A REVIEW ARTICLE ON RECENT ADVANCES IN MEDICINAL PROPERTIES OF NATURALLY OCCURRING HIMACHALENES

Shalini1, Priyankul Palia1*, Amit Chaudhary1, Nitika Sharma2, Shivali2

1Department of Pharmaceutical Chemistry, School of Pharmacy, Abhilashi University, Teh. Chachyot, Distt. Mandi (H.P.), PIN: 175028

*Corresponding Author Phone no. +918219646635

E-mail: priyankulpalia23@gmail.com

Abstract

Plant and plant derived material plays a very crucial role in synthesizing many organic compounds. From ancient times, cedarwood oil, extracted from Cedrus deodara, has been used for various medicinal purposes externally. Naturally occurring himachalenes are alpha-cis-himachalene, beta-himachalene and gamma-cis-himachalene which have been extracted from cedarwood oil. These isomers have been used in synthesis of benzocycloheptene derivatives which further showed anti- depressant and anti-microbial properties. Numerous other therapeutic aspects also have been found in cedarwood oil. This review describes the general introduction, properties, synthesis of himachalenes, pharmacological activities and medicinal importance of Cedrus deodara along with recent advancements in research related to this species. Currently, there are ongoing researches being carried out for vast exploration of medicinal benefits of naturally occurring himachalenes.

Keywords: Himachalenes, Cedrus deodara, plant, cedarwood oil, medicinal.

1. INTRODUCTION

Cedrus genera, which belong to family Pinaceae, is considered as one of the world’s most beneficial and widely planted genera. [1]

The Himalayan cedar (Cedrus deodara) is known for presence of himachalenes as major constituents plays an important role as perfume fixative in perfumery and pharmaceutical industries.[2,3] Cedrus genus species are mainly used as a potent molluscicidal and also used for skin diseases. The cedarwood oil (figure 1) acts as antiseptic, anti-inflammatory, analgesic, immunomodulatory, sedative, and diuretic agent. It is useful in UTI’s, hair loss, cellulite, tuberculosis, dandruff, arteriosclerosis, dentifrices, and psoriasis.[4]

Figure 1: Cedrus deodara images of branchlets, cedarwood oil and trees

1

It is mainly composed of three sesquiterpenic bicyclic hydrocarbons i.e., α-cis-himachalene, β-himachalene, and γ-cis-himachalenes containing hexahydrobenzocycloheptene as basic skeleton (figure 2).[5,6] These three himachalenes vary from each other only in the position of an ethylene linkage in the seven membered ring. Himachalenes have been subjected to various modifications, for example, cyclopropanation, oxidation, hydroxylation and epoxidation and total synthesis.[2,7,8,9]

α-cis-himachalene β-himachalene γ-cis-himachalene

Figure 2: structures of himachalenes

Pyrrolone-fused benzosuberene (PBS) moieties which have been synthesized from isomeric mixture of himachalenes are considered as an attractive source in therapeutics.[10] Benzocycloheptenes have been prepared by different methods viz. by enlarging six membered rings, cyclization,[11,12] and coupling reactions or from benzocycloheptanone.[13] Substituted benzocycloheptenes, SB-612111 which is an ORL-1 receptor antagonist can be utilised as important adjunct for chronic pain therapy and in hyperalgesia.[14] Benzocycloheptenes have been reported in various treatments such as for the treatment of urinary bladder, neurodegenerative diseases, cardiovascular diseases, sarcoma, carcinoma, pain relief and as an anti-depressant. They also have strong affinity for opiate receptors. Derivatives of benzocycloheptene like piperidine and piperazine exhibit anti-arrhythmic effect.[7]

1.1 Cedrus deodara

Cedrus deodara (figure 1), the himalayan cedar (also known as devdar/deodar), is a species native to western Himalayas which occurs at an altitude of 1650-2400m above sea level. It is a type of large evergreen coniferous tree which reaches approximately 65-85m in height with 4m diameter having a conical crown with parallel branches and its branchlets are drooping. Leaves of devdar tree are stiff, sharp pointed needle-like and the bark is greyish brown, dark in colour. In Himachal Pradesh, the total 68,872-hectare area is covered under Cedrus deodara forest and it is found in Mandi, Chamba, Manali, Kinnaur, Sirmour, Shimla and kangra region.[15] The scientific classification and chemical composition of Cedrus deodara is depicted in table 1 and 2 respectively. [16,17]

Table 1: scientific classification of Cedrus deodara

Kingdom PlantaeDivision Pinophyte

Class PinopsidaOrder PinalesFamily PinaceaeGenus CedrusSpecies deodara

Table 2: chemical composition of Cedrus deodara

CHEMICAL COMPOSITION PERCENTAGE %Organic Carbon (C) 83.50

Nitrogen (N) 0.28Phosphorus (P) 0.055Potassium (K) 0.06Calcium (Ca) 2.60

Magnesium (Mg) 0.017

1.2 Significance of Cedrus deodara

In India, essential oil production of Cedrus deodara started in late 1950’s and is found to be around 150 tonnes per year of the world’s total production.[18] Each part of Cedrus deodara tree provides medicinal importance. Leaves are used for flavouring foods, beverages and in treatment of rheumatism, diabetes, cancer, stomach disease, inflammation in tuberculous glands, etc. Root extracted oil is utilized as an anti-ulcer drug.[15] The wood and bark extracts are used for various properties such as insecticidal, spasmolytic, anti-oxidative, hepatoprotective, etc.[19]

2

1.3 Chemical constituents of Cedrus deodara

Earlier chemical investigations of Cedrus deodara showed that it consists of sesquiterpenes as well as glycosides. [20] Later investigations of the extract along with essential oil of woodchips of Cedrus deodara identified a total of twenty-six constituents from extract and thirty-four constituents from essential oil respectively by hydrodistillation and percolation. The major constituents of samples found are himachalenes (23.5-68.5%) namely, β-himachalene (38.3%), α-himachalene (17.1%) and γ-himachalene (12.6%) in essential oil and atlantones (15.0-61.6%) i.e., E-γ-atlantone (38.5%) and E-atlantone (10.2%) in extract. The other constituents found in C. deodara wood are himachalol, allohimachalol, deodarone, β -himachalene monoepoxide, deodardione, diosphenol, limonene carboxylic acid, atlantone himachalene oxide, oxidohimachalene, dehydro-ar-himachalene and cis-α-bisabolene. The structures of some of chemical constituents present in Cedrus deodara are as following (Figure 3): [5,21]

3

Figure 3: chemical structures of chemical constituents of Cedrus deodara

1.4 Synthesis of Himachalenes

Numerous methods or reaction mechanisms have been performed for the synthesis of himachalenes since the isolation of himachalenes. De mayo et al., the first one to carry out total synthesis of himachalenes, used a seven-step method to yield beta-himachalene (figure 4). Wenkert and Malmura carried out second synthesis dependent on intramolecular Diels-Alder cycloaddition of trienone to give alpha- and beta-himachalenes (figure 5).[20,21]

4

Figure 4: total synthesis of α-trans- and β-himachalenes developed by de mayo

Figure 5: synthesis of α-cis- and β-himachalene by intramolecular diels-alder reaction

