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Title: Phytomedical studies on the Amazonian traditional medicine "Chuchuguasa" (Maytenus laevis Reissek)
Author: Mouad, Hazar Abdul Razzaq
ISNI:       0000 0004 6062 0359
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
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The importance of natural products and medicinal plants has continued to grow due to their significant role in the search for new drugs or precursors of potent drugs with minimal side effects for the treatment of numerous illnesses. The Amazonian Rainforest represents the most extensive resource of natural diversity remaining on the planet. The unsurpassed knowledge, culture and medicinal practices, created by its indigenous people over thousands of years, have formed rich foundations for ethnobotanical studies about traditional medicinal plants which might be potential sources of biologically active phytochemicals. Regretfully, this may not be so for very much longer, due to the rate of deforestation and the effects of westernisation on these native societies. From the Amazonian basin, Resguardo Monochoa area of Caquetá-Medio in Colombia, a plant locally named "Chuchuguasa" was collected (root and stem bark) by well known Amazonian sabedores from the indigenous Uitoto and Muinane communities who identified the tree as a Maytenus laevis Reissek (Celastraceae). Following a strict collecting methodology, the plant material (the roots in particular) was chosen from the side of the tree that receives the first rays of sun at 5 am. This plant is used in traditional medicine for several purposes mainly in the form of an alcoholic extract (aguardiente). A considerable amount of phytochemical investigation had already been performed on the Maytenus species associated with Chuchuguasa (mainly the stem bark), however, there is little information so far about the chemistry of M. laevis, particularly that involving the root bark. This project aimed to carry out further phytochemical work on the root and stem barks of M. laevis in an attempt to isolate constituents, which may possess biological activities that could be exploited. Twenty compounds were isolated from solvent extracts of the two plant materials of M. laevis, in addition to a polymer which was characterised as trans-1, 4-polyisoprene (Gutta-percha). Six compounds were identified as novel and were given the names 22(β)-hydroxycelastrol, 22(α)-hydroxynetzahualcoyene, 2,22-dihydroxy-3-methoxy-15, 12-dioxo-5, 8-oxa-24, 30-dinor-5, 6-seco-friedelan-1,3,5(10)-trien-6-al (trivial name jujuborreal*), methyl 2, 3, 22α-trihydroxy-24, 25-dinorfriedelan-1,3,5(10),6,8,14-hexaen-29-oate, 15(β)-acetoxyfriedelane-1,3-dione, and (4R, 4aR, 6aR, 7aS, 8aR, 12aR, 12bS, 14aR, 14bS)- 4, 4a, 8a, 11, 11, 12b, 14a-heptamethyl-7-methyleneoctadecahydrobenzo[a]naphtho[2,1-f]azulene-1, 3(2H,14bH)-dione (trivial name 1,3-dioxocorredor-14,26-ene). The remaining fourteen compounds were not novel and composed of nine triterpenoids of friedelane, norfriedelane and aromatic-types including canophyllol, friedelane-1,3-dione, 28-hydroxyfriedelane-1,3-dione, netzahualcoyondiol, netzahualcoyone, pristimerin, celastrol, salaquinone A, regeol A, two steroids (stigmast-4-en-3-one and β-sitosterol), two simple phenolics (p-hydroxybenzaldehyde and 3,4-dihydroxybenzoic acid) and one isocoumarin (± mellein). Nevertheless, 8 of them are reported for the first time from M. laevis and from those other related species that are often referred to as Chuchuguasa. The structures of the new and known compounds were all elucidated by spectroscopic methods. The novel compound, 1,3-dioxocorredor-14,26-ene, was identified with the aid of X-ray crystallography and was shown to be the first of a new skeletal class of triterpenes for which the name corredorane is suggested. A preliminary in vitro cytotoxicity assessment of the crude extracts and most of the isolated compounds was carried out against the cancer cell line A375 (human, malignant melanoma cell line) and the normal cell line Hs27 (human, skin fibroblast cell line) using a resazurin assay. The n-hexane and ethyl acetate extracts of both parts of the plant showed selective activity on the cancer cells, but those of the root barks were the most potent with an EC50 of 2.9 μg/ml. This effect was linked in part to the extracts’ contents of triterpenoids of quinonemethides and nor-friedelanes types. The compounds under the aforementioned classifications were major components of the root bark extracts, but minor in those of the stem bark; hence, this reflected the potency of the effects exerted by these extracts. All the isolated quinonemethides displayed high toxicity to both cell lines, however, netzahualcoyondiol, celastrol, and the new compound 22(β)-hydroxycelastrol exerted selective toxicity to the cancer cells at the lowest tested concentration (3.125 μg/ml) with EC50 values of 3.5, 5.1 and 4.4 μM, respectively. The two nor-friedelanes (salaquinone A and jujuborreal), along with the new aromatic triterpene [methyl 2, 3, 22α-trihydroxy-24,25-dinorfriedelan-1,3,5(10),6,8,14-hexaen-29-oate] also showed selective toxicity to the cancer cells, with salaquinone A being the most potent (EC50 1.4 μM). All the friedelane triterpenoids, isolated mainly from the stem bark, were either not active or weakly active with EC50 >100 μg/ml. These findings provide some scientific support for the traditional use of the plant (root bark) as an anti-tumour therapy in skin cancer and appear to confirm some of the knowledge shared by the Amazonian sabedores. The crude extracts and some of the isolated compounds were also screened in vitro for anti-trypanosomal activity against Trypanosoma brucei brucei (S427) blood stream forms using an Alamar BlueTM microplate assay. Suramin and dimethylsulfoxide (DMSO) were used as positive and solvent controls, respectively. Preliminary screening of the crude extracts showed very potent activity at a concentration of 20 μg/ml, with the exception of the methanol extracts. All the screened quinonemethides, salaquinone A, regeol A and protocatechuic acid (PA) displayed high activity at 20 μM with cell viability values less than 10% of the control value. These compounds were then tested at a lower concentration of 5 μM and they all maintained their efficacies except regeol A and PA. These findings, although preliminary, propose a new potential therapeutic use of M. laevis (the root and stem barks), which could lead to the discovery of potent agents for the treatment of related parasitic diseases that are considered endemic in its habitat, such as Chagas disease (Trypanosoma cruzi Chagas).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available