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From sesquiterpenes we will continue to our next group of the terpenoids substances. We talked about 10C "monoterpenes" , 15C "sesquiterpenes" , and now we'll talk about 20C "Diterpenes" substances. We know that the aliphatic compound is the first compound in the biosynthesis of any subclass of the terpenoid substances, and we classified it as a regular terpenoid substance because the chain elongation is achieved by addition of an IPP to the phosphorilated N of the biosynthesized chain which is Farnesyl Pyrophosphate -or Farnesyl Diphosphate- with the pyrophosphate group IPP CH2P group electrophilic attack on the pyrophosphate . and we obtain the aliphatic chain of the diterpene GGPP, because the GPP the 10C was the basic unit of monoterpenes and we have 20 carbon so it's a repetition ten ten GGPP "gerenyle gerenyle pyrophosphate" it's the basic acyclic compound or acyclic precursor of this big class of secondary metabolites which termed as the phenityle terpenoids and not like the FPP and its derivatives, we are restricted with the GPP to certain plants families. We said FPP primary found in the family Asteraceae in the case of GGPP as the basic unit of the diterpenoid we are talking about constituents which are ubiquitous in all green plants, because the basic unit or the derivative of GGPP "its reduced derivative phytol one double bond, mono unsaturated alcohol phytol " is found in the side chain of chlorophyll so presumably " "من المفروض any plant which has chlorophyll in its nucleus we'll find a diterpenoid compound so presumably the diterpenoid are very very widely distributed. Therefore we are saying there are ubiquitous broad occurring secondary metabolites not like the sesquiterpenoid compounds. So side chain of the chlorophyll is based on phytol as a mono unsaturated derivative of the GGPP. We have as a side chain an alkylating agent, because as you remember when we start with hemeterpenoid we can use it as an alkylating agent; as newly synthesized terpenoids have the same terminal group after eliminating the pyrophosphate they can be used as alkylating agents not only the hemeterpenoid as (meroterpinod or mixed terpenoid) although they are the only ones that are found as alkylating agents, also we have the side chain of tocoferol of vit.E and vit.K. We have another 20c diterpenoid which is vit.A or retinic acid but although it is 20 C it is a derivative of tetraterpenes (splitted). Then another proof that diterpenoids are widely distributed in nature is the plant growth regulators Gebberellins ,so we have both chlorophyll and Gibberellins that are very important compounds in higher plants of 20C or 18c diterpinoid indicate that is widely distributed in nature. We also have other potent biological and industrial active compounds as well as anticancer chemotherapeutic taxol and sweetening agents and adaptogenic ginkolytes. Unfortunately also there are toxic cocarcinogenic substances (tumor promoter) especially in long term 1 use and some other toxins like alpha- meta toxin!! , and some are in the structure of alkaloids. The first compound of diterpenoids is Phytol: 1- Monounsaturated aliphatic compound (possesses only one double bond in its structure) 2- It is found as an alkylating agent in Vit.K and Vit.E 3- Also it is a side chain in chlorophylls So it is the most common simple diterpinoid found with many important metabolites The other is Gibberellins 1- It has been isolated 1st time from fungus Gibberella fujikurio by Japanese scientist 2- It has been found that it stimulates the growth of seed and elongation of stem, so it is a growth promoting agent ,( opsonin another promoting agent but it is an alkaloid ) 3- A lot of Gebberllins have been isolated, so they are differentiated by using letters A,B,C… and numbers as subscripts as A13 ,C19,, so in different isolated new compounds in order to make it less complicated in name instead of using the name of the fungus( Gibberell fujikurio )to name the secondary metabolites 4- It is tetracylic type of cyclic diterpenoid from acyclic so this complexity due to many steps in their biosynthesis 5- Primarily we have 2 groups have been isolated A13 gibberllin and C19 gibberellic acid , representative 19c acid in this class of growth promoting agent in higher plants. Forskolin is a Compound isolated from Roots of Coleus forskohlii, a plant used in india , it is possessing +ve inotropic action so it can be used in treatment of different cardiovascular disorders (hypertension,..) and for the treatment of bronchial asthma. Anti-hypertensive activity is based on several studies, and these studies indicate the responsibility of this compound to treat these disorders, it is major acting as diterpenoids compounds, it is completely different from digitalis glycosides in stimulation of adenylyl cyclase activity. Diterpenoid cmpds of these substances with regard to the CVS activity are completely different than digitalis glycosides, it stimulates adenyl cyclase activity. Now we will talk about Stevia rebaudiana which contains the secondary metabolite Stevioside which is 200 times sweeter than sucrose, and considered as non-calorie