2. RECENT ADVANCES IN MEDICINAL PROPERTIES5

The cedarwood oil mainly consists of himachalenes and atlantones. The oil characterized by high percentage of himachalenes is called super rectified oil whereas high percentage of atlantones containing oil is known as perfumery grade. [22] The application of Cedrus deodara as mentioned in the ayurvedic system of medicine for curing different ailments has shown its pharmacologically active properties like anti-cancer, anti-inflammatory, diuretic, spasmolytic, anti-fungal and molluscicidal. [23,24] Tanwar G. et al., (2019) synthesized PBS compounds i.e., pyrrolone-fused benzosuberene compounds. These were semi-synthesized from α-,β-,γ-himachalenes which have been previously extracted from the essential oil of Cedrus deodara following amino-vinyl-bromide substituted benzosuberenes as intermediates. They further evaluated them in vivo against human zebrafish model of pentylenetetrazol-induced seizures and hence concluded that PBS-8 could be developed as a potential antiepileptic. [10] Oukhrib A. et al. (2018) reported the chemistry of himachalenes and atlantones from Cedrus by discussing the major sesquiterpenes isolated from the essential oil of cedar and described some total synthesis and chemical transformations of the himachalenes and atlantones from Cedrus.[20] Chaudhary A. et al., (2014) synthesized five new 2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidine-amine derivatives from α-dehydro-ar-himachalene along with different aryl himachalane derivatives and performed anti-microbial activity which showed enhanced anti-microbial activity as compared to aromatized derivatives. [21] Chaudhary A. et al., (2012) synthesized benzocycloheptene amino vinyl bromide derivatives from isomeric mixture of himachalenes through two step synthesis. They evaluated these derivatives for anti-depressant activities which showed piperazine substituted derivative had better activity to be considered as lead moiety accepted for further modifications in yielding more efficacious and potent anti-depressant drugs.[7] Hossini I. et al., (2011) synthesized acyl-ar-himachalene (3,5,5,9-tetramethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-ethanone) and a new acyl-hydroperoxide (1-(8-ethyl-8-hydroperoxy-3,5,5- trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethanone) by carrying out friedal-craft acylation of ar-himachalene, a sesquiterpenic hydrocarbon which was obtained by catalytic dehydrogenation of α-, β- γ-himachalenes.[2]

3. PHARMACOLOGICAL ACTIVITIES OF CEDRUS DEODARA

3.1 Insecticidal Activity

Since cedarwood oil is obtained from natural source, it does not pollute environment and hence it is widely utilised as an alternative for modern pesticides against various insect-pests. Different studies of oil fractions obtained from Cedrus deodara has revealed insecticidal properties against different insects like Callosobruchus analis, Musca domestica, adult Anopheles stephensi, etc.[24] It is also effectively used for dermal problems found in goats, sheep and dogs.[25]

3.2 Molluscicidal Activity

Studies related to various combinations of the essential oils of neem tree and Cedrus deodara along with powder obtained from garlic, ginger’s rhizomes, custard apple seed powder exhibited toxic effect against molluscs.[26]

3.3 Anti-Fungal Activity

The essential oil obtained from Cedrus deodara has proven to be very effectual against various fungus species viz. Aspergillus niger, Alternaria alternata, Alternaria porri, Aspergillus niger and many more. It provided a broad fungitoxic spectrum which acts by inhibition of mycelial growth in fungi.[27,28]

3.4 Anti-Inflammatory

Ancient ayurvedic studies and practices as well as current on-going research has revealed that the mast cell stabilising activity and leukotriene synthesis inhibition of cedarwood oil has contributed to its anti-inflammatory activities.[29] The application of essential oil of Cedrus deodara decreased the neutrophils number at inflammation site and reduced inflammatory mediators.[29,30]

3.5 Other Activities

Cedrus deodara has exhibited spasmolytic activity with 50% ethanolic extract of wood and himachalol. [31] Increased doses of alcoholic extracts of Cedrus deodara revealed anti-convulsant activity and anxiolytic properties.[32] Also, it has shown anti-bacterial action against Staphylococcus aureus, Bacillus cereus, Escherchia coli, etc. Numerous other activities are present which reveals the medicinal value of Cedrus species.[33]

4. CONCLUSIONS

Cedrus deodara species have remained a keen subject of interest for researchers due to its tremendous medicinal benefits in pharmaceutical industry. The use of different parts of this species for pharmacological purpose and in curing various ailments has provided a valid proof of its tremendous worth in pharmaceutical field. Yet the works reported regarding this species are still on going around the world to discover other essential utilization of himachalenes as basic novel moiety from natural source for various organic synthesis. Exploration of green approach for simultaneous reactions to be carried out using Cedrus species is also an area of interest. Advancements are leading to serve the purpose of consistency in research and development.

