Phytol & retinol (Diterpenoids)

Diterpenoid

1. Phytol & Retinol Presented By: Diwan M. Pharm , Pharmaceutical Chemistry Chemistry Of Natural Products

2. Phytol  is an acyclic  diterpene   alcohol  that can be used as a precursor for the manufacture of synthetic forms of  vitamin E  and  vitamin K1 . In  ruminants , the gut fermentation of ingested plant materials liberates phytol, a constituent of  chlorophyll , which is then converted to  phytanic acid  and stored in fats. In shark liver it yields  pristane . IUPAC name : 3,7,11,15-tetramethyl-hexadec-2-en-1-ol Chemical formula : C 20 H 40 O Molar mass : 296.539 g·mol − 1 Colourless to yellow viscous liquid; Faint floral aroma Practically insoluble to insoluble in  water Soluble (in ethanol ) Density :0.847-0.863 Introduction

3. Chlorophyl l Vit . E Vit . K

4. Elemental analysis shows that Molecular formula of phytol is: C 20 H 40 O Phytol belongs to diterpenoid class of terpenoids It contains four isoprene units joins head to tail Degree of unsaturation = x + 1 – y/2 = 21-20 =1 Hydrogenation of phytol forms dihydophytol Phytol contain one double bond. Structure Determination of phytol

5. On analyzing the spectra of compound 1, it appears to be an extension of phytol by additional double bound and methyl groups. While phytol is C-20, compound 1 is a C-26 compound with additional CH3 at C-22, CH2 at C-16, C-17 and C-20 , at C-19 and at C-18. This compound (2E, 18E)-3,7,11,15,18- pentamethylhenicosa-2,18-dien-1-ol, named eluptol , appears new and it is also being reported for cholinesterase inhibitory activity for the first time. Structral Elucidation

6. Nature of oxygen: Phytol forms monoacetate derivetive with Ac 2 O/ Pyridine. Oxidation of Phytol with same no of carbon atoms. Phytol is an primary alcohol. Phytol is an acyclic molecule. C 20 H 40 O C 20 H 38 O ( Phytenic acid) Ac 2 O Pyridine Monoacetate derivative of phytol Position of double bond: O zonolysis CrO 3

7. Synthesis of Phytol

8. Hydrolysis of Chlorophyll

9. P hytol is likely the most abundant acyclic isoprenoid compound present in the biosphere and its degradation products have been used as biogeochemical tracers in aquatic environments . Phytol is used in the fragrance industry and used in cosmetics, shampoos, toilet soaps, household cleaners, and detergents . Phytol is also used in some Cannabis distillate vapes as a diluent .  Its worldwide use has been estimated to be approximately 0.1–1.0 metric tons per year . Phytol a diterpene alcohol, in a mouse model of acute inflammation, and phytol effect on leukocyte recruitment, cytokines levels, and oxidative stress. The anti‐inflammatory activities of phytol were assessed by measuring paw edema induced by different inflammatory agents (e.g., λ‐ carrageenan , compound 48/80, histamine, serotonin, bradykinin , and prostaglandin E 2  [PGE 2 ]) Applications

10. Retinol Retinol , also known as  vitamin A 1 -alcohol, is a  vitamin  in the  vitamin A   family  found in food and used as a  dietary supplement . As a supplement it is ingested to treat and prevent  vitamin A deficiency , especially that which results in  xerophthalmia .  In regions where deficiency is common, a single large dose is recommended to those at high risk a couple of times a year .  It is also used to reduce the risk of complications in those who have  measles .  It is used by mouth or  injection into a muscle . Retinol at normal doses is well tolerated .  High doses may result in an  enlarged liver , dry skin, or  hypervitaminosis A .  High doses during  pregnancy  may result in harm to the baby .  It is converted in the body to  retinal  and  retinoic acid  through which it acts .  Dietary sources include fish,  dairy products , and meat . Retinol was discovered in 1909, isolated in 1931, and first made in 1947.  It is on the  World Health Organization's List of Essential Medicines .  Retinol is available as a  generic medication  and  over the counter . Formula: C 20 H 30 O Molar mass; 286.4516  g·mol −1

11. Vitamin A is found in many foods, including carrot, broccoli, sweet potato, pumpkin, etc. Vitamin A has multiple functions: it is important for growth and development, for the maintenance of the immune system and good vision. It also helps to maintain the health of the mucous membrane and the skin, so many anti-aging creams contain vit . A A deficiency of vitamin A causes night blindness, as well as dry eyes and skin. Vitamin A ( Retinol )

12. Elemental analysis shows that Molecular formula of retinol is: C 20 H 30 O Retinol belongs to diterpenoid class of terpenoids It contains four isoprene units joins head to tail Degree of unsaturation = x + 1 – y/2 = 21-15 =6 Nature of Oxygen: Vitamin A on reaction with p- nitrobenzoic acid leads to formation of ester. This confirms vitamin A contains a hydroxyl group. C 20 H 30 O Formation of ester Structure Determination of Retinol p-NO 2 C 6 H 4 COOH

13. Analysis of unsaturation : Vitamin A reacts with five molecule of Hydrogen and form perhydrovitamin A Therefore it contains five C=C . Presence of one ring: The deoxygenated parent saturated hydrocarbon of vitamin A is C 20 H 40 , which corresponds to C n H 2n molecular formula. This proves the presence of one ring in vitamin A. Ozonolysis : Ozonolysis of Vitamin A produces one molecule of gernoic acid. It was known to chemists that β -ionone also forms gernoic acid on ozonolysis . Therefore, vitamin A may contain one β -ionone unit. Structure Determination of Retinol