sweetening agent, and their major compounds that are responsible for sweetening such as Stevioside which is a diterpine tricyclic compound, but it is not used 2 in Jordan because until now it is not accepted by FDA according to its safety. And there are a several studies which indicate that Stevioside is possessing mutagenic activity. So, due to mutagenicity, Stevioside is not yet accepted by FDA. It is available in market in japan and in many countries as a non-color sweetening agent; the producer company is responsible for adverse rxns if any occur. Our next biologically active compound is one of the most important and therapeutically used chemotherapeutic agent is Taxol which has been isolated early in 1970s by screening program of naturally acting anticancer in USA that screen 1000s of plants against 6 common different types of cell lines for anticancer activity so find many compounds work as broad spectrum anticancer , and it is firstly isolated from Taxus brevifolia ( Pacific Yew ) in Canada as well as from Taxus baccata and the difference is that baccata is growing in Europe The compound isolated (structure not for memorizing) but mention the important points that are relating to its bioactivity. It is a diterpenoid compound but it has a N in its side chain can be considered theoretically as pseudo alkaloid; because any compound by the definition that contains N considered as alkaloids but here the N ( the precursor a.a is isoserine ) is not a part of the heterocyclic ring so it is pseudo , but it is included here in diterpenoid because its biological activity is due to diterpenoid nucleus and chemistry. Its complex structure contains rings A, B, C ,, the ring a , and c are hexacycles linked via central 8 membered ring ( unusual) and moreover we have the oxetane 4 membered - o -ring attaches ,4,5,and 20 which is necessary for its biological activity plus the presence of side chain at c13 which is a derivative of 3’ isoserine which prossess the subtitueted N. Then we have another benzoyl group at c2 we have 2 acetyl groups, we have a substitueted tricyclic ring structure with the six membered ring A, B and C with an oxetane ring. Several analogs have been prepared, the main modification is attaching a side chain instead of the hydroxyl group at carbon number 13. So, different semisynthetic derivatives are prepared by replacing the side chain substituents and C13. Taxol is an important compound in the treatment of cancer; its potency is attributed to the modifications on the side chain attached to position 13. 3 The first isolation from the Pacific yew (Taxus brevifolia), it was found that this cmpd occurs in the bark of this plant. These trees are very slowly growing trees, and taxol occurs in barks in very low concentrations, in order to obtain 1 Kg taxol we need 7-8 tons of the bark, large quantities of barks gives very small amounts …. So we need to find other sources of this taxol and it has been found that taxus baccata contains not exactly the taxol, and can be converted to taxol (semisynthetic), but these precursors of the taxol which devoid the acetyl group at C10 on the side chain, so here we have the two active compounds which are isolated from the leaves - which are renewable parts. - Baccatin: acetyl group on carbon number 10 - OH group on C13 is free. - We can prepare from these major compounds taxol or other derivatives using the free OH at C13 - In baccatin we have the acetyl group at C10 which is available and the side chain can be modified, so baccatin and deacetylbaccatin both are found in the leaves of T.baccata, and they are more water soluble than taxol. - These anticancer agents are used in advanced stages of breast cancer, cervical cancer, lung cancer, head and neck cancer and many types of carcinoma - The major disadvantage of taxol is its low water solubility, and by using other agents we can improve its solubility and biological activity. - These anticancer agents are also considered as anti-mycotic agents. We will start our discussion with Ginkgo biloba (G.biloba), Ginkobiloba is available in different pharmaceutical preparations. In ginkobiloba we don't isolate the single cmpd, it's a standaradized crude extract based on flavonoids and terpenoids. It's one of the exceptions that it's not a pure isolated cmpd but it's a standardized crude mixture containing 24% flavonoids and 6 % terpenes. We have two major classes of secondary metabolites: 1. flavonoids (already discussed in chapter of flavonoid such as Rutin, Quercetin ) 2. terpenoids are again subdivide into diterpenoid and sesquterpeneoid . In both classes we have (lactones) so diterpenoid lactones and sesqueterpenoid lactones. Its structure is complex polycyclic, different numbers of the rings and poly substituted. 