REFERENCE:

6

1. Rao JM, Srinivas PV, Yadav JS, Raghavan KV. Pharmaceutical and herbal composition comprising wikstromol and/or matairesinal, its use as hepatoprotectant and process for their isolation from Cedrus deodara. World Intellectual Property Organisation. 2002. WO02/34277 A.;1.

2. Hossini I, Harrad MA, Ait Ali M, El Firdoussi L, Karim A, Valerga P, Puerta MC. Friedel-Craft acylation of ar-himachalene: Synthesis of acyl-ar-himachalene and a new acyl-hydroperoxide. Molecules. 2011 Jul;16(7):5886-95.

3. Shashi B, Jaswant S, Madhusudana RJ, Kumar SA, Nabi QG. A novel lignan composition from Cedrus deodara induces apoptosis and early nitric oxide generation in human leukemia Molt-4 and HL-60 cells. Nitric oxide. 2006 Feb 1;14(1):72-88.

4. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN. Studies on the anti-inflammatory and analgesic activity of Cedrus deodara (Roxb.) Loud. wood oil. Journal of Ethnopharmacology. 1999 Apr 1;65(1):21-7.

5. Chaudhary A, Kaur P, Singh B, Pathania V. Chemical composition of hydrodistilled and solvent volatiles extracted from woodchips of Himalayan Cedrus: Cedrus deodara (Roxb.) Loud. Natural product communications. 2009 Sep;4(9):1934578X0900400920.

6. Pandey RC, Dev S. Studies in sesquiterpenes—XXX: Synthesis of ar-himachalene and himachalanes. Tetrahedron. 1968 Jan 1;24(10):3829-39.

7. Chaudhary A, Das P, Mishra A, Kaur P, Singh B, Goel RK. Naturally occurring himachalenes to benzocycloheptene amino vinyl bromide derivatives: as antidepressant molecules. Molecular diversity. 2012 May 1;16(2):357-66.

8. Daoubi M, Hernández-Galán R, Benharref A, Collado IG. Screening study of lead compounds for natural product-based fungicides: antifungal activity and biotransformation of 6α, 7α-Dihydroxy-β-himachalene by Botrytis cinerea. Journal of agricultural and food chemistry. 2005 Aug 24;53(17):6673-7.

9. Joseph TC, Dev S. Structure of himachalenes. Tetrahedron Letters. 1961 Jan 1;2(6):216-22.10. Tanwar G, Mazumder AG, Bhardwaj V, Kumari S, Bharti R, Singh D, Das P, Purohit R. Target identification, screening and

in vivo evaluation of pyrrolone-fused benzosuberene compounds against human epilepsy using Zebrafish model of pentylenetetrazol-induced seizures. Scientific reports. 2019 May 27;9(1):1-2.

11. Lynch KR, MacDonald TL, inventors; University of Virginia Licensing, Ventures Group, assignee. Benzocycloheptyl analogs having sphingosine 1-phosphate receptor activity. United States patent US 7,915,315. 2011 Mar 29.

12. Hattori K, Tanaka A, inventors; Fujisawa Pharmaceutical Co Ltd, assignee. Benzocycloheptene derivatives. United States patent US 6,384,072. 2002 May 7.

13. Bohlmann R, Kroll J, Kuenzer H, Hegele-Hartung C, Lessl M, Lichtner R, Nishino Y, inventors; Bayer Pharma AG, assignee. Benzocycloheptenes, process for their production, pharmaceutical preparations that contain that latter as well as their use for the production of pharmaceutical agents. United States patent US 7,145,015. 2006 Dec 5.

14. Zaratin PF, Petrone G, Sbacchi M, Garnier M, Fossati C, Petrillo P, Ronzoni S, Giardina GA, Scheideler MA. Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (–)-cis-1-methyl-7-[[4-(2, 6-dichlorophenyl) piperidin-1-yl] methyl]-6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). Journal of Pharmacology and Experimental Therapeutics. 2004 Feb 1;308(2):454-61.

15. Kumar S, Kumar A, Kumar R. Himalayan (Himachal region) cedar wood (Cedrus deodara: Pinaceae) essential oil, its processing, ingredients and uses: A review. Journal of Pharmacognosy and Phytochemistry. 2019;8(1):2228-38.

16. Gupta S, Walia A, Malan R. Phytochemistry and pharmacology of cedrus deodera: an overview. International Journal of Pharmaceutical Sciences and Research. 2011 Aug 1;2(8):2010.

17. Nigam MC, Ateeque A, Misra LN. Composition of the essential oil of Cedrus deodara. Indian perfumer. 1990;34(4):278-81.18. Coppen JJ. Flavours and fragrances of plant origin. FAO; 1995.19. Shashi B, Jaswant S, Madhusudana RJ, Kumar SA, Nabi QG. A novel lignan composition from Cedrus deodara induces

apoptosis and early nitric oxide generation in human leukemia Molt-4 and HL-60 cells. Nitric oxide. 2006 Feb 1;14(1):72-88.

20. Oukhrib A, Zaki M, Benharref A. The chemistry of the himachalenes and atlantones from Cedrus. ARKIVOC: Online Journal of Organic Chemistry. 2018 Jan 1;2018.

21. Chaudhary A, Sood S, Das P, Kaur P, Mahajan I, Gulati A, Singh B. Synthesis of novel antimicrobial aryl himachalene derivatives from naturally occurring himachalenes. EXCLI journal. 2014;13:1216.

22. Shashi B, Jaswant S, Madhusudana RJ, Kumar SA, Nabi QG. A novel lignan composition from Cedrus deodara induces apoptosis and early nitric oxide generation in human leukemia Molt-4 and HL-60 cells. Nitric oxide. 2006 Feb 1;14(1):72-88.

23. Chopra RN, Nayar SL, Chopra IC. Glossary of Indian Medicinal Plants. New Delhi: Council of Scientific and Industrial Research.

24. Singh D, Agarwal SK. Himachalol andβ-himachalene: Insecticidal principles of himalayan cedarwood oil. Journal of Chemical Ecology. 1988 Apr 1;14(4):1145-51.

25. Sharma DK, Saxena VK, Sanil NK, Singh N. Evaluation of oil of Cedrus deodara and benzyl benzoate in sarcoptic mange in sheep. Small Ruminant Research. 1997 Dec 1;26(1-2):81-5.

26. Singh K, Singh DK. Molluscicidal activity of plant derived molluscicides. Journal of herbs, spices & medicinal plants. 1998 Jan 8;5(2):67-72.

27. Dikshit A, Dubey NK, Tripathi NN, Dixit SN. Cedrus oil—a promising storage fungitoxicant. Journal of stored products research. 1983 Oct 1;19(4):159-62.

7

28. Singh J, Tripathi NN. Inhibition of storage fungi of blackgram (Vigna mungo L.) by some essential oils. Flavour and Fragrance Journal. 1999 Jan;14(1):1-4.

29. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN. Membrane stabilizing activity—a possible mechanism of action for the anti-inflammatory activity of Cedrus deodara wood oil. Fitoterapia. 1999 Jun 1;70(3):251-7.

30. Shinde UA, Kulkarni KR, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN. Mast cell stabilizing and lipoxygenase inhibitory activity of Cedrus deodara (Roxb.) Loud. wood oil.

31. Dhayabaran D, Florance J, Nandakumar K, Puratchikody A. Isolation and anxiolytic activity of 3, 4-bis (3, 4-dimethoxyphenyl) furan-2, 5-dione from the ethanolic extract of heart wood of Cedrus deodara. Medicinal Chemistry Research. 2012 Nov 1;21(11):3460-4.

32. Viswanatha GL, Nandakumar K. Anxiolytic and anticonvulsant activity of alcoholic extract of heart wood of Cedrus deodara Roxb in rodents. Asian Journal of Pharmaceutical Research and Health Care. 2009;1(2).

33. Zeng WC, Zhang Z, Gao H, Jia LR, He Q. Chemical composition, antioxidant, and antimicrobial activities of essential oil from pine needle (Cedrus deodara). Journal of food science. 2012 Jul;77(7):C824-9.

8