14. Structure Determination of Retinol

15. Structure Determination of Retinol

16. Retinol is synthesized from the breakdown of  β-carotene . First, the  β-carotene 15-15’-monooxygenase  cleaves β-carotene at the central double bond, creating an epoxide . This epoxide is then attacked by water creating two hydroxyl groups in the center of the structure. The cleavage occurs when these alcohols are reduced to the aldehydes using NADH. This compound is called retinal. Retinal is then reduced to retinol by the enzyme  retinol dehydrogenase . Retinol dehydrogenase is an enzyme that is dependent on NADH Biosynthesis

17. Synthesis of Retinol ( Reformatsky rxn )

18. Synthesis of Retinol (Wittig rxn )

19. Many different geometric isomers of retinol, retinal and retinoic acid are possible as a result of either a  trans  or  cis  configuration of four of the five  double bonds  found in the  polyene  chain. The  cis  isomers are less stable and can readily convert to the all- trans  configuration (as seen in the structure of all- trans -retinol shown at the top of this page). Nevertheless, some  cis  isomers are found naturally and carry out essential functions. For example, the 11- cis -retinal isomer is the  chromophore  of  rhodopsin , the  vertebrate   photoreceptor  molecule. Rhodopsin is composed of the 11-cis-retinal covalently linked via a  Schiff base  to the  opsin  protein (either rod opsin or blue, red or green cone opsins ). The process of vision relies on the light-induced isomerisation of the chromophore from 11- cis  to all- trans  resulting in a change of the conformation and activation of the photoreceptor molecule. One of the earliest signs of vitamin A deficiency is night-blindness followed by decreased visual acuity. Many of the non-visual functions of vitamin A are mediated by retinoic acid, which regulates gene expression by activating nuclear  retinoic acid receptors .  The non-visual functions of vitamin A are essential in the immunological function, reproduction and embryonic development of vertebrates as evidenced by the impaired growth, susceptibility to infection and birth defects observed in populations receiving suboptimal vitamin A in their diet. Chemistry

20. The   retinal  molecule inside an  opsin  protein absorbs a photon of light. Absorption of the photon causes  retinal  to change from its  11-cis-retinal  isomer into its  all-trans-retinal  isomer. This change in shape of  retinal  pushes against the outer  opsin  protein to begin a signal cascade, which may eventually result in chemical signaling being sent to the brain as visual perception. The  retinal  is re-loaded by the body so that signaling can happen again. Chemistry of vision

21. Vitamin A is a fat soluble Vitamin. Present only in foods of animal origin Its provitamins carotenes are found in plants Chemistry : Retinol , retinal and retinoic acid are termed as vitamers of Vitamin A It is a primary alcohol containing β- ionone ring The side chain has two isoprenoid units, four double bonds and one hydroxyl group Retinols present in animal tissues as retinyl ester with long chain. Retinol (Vitamin A Alcohol)

22. This is an aldehyde form obtained by the oxidation of retinol. Retinal and retinol are interconvertible Retinal Retinal ( vit . A Aldehyde )

23. This is produced by the oxidation of retinal Retinoic acid cannot give rise to the formation of retinal or retinol Retinoic acid ( vit. A acid)

24. All the compounds with vitamin A activity are referred as retinoids They are poly- isoprenoid compounds having beta-ionone ring system The retinal may be reduced to retinol by retinal reductase and it is reversible Retinal is oxidized to retinoic acid , which cannot be converted to the other forms Retinol ( alcohol ) Retinal ( aldehyde ) Reductase NAD+ NADH + H+ Retinoic acid

25. Medical Uses: Retinol is used to treat  vitamin A deficiency . Three approaches may be used when populations have low vitamin A levels : Through dietary modification involving the adjustment of menu choices of affected persons from available food sources to optimize vitamin A content. Enriching commonly eaten and affordable foods with vitamin A, a process called fortification. It involves addition of synthetic vitamin A to staple foods like margarine, bread, flours, cereals and other infant formulae during processing By giving high-doses of vitamin A to the targeted deficient population, a method known as supplementation.

26. Phytol https ://en.wikipedia.org/wiki/Phytol#:~:text=Phytol%20is%20an%20acyclic%20diterpene,acid%20and%20stored%20in%20fats . ‘Mach Jennifer’ Phytol from Degradation of Chlorophyll Feeds Biosynthesis of Tocopherols Article  in  The Plant Cell · October 2015 Netscher , Thomas (2007). "Synthesis of Vitamin E". In Litwack , Gerald (ed.).  Vitamin E . Vitamins & Hormones.  76 .   doi : 10.1016/S0083-6729(07)76007-7 .  ISBN   978-0-12-373592-8 .  PMID   17628175 https:// pubchem.ncbi.nlm.nih.gov/compound/Phytol Retinol https://en.wikipedia.org/wiki/Retinol#:~:text=Retinol%20is%20synthesized%20from%20the,double%20bond%2C%20creating%20an%20epoxide.& text=Retinal%20is%20then%20reduced%20to,that%20is%20dependent%20on%20NAD H.   World Health Organization  (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 500.  hdl : 10665/44053 .  Amer M, Maged M: Cosmeceuticals versus pharmaceuticals. Clin Dermatol . 2009, 27 (5): 428-430. 10.1016/j.clindermatol.2009.05.004. References