was established by Bredt in 1893, that of pinene by Wagner in 1894 and that of citral by Tiemann in 1895. b-Carotene was isolated in 1837 by Wackenrodder from carrots, and its correct molecular form was determined in 1907 by Willstдtter.
The period since 1945 has seen an extensive explosion iatural product chemistry due to the advent of chromatographic and spectroscopic techniques. The discovery of the isoprene unit is the basis of the concept of the “isoprenic rule” edicted in 1953 by Ruzicka L and completed by Lynen F et al. and Bloch K et al.
Mevalonic acid was shown in 1956 to be a biosynthetic precursor of cholesterol and later, its incorporation into a number of terpenoids has been demonstrated. Actually, an increasing number of terpenoids are described in the plant kingdom and many of them were shown to have important biological activities. Thus, several sesquiterpenes and diterpenes have antibiotic properties, some sesquiterpenes and diterpenes are insect and plant hormones, respectively.
CAMPHOR RACEMIC
Camphora racemica
C10H16O М. м. 152,2
Racemic camphor contains not less than 99,0 % and not more than 100,5 % (1RS, 4RS)-1,7,7–trimethylbicyclo[2.2.1]heptan-2-one.
CHARACTERS
Appearance. A white, crystalline or friable, crystalline masses, highly volatile even at room temperature.
Solubility. Slightly soluble in water, very soluble in alcohol 96% R and in light petroleum R, freely soluble in fatty oils, very slightly soluble in glycerol R.
IDENTIFICATION
А. Dissolve 1,0 g substance in 30 ml of methanol R. Add 1,0 g of hydroxylamine hydrochloride R and 1,0 g of anhydrous sodium acetate R. Boil under a reflux condenser for 2 hours. Allow to cool and add 100 ml water R. A precipitate is formed. Filter, wash with 10 ml water R and recrystallize from 10 ml of mixture of 4 vomumes of alcohol R and 6 volumes of water R. The crystals, dried in vacu, melt at 118 ºС to 121 ºС.
В. Dissolve 0,01 g substance in 1 ml of sulfate acid R. Add to this solution 1 ml 1 % of vanillin in sulfate acid R and 1 ml water R. Red-violet coloration appears:
С. Dissolve 0,01 g substance in 1 ml of sulfate acid R. Add to this solution 3 ml of p-dymetylamynobenzaldehyd solution in sulfate acid R. Pink coloration appears:
D. Dissolve 0,05 g substance in 1 ml of hydrochloric acid concentrate R. Add 3 ml solution of solution of 2,4-dynitrofenilhidrazyn in hydrochloric acid R. Boil. Yellow coloration appears and after 5 minute yellow precipitate is formed :
TEST ON PURITY
pH. Dissolve 1.0 g in 10 ml of 96% alcohol R and add 0.1 ml of phenolphthalein solution R1, colorless solution. The color of the solution should be changed by adding no more than 0.2 ml of 0.1 M sodium hydroxide solution.
ASSAY
Oxime method.
In flask connected with a reflux condenser, put 1.0 g of substance, add 25 ml of hydroxylamine hydrochloride (6.0 g of hydroxylamine hydrochloride, 10 ml of water R and 90 ml of 96% alcohol R) and boil in a water heater for 60 minutes. Then refrigerator wash 30 ml of water R, disconnected from the bulb. Hydrochloric acid, which will forme, titrate 0.5 M solution of sodium hydroxide (indicator – 1% solution bromfenolovoho blue):
HCl + NaOH → NaCl + H2O
Em = М. м.
1 ml of 0,1 М sodium hydroxide solution corresponds to
STORAGE
In densely blocked non-metallic container, protected from light.
ACTION AND USAGE
CNS stimulant and cardiotonic agent for the treatment of acute and chronic heart failure, with collapse, respiratory depression, poisoning by hypnotics and narcotics. Camphor racemic used only externally as an irritant and antiseptic.
Camphor /ˈkæmfər/ is a waxy, flammable, white or transparent solid with a strong aromatic odor.[3] It is a terpenoid with the chemical formula C10H16O. It is found in wood of the camphor laurel (Cinnamomum camphora), a large evergreen tree found in Asia (particularly in Sumatra, Borneo and Taiwan) and also of Dryobalanops aromatica, a giant of the Bornean forests. It also occurs in some other related trees in the laurel family, notably Ocotea usambarensis. Dried rosemary leaves (Rosmarinus officinalis), in the mint family, contain up to 20% camphor. It can also be synthetically produced from oil of turpentine. It is used for its scent, as an ingredient in cooking (mainly in India), as an embalming fluid, for medicinal purposes, and in religious ceremonies. A major source of camphor in Asia is camphor basil.
Norcamphor is a camphor derivative with the three methyl groups replaced by hydrogen.
Camphor can be produced from alpha-pinene, which is abundant in the oils of coniferous trees and can be distilled from turpentine produced as a side product of chemical pulping. With acetic acid as the solvent and with catalysis by a strong acid, alpha-pinene readily rearranges into camphene, which in turn undergoes Wagner-Meerwein rearrangement into the isobornyl cation, which is captured by acetate to give isobornyl acetate. Hydrolysis into isoborneol followed by oxidation gives racemic camphor.
By contrast, camphor occurs naturally as the D-enantiomer.
In biosynthesis, camphor is produced from geranyl pyrophosphate, via cyclisation of linaloyl pyrophosphate to bornyl pyrophosphate, followed by hydrolysis to borneol and oxidation to camphor.
Reactions
Typical camphor reactions are
- oxidation with nitric acid,
- conversion to isonitrosocamphor.
Camphor can also be reduced to isoborneol using sodium borohydride.
In 1998, K. Chakrabarti and coworkers from the Indian Association for the Cultivation of Science, Kolkata, prepared diamond thin film using camphor as the precursor for chemical vapor deposition.
