Study on chemical constituents and biological activities of two species markhamia stipulata var. canaense v.s. dang and stereospermum binhchauensis v.s. dang of bignoniaceae

Cytotoxic activity on the cancer cell line of some compounds isolated

from M. stipulata var. canaense V.S. Dang with a concentration of 100 µg/mL,

showed that the compounds MS02, MS05, MS13, MS16 have cyctotoxic activity.

Especially, compound MS02 has high cytotoxic activity on cancer cell lines

MCF-7, HeLa, Hep G2, NCI-H460, Jurkat with IC50, respectively: 16.51 ± 0.22,

29.55 ± 1.64; 25.26 ± 1.06; 24.21 ± 0.38; 14.72 ± 0.38 (µg/mL). From the results

of the cytotoxic activity test of cycloartane compounds from M. stipulata var.

canaense V.S. Dang has suggested some initial comments on the relationship

between chemical structure and cytotoxic activity: Among the isolated

cycloartane compounds (MS01-MS05), the MS02 exhibits activity strong on 5

cancer cell lines, Which has a hydroxy group at C-7. While MS03 has weak

activity, there is hydroxy group on C-22 instead of C-7, MS05 is active but lower

than MS02 when there is both hydroxy group at C-7 and hydroxy group at C-24

and C-25, and MS01 is also less active than MS02 without hydroxy group at the

C-7 position and on the branch line (HeLa, 34.74 µg/mL) [109]. This showed that

triterpenes compounds with cycloart-24-en-28-oic acid framework with hydroxy

groups on the branch wire reduced the inhibitory activity of cancer cells, while the

hydroxy group at C-7 enhanced active.

