Bioactive Sesquiterpene.pptx

Bioactive Sesquiterpene

1. Bioactive Sesquiterpene Coumarins From Plants By Muhammad Rashad

2. INTRODUCTION Sesquiterpene coumarins (SCs) are members of a small group of natural products isolated from plants. They are mainly present in 12 genera, but the genus Ferula is considered as the major origin of natural SCs (72 %). F. assafoetida is known as a traditional medicine for the therapy of asthma, epilepsy, stomachache, flatulence, intestinal parasites, weak digestion, and influenza. The mechanism involved is anti-inflammatory effects. Most SCs were isolated and purified by multiple chromatography methods.

3. STRUCTURE TYPE AND IMPORTANT REPRESENTATIVES SCs is composed of a sesquiterpene unit and a coumarin frame through C–O–C or C–C bridge, by the ether linkage. There are three kinds of coumarin fragments, including umbelliferone (7-hydroxycoumarin), scopoletin (6-methoxy-7-hydroxycoumarin), and isofraxetin (6,8-dimethoxy-7-hydroxycoumarin), while the sesquiterpene unit mainly presents as chain sesquiterpenes, monocyclic sesquiterpenes, bicyclic sesquiterpenes, and other type sesquiterpenes. Subtype A – umbelliferone derived SCs Subtype B – scopoletin derived SCs Subtype C – isofraxetin derived SCs Subtype D – other SCs

4. Subtype A – umbelliferone derived SCs Composed of umbelliferone and sesquiterpene unit through the ether bond It is the major type of SCs. Abundent in the genus Ferula According to the characteristics of sesquiterpene structure, they can be further subdivided into three categories. Subtype A-1 umbelliferone -chain sesquiterpene Subtype A-2 umbelliferone monocyclic sesquiterpene Subtype A-3 umbelliferone bicyclic sesquiterpene

5. Subtype A-1 Umbelliferone -Chain Sesquiterpene To date, 14 compounds of this type have been identified, and 2 of them are found as glycosides. This type of SCs is relatively simple, which mainly present as two kinds of structures. The structural differences are found to be the substituents (hydroxyl, acetyl, and glycosyl) on the side chains of sesquiterpene units.

6. Names Origins Umbelliprenin (Simplest SC) F. sinkiangensis ; F. fukangensis ; F. tunetana ; F. szowitsiana ; F. flabelliloba ; F. assafoetida ; F. campestris; F. teterrima 8’-Hydroxyumbelliprenin F. assafoetida 9’-Hydroxyumbelliprenin F. assafoetida 8’-Acetoxy-5’- hydroxyumbelliprenin F. assafoetida Asacoumarin F. assafoetida 5’-Acetoxy-8’- hydroxyumbelliprenin F. assafoetida Examples of umbelliferone -chain sesquiterpene

7. Subtype A-2 umbelliferone monocyclic sesquiterpene Subtype A-2 umbelliferone -monocyclic sesquiterpene is made of a monocyclic sesquiterpene and 7-hydroxycoumarin through the ether bond. So far, 25 SCs have been characterized with monocyclic side chain in the form of five-membered, six-membered, or seven-membered ring. All the structures exist in the plants of genus Ferula .

8. Examples of umbelliferone monocyclic sesquiterpene Names Origins Farnesiferol C (31) F. sinkiangensis ; F. assafoetida ; F. szowitsiana Ferulsinaic acid (32) F. sinaica Sinkiangenorin D (33) F. sinkiangensis Asimafoetidnol (34) F. assafoetida

9. Subtype A-3 umbelliferone bicyclic sesquiterpene Umbelliferone -bicyclic sesquiterpene type is made of bicyclic sesquiterpene and 7-hydroxycoumarin linked by ether linkages. It is the main type of SCs distributed in the genus Ferula , including 73 compounds reported. The sesquiterpene units of subtype A-3 are mainly observed as two six membered rings, most of which are in the form of aglycone. At present, only five, i.e., persicaoside A (80), persicaoside B (81), cauferoside (82), gumoside A (83), and gumoside B (84), have been found in the form of glycosides. Interestingly, the sesquiterpene unit of sinkiangensis E (75) is a special bicyclodecane structure.

10. Examples of umbelliferone bicyclic sesquiterpene

11. Scopoletin -derived SCs are composed of scopolamine and sesquiterpene unit via ether linkages. There are two forms of sesquiterpene units Chain (subtype B-1) Bicyclic (subtypes B-2 and B-3) Up to now, only a few natural SCs have been found as this type from Ar. Persica and E. portlandica . 2. Subtype B – scopoletin derived SCs

12. Examples of scopoletin derived SCs

13. Isofraxidin -derived SCs are composed of isofraxidin and sesquiterpene unit linked through ether bond. There are only 28 constituents belonging to this type, mainly distributed in Ac. depressa , Ac. ochroleuca , Ac. tripartite, Ar. annua, Ar. pontica , Ar. abrotanum, Ar. persica, Ar. gemlinii , and An. Cretica species. 3. Subtype C – isofraxetin derived SCs

14. Examples of isofraxetin derived SCs

15. The three types of SCs described above are linked by a bridge from sesquiterpene to 7-hydroxy group in coumarin unit. However, there are still some natural SCs which are formed by other types of connection, for example, C–C bond at C-3 or C-8, C–O bridge formed by 4-hydroxy in coumarin, 3-isoprene cyclized to form furan ring (159–162) or pyran ring (155-156), and 7,8-dihydroxy in coumarin connected with sesquiterpene to form a dioxane (144–146). Totally, there are 38 SCs reported as this category. 4. Subtype D – other type SCs

16. Examples of other types SCs

17. Physical and Chemical Properties SCs are mostly colorless, yellow solids or oils. They mainly exist as aglycones and rarely as glycosides. Usually, SCs are insoluble in water, while they are soluble in chloroform, petroleum ether, ethyl acetate, acetone, and other organic solvents

18. Spectral Characteristics of SCs Characteristic absorption peaks in IR spectra of SCs are usually caused by lactone ring (1700–1730 cm -1 ) and aromatic ring (1600–1620 cm -1 ) functional groups in the coumarin fragment. In the electron impact ionization mass spectrometry (EI/MS), SCs display weak molecular ion peaks or dehydration peaks. There 24 carbon signals observed for the skeleton in 13 C NMR spectra, including 15 signals for the sesquiterpene unit and 9 characteristic carbons assigned for the coumarin unit.

19. BIOLOGICAL ACTIVITIES Although the number of SC is small, their diverse biological activities have attracted more attention of scientists including Antitumor (cell apoptosis) Antiinflammatory Anti-inflammatory Antibacterial Antivirus Antiparasitic Antiulcer

20. The Bioactive Molecules and Their Activities

21. Biosynthetic Pathway Most SCs’ scaffolds are formed by condensation of coumarin units and sesquiterpene segments via dehydration of the ether bond. As for the coumarin skeleton, the benzo-a-pyrone is mostly biosynthesized through shikimic acid pathway. The critical intermediate products and reaction steps are shown in Fig. 8.8 briefly. However, sesquiterpene fragments are composed by three isoprenes and the specific synthetic pathway is shown in Fig. 8.9.

22. Possible biotransformation pathways of 3’S,5’S,8’R,9’S,10’R-kellerin 3’S,5’S,8’R,9’S,10’R-kellerin Ferukrin Gummosin

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