4 O O OH O R2 O O R3 O R1 O Ginkgolide A Ginkgolide B Ginkgolide C Ginkgolide J Ginkgolide M R1 OH OH R2 H OH R3 H H OH OH OH OH H H OH OH OH The characteristic for the diterpenoid is the lactone ring and for sesqueterpenoid is also lactone ring. Both (diterpenoid and sesqueterpenoid) have biological activity from lactone ring that means that the lactone ring is responsible for biological activity of terpenoid. The Ginkgo is one of the exception class not use purified secondary metabolite but standardized crude extract : the standardized crude extract contains 24% flavonoid and 6% terpenes, so they have the synergistic activity somehow of flavonoid and terpenoid for observing the biological activity of the substances. There is another requirement for this ginkgo, because we are using crude drug while crude drug even go further standardization then there is different other secondary metabolites and one of them is Gingolic acid (alkyl derivative). GINGOLIC ACID: R COOH 13 OH Gingolic acid(s) R = 15:1 ( 8 ) R = C 13-17 (0-1 double bond) It's a free partial phenolic compound with very short R chain (13 – 17 carbons). It is very irritant substance and it causes dermatitis as well as to a certain degree it is not very highly mutagenic. It has certain mutagenicity so any preparation containing this gingolic acid or phenolic derivative must to be nearly free (contain less than 5 P.P.M of this Gingolic acid phenolic derivative, so standardization is required to determine concentration of this toxic compound), because it is responsible for irritant and mutagenicity to a certain degree. MEDICAL VALUE OF GINKGO: In fact it is used to early management of the senile people specially elderly people in order to improve cerebrovascular circulation 5 and peripheral circulation, it will improve the mental and physical performance of senile and elderly people and this substance has potent and selective activity against PAF(platelet activating factor). That means it has protective effect or immuno-protective effect. By experiment we found the Gingolide and Ginkgo extract has anti-inflammatory activity and improvement in cerebral circulation. It is (not drug) plant which is used in treatment of dementia (Alzheimer’s symptoms) What is the difference between dementia and senile people ???? Both treated by G.biloba but the senile (age dependent) is impairment of cerebral circulation because of old age but the cause of dementia is impairment of transmission of neurotransmitter so it is a disease (pathological case). What are the common symptoms of elderly people?? Note: these symptoms treated by G.biloba and its extract. These symptoms resulted from impairment in cerebral circulation. There are 12 major symptoms common in elderly people: 1. Difficulty in concentration 2. Difficulty in short term memory (definitely seen when you talk to your grandparents, they will not remember what just before a while but they could remember what happened in long 80 year ago, so there is a decrease in the short term memory and improvement in long term memory, so senile talking about childhood in very late age) 3. Absent mindedness 4. Confusion 5. Lack of energy and apathy 6. Tiredness 7. Decreased physical performance 8. Depressive mood 9. Anxiety 10. Dizziness 11. Frequent headache is the common 12. Tinnitus sound in ear These symptoms are not considered a pathological condition because they are signs of getting old or senile. Different sign of senility is not exam topic but it is a general information or knowledge when we are talking about senile people 6 Note: the term elderly people become delayed, i.e. in the past a person with 50 years was consider elderly but now a person with 60 or more considered elderly and might develop senility. G.biloba improves senile condition but it should be considered in relation to the rest of drugs that taken by the elderly person (it is contraindicated in different conditions especially patients taking antiepileptic drugs and asthmatic patients, people taking hypo or hypertensive drugs and spatially anticoagulant drug) But a HTN is a common disease for elderly people, so if you want to administer the anti-hypertensive drugs along with G.biloba, this must be under supervision of the physician. We have in Jordan tea packs of the G.biloba and most of the studies indicate that the common drug in tea packs is not very beneficial so the study indicates that it should be standardized and should be available in the form of herbal tea mixture containing among other plant barks also G.biloba. Until now we talked about terpenoid and diterpenoid substances with medicinal value but we have also toxic diterpens and these found in many ornamental plants and it is specially precursor of allergy (dermatitis) dermatism problem observed in gardeners. *Note: ornamental plants from family Euphorbiaceae and Thymelaceae. The Euphorbiaceae is very widely distributed in Jordan and the milky juice extracted from euphorbiacea will form dermatitis if it was handled without gloves. The phorbol ester (which is toxic diterpenes extract from euphorbiaceae and thymelaceae) classified as carcinogenic compounds (promoter of tumor formation). The other class of the toxic diterpenes is Andomedotoxin (gryanotoxin 1) from family Ericaceae, they are again irritant to the mucus membranes and they cause vomiting diarrhea dizziness and GIT disturbances if taken internally. If bees used Ericaceae plants for making honey, then we will obtain toxic honey! Note: Ericaceae is considered as an ornamental plant. OH H3C OH OR HO OH CH3 H3C CH3 OH O OH Phorbol OH CH3 Andromedotoxin (Gryanotoxin I) R=COCH3 7