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O CHI MINH, 2020 This thesis was completed at: Graduate University Science and Technology - Vietnam Academy of Science and Technology Adviser 1: Assoc. Prof. Dr. Mai Dinh Tri Adviser 2: Assoc. Prof. Dr. Tran Cong Luan 1st Reviewer: 2nd Reviewer: 3rd Reviewer: The thesis will be defended at Graduate University of Science and Technology - Vietnam Academy of Science and Technology At hour.day. month .2020 Thesis can be found in - The library of the Graduate University of Science and Technology, Vietnam Academy of Science and Technology. - The National library of Viet Nam 1 INTRODUCTION 1. The urgency of the thesis Vietnam is a country located in the tropical monsoon region with an extremely rich and diverse plant source, including many valuable medicinal plants that our ancestors have used for a long time to treat a variety of diseases that show the importance of medicinal plant resources. In recent years, according to the socio-economic development, the demand for health care has been constantly increasing, scientists are going on looking for active substances with curative properties of natural origin. Many natural compounds have been isolated and widely applied. They are used to produce medicines, plant protection drugs, as raw materials for food, pharmaceutical and cosmetic industries by safety, few side effects, environmentally friendly. Therefore, the search and study of the chemical composition and biological activity of medicinal plants in order to detect attractive active compounds from herbs is a very necessary issue. The Markhamia and the Stereospermum genus of Bignoniaceae famila are distributed in tropical and subtropical regions of Africa, China and Southeast Asian countries such as Vietnam, Laos, Cambodia, and Thailand. The research results of some species in these 2 genus have discovered many interesting biological properties such as hypoglycemia, antibacterial, anti-inflammatory, antioxidant, and analgesic ... Markhamia stipulata var. canaense V.S. Dang and Stereospermum binhchauensis V. S. Dang are two newly discovered species in 2015. Up to now, there have not been any studies on the chemical composition and biological activity of the two species. So based on that science, we chose the topic "Study on chemical constituents and biological activities of two species Markhamia stipulata var. canaenses V.S. Dang and Stereospermum binhchaunesis V.S. Dang of Bignoniaceae” contribute to the scientific basis for the study and application of these two species in the future. 2 2. The objectives of the thesis Study on chemical constituents of two species Markhamia stipulata var. canaense V.S. Dang and Stereospermum binhchaunesis V.S. Dang. Evaluation of biological activities of isolated compounds to find potential compounds. 3. The main contents of the thesis 1. Isolation of compounds from the leaves of Markhamia stipulata var. canaense V.S. Dang and Stereospermum binhchaunesis V.S. Dang. 2. Determination of chemical structures of the isolated compounds. 3. Evaluation on the cytotoxic activity and -glucosidase inhibiting of the isolated compounds. CHƯƠNG 1: OVERVIEW The overview of internal and international researches related to our study. CHƯƠNG 2: METHODS 2.1. Plant materials The leaves of M. stipulata var. canaense V.S. Dang were collected in Ca Na, Thuan Nam District, Ninh Thuan Province, Vietnam, in June 2016, and identified by Dr. Van Son Dang, Institute of Tropical Biology. The leaves of S. binhchauensis V.S. Dang were collected in Binh Chau, Phuoc Buu District, Ba Ria Province, Vietnam, in June 2016, and identified by Dr. Van Son Dang, Institute of Tropical Biology. 2.2. Chemicals This section presents solvents and chemicals used in experiments 2.3. Isolation Methods This section presents methods for isolating pure compounds: thin-layer chromatography (TLC) and column chromatography 3 2.4. Methods for determination of chemical struture of compounds General methods to determine the chemical structure of the compound are a combination of physical parameters and modern spectroscopic methods including Mass spectrometry and high-resolution mass spectrometry (HR-ESI- MS), magnetic resonance spectrum (1D, 2D-NMR), ultraviolet-visible (UV), infrared (IR) and optical rotation ([]D). 2.5. Methods for evaluation of biological activities This section presents chemicals and equipment for the biological activity test method. CHƯƠNG 3: EXPERIMENTALS 3.1. Extraction This section presents the process of making methanol extracts and partitioned extract from M. stipulata var. canaense V.S. Dang and S. binhchauensis V.S. Dang. 3.2. Isolation This session presents in detail the isolated procedure of 28 compounds from M. stipulata var. canaense V.S. Dang and S. binhchauensis V.S. Dang as shown in schemes 4.1, 4.2, 4.3, 4.4. 4 Schemes 4.1. Isolation compounds from extract MSH 5 Schemes 4.2. Isolation compounds from extract MSE 6 Schemes 4.3. Isolation compounds from extract SBH 7 Schemes 4.4. Isolation compounds from extract SBE 8 3.3. Physical properties and spectroscopic data of the isolated compounds from M. stipulata var. canaense V.S. Dang This section presents physical properties and spectroscopic data of 17 compounds from M. stipulata var. canaense V.S. Dang 3.4. Physical properties and spectroscopic data of the isolated compounds from S. binhchauensis V.S. Dang This section presents physical properties and spectroscopic data of 11 compounds from S. binhchauensis V.S. Dang 3.5. Biological activities of isolated compounds This section presents methods for testing cytotoxic and α-glucosidase inhibiting activity. CHƯƠNG 4. RESULTS AND DISCUSSIONS 4.1. Isolated compounds From n-hexane extract (MSH) and EtOAc extract (MSE) of leave M. stipulata var. canaense V.S. Dang isolated 17 compounds. From n-hexane extract (SBH) and EtOAc extract (SBE) of leave S. binhchauensis V.S. Dang isolated 11 compounds. 4.2. Determination the chemical structure of isolated compounds This section presents results of spectral analysis and determines the structure of 28 compounds isolated from Markhamia stipulata V.S. Dang and Stereospermum binhchaunesis V.S. Dang species. MS01 : Mollic acid MS02: Markhacanasin A CC silica gel CHCl3-MeOH, thu được 4 phân đoạn CC silica gel n- hexane-EtOAc- MeOH, thu được 6 phân đoạn -CC silica gel CHCl3-MeOH 20/1 9 MS03: Markhacanasin B MS04: Markhacanasin C MS05: Epi- Markhacanasin C MS06: Acid Oleanoic MS07: Acid Ursolic MS08: Acid 6β,19α-dihydroxyursolic 10 MS09: Apigenin MS10: Luteolin MS11: 4’,7-dimethylapigenin MS12: Naringenin MS13: Apigenin 7-O-β-D- glucopyranoside MS14: Luteolin 7-O-β-D- glucopyranoside MS15: Tectoquinone MS16: 1-hexadecanoyl-sn-glycerol 11 MS17: Markhasphingolipid A SB01: Chrysin 5,7-dimethyl ehter SB02: Kaempferol SB03: Luteolin SB04: Luteolin 7-O-β-D- glucopyranoside SB05: Naringenin 7-O-β-D- glucopyranoside SB06: Eriodictyol 7-O-β-D- glucopyranoside 12 SB07: Specioside SB08: Lupeol SB09: Acid oleanoic SB10: Bergapten SB11: ,7-dihyroxychromone Below details the method for determining the structure of the new compounds MS02. MS02 was obtained as a white amorphous powder. The molecular formula was established as C30H48O5 by HR-ESI-MS data ([M+NH4] + m/z 506.3826, calcd. 506.3845). 13 The 13 C-NMR and DEPT spectrum, showed MS02 has thirty carbons including: one carbonyl carbon, two olefinic carbons, three oxygenated methine carbons, five quaternary carbons, four methine carbons, nine methylene carbons, six methyl carbons. The presence of six methyl groups, one methