Rivka Ofir. Medical Research Archives vol 8 issue 7. Medical Research Archives RESEARCH ARTICLE "Desert Chemotypes": The Potential of Desert Plants-Derived Metabolome to Become a Sustainable Resource for Drug Leads Author Rivka Ofir PhD; BGU-iPSC Core Facility Regenerative Medicine & Stem Cell (RMSC) Research Center, Ben Gurion University of the Negev and Dead Sea&Arava Science Center, Israel Email: [email protected] Abstract Plants secondary metabolites that are essential for plant survival in its environment are a useful resource for drug discovery in the area of combination therapy. Desert plants, in particular, have a lot to offer; they experience stress conditions and activation/repression of pathways that lead to biosynthesis of unique compounds. The current knowledge on the effectiveness of combination therapy as compared to single treatment support the use of active plant-derived extracts or fractions composed of several metabolites. A set of metabolites, termed "metabolite signature", within an active fraction, will serve as a guide in the process of desert plants domestication. The combination of modern methods of transcriptome, proteome and metabolome analyses with precision agriculture, will pave the way to produce sustainable plant biomass for pharmaceutical industries. Key words: plant metabolite, combined therapy, Terpenes, Flavonoids, Copyright 2020 KEI Journals. All Rights Reserved Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 2 of 15 1. Many Drugs are Based on Plant– discover new agents that will act instead of, Derived Compounds or in synergy with, accepted chemotherapy Plant metabolites contribute to the chemical treatments 11. Models of neurodegenerative diversity of bioactive compounds and can brain diseases involve screening plant- serve as additional source of leads apart from derived compounds which inhibit man-made compounds. inflammation; these models are based on the Most of the existing or new drugs discovered recent documentation of neurodegeneration- so far are secondary metabolites of plant inflammation relationship in various brain origin which are used as a whole, modified, diseases 12, 13. Active plant compounds may or modeled in resemblance of phytoleads 1. slow the deterioration from Plant-derived natural products serve as a neurodegenerative brain diseases; challenging resource for novel drug leads; the pharmaceutic interventions for treating process involves screening natural chronic neurodegenerative diseases will be compounds and identifying "screening hits" focused on reducing/terminating the followed by preclinical studies in animal inflammatory state 14. models in order for the compound to be considered a "drug lead" 2. The current drug 3. Plant Metabolites as Leads- discovery process using plant extracts relies Phytochemicals (Terpenes, Flavonoids, on bioactivity-guided fractionation, which Saponins, Tannins) has led to the isolation of many important 3.1. Terpene, the largest group of natural drugs like paclitaxel, camptothecin, salicin, compounds; terpenoids, also referred to as quinine, artemisinin, forskolin, galantamine, terpenes, are classified as monoterpenes apomorphine, cannabidiol, capsaicin, (C10), sesquiterpenes (C15), diterpenes (C20), 3-9 noncatecholamine, chloroquine and more . and sesterterpenes (C25). Among the most Although the bioprospecting process in the important terpene-based pharmaceuticals are last few years has led to identifying many the anticancer drug taxol® , the antimalarial plant-derived compounds with drug artimesinin; and more terpenoid-based pharmaceutical value, it is possible that leads for drugs were documented 15. Certain advanced methods and equipment for terpenes like curcumin that showed anti- metabolites analysis will improve and hasten inflammatory, antioxidant, anticancer the discovery of more high-value plant- activities in in vitro models, are considered as derived compounds with pharmacological alternative medicine 16. Interestingly, the activity 10. content of desert plants-derived monoterpenes, oxygenated terpenes and 2. Human Diseases Models Used for sesquiterpenes is dependent on annual Screening Plant-Derived Drugs precipitation 17, 18. Many models of cancer diseases serve as targets for screening plant attributes; tumor 3.2. Flavonoids, belong to the family of cells develop resistance to chemotherapy polyphenolic secondary metabolites; plant quite rapidly, and it is an urgent need to derived flavonoids were investigated mainly Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 3 of 15 against cancer 19-21 and diabetes 22. The around the globe, with emphasis in more flavone skeletal structure and the phenolic detail on research of several plants from the composition have an impact on the Arava and Negev deserts of Israel. antioxidant activity of flavonoids 23-25 and on their anti-cancer activity and anti-diabetic 4.1. Global Arid Zones and Medicinal activity 26, 27. Currently, plant flavonoids are Plants routinely used as additional products by the Studies of desert plants from Mexico pharmaceutics and nutraceutics industries 28. (Jatropha dioica, Flourensia cernua, Turnera diffusa and Eucalyptus camaldulens 3.3. Saponins, are secondary metabolites of is) showed that these plants are rich in glycosidic nature consisting of a triterpene or polyphenolic compounds exhibiting steroid aglycone; they have pharmacological antioxidant activity 36. Plants from the properties related to cancer inhibition and Tunisian desert (Marribium deserti, Rhus hormones stimulation 25, 29, 30. tripartita (Rh. tripartitum),Artemisia herba- alba Asso,Colocynthis vulgaris (L.) Schard. 3.4.Tannins, are a class of complex Ephedra alata Decaisne, Astragalus biomolecules of a polyphenolic nature gombiformis Pomel Calligonum synthesized by a large variety of plants, in comsum Hérit, Nitraria retusa (Forsk) which they are used as antipredator or Asch), are used in traditional medicine; pesticide agents 31. Tannins extracted from extracts of these plants are being used for many vegetables and desert plants like drug discovery 37. Acacia mearnsii, Yellow Dock and other plants, show antioxidant activity, leading to 4.2. Middle Eastern Desert Plant Derived- the development of tannin-based dietary Metabolites supplements 32-35. 4.2.1. Achillea fragrantissima (Forssk) Sch. Bip. (Af). Extract of Af, a desert plant used 4. Desert Plants and Leads for Drugs for many years in traditional medicine in the Screening desert plant-derived Arabia region (Figure 1A), showed anti- extracts/metabolites results in the neuroinflammatory effects in vitro 38. identification of active extracts or pure Achillolide A, a sesquiterpene lactone and metabolites; these may be considered as drug Flavonoid 3,5,4′-trihydroxy-6,7,3′- leads. Extracts contain several compounds trimethoxyflavone (TTF) that were isolated and have the advantage of potential from Af, downregulated microglial activation 39 combined treatment and synergism between , prevented hydrogen peroxide (H2O2)- the activities of the compounds. When an induced astrocytes death 40, protected active pure metabolite is identified, its neuroblastoma cells from glutamate toxicity mechanism of action can be studied more 41 and interfered with Aβ-induced processes precisely. in Neuro2a (N2a) cells and protected them This review covers research on plant-derived from its toxicity 42. compounds from various desert/arid areas Copyright 2020 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Rivka Ofir. Medical Research Archives vol 8 issue 7. July 2020 Page 4 of 15 4.2.2. Asteriscus graveolens (A. graveolens). type 2 (HSV-2) and respiratory syncytial Extract of A. graveolens, an endemic Middle virus type B (RSV-B) 50; the active Eastern medicinal plant, located in extreme compound, isolated using bio-guided assays, desert environments (Figure 1B), is cytotoxic was identified as guggulsterone 51. A broad- to cancer cells but not to non-cancerous cells; spectrum of activity against both Gram- its activity was accompanied by a positive and Gram-negative bacteria, in concentration- and time-dependent addition to fungi, was identified in C. appearance of apoptosis, and high levels of gileadensis 52, 53. Reactive Oxygen Species (ROS) 43. Combining a plant fraction rich in 4.2.5. Artemisia judaica L.( A. sesquiterpene lactone asteriscunolide Judaica). The essential oil of A. judaica , a isomers with several toxic chemotherapeutic medicinal plant growing in the desert areas of drugs, enabled to reduce the concentration of Jordan (Figure 1E), has therapeutic potential these toxic drugs and still achieve effective for the treatment of disseminated candidiasis, treatment in vitro 44. A. graveolens in vitro, it inhibits Nitric Oxide (NO) metabolites: cis ‐chrysanthenyl acetate, production elicited by LPS in macrophages, myrtenyl acetate, and kessane, showed highlighting its potential anti-inflammatory antimicrobial activities 45. activity 50. The main metabolic content of A. judaica from the desert of Israel and from the 4.2.3. Pulicaria incisa (Lam.) DC (Pi). desert of Sinai are artemisyl-oil type Infusion prepared from Pi, a desert plant (characterized by the existence of artemisyl- containing high amounts of unsaturated fatty skeleton-type compounds in the essential oil) acids and has been used for many years in and piperitone-oil type (characterized by the traditional medicine (Figure 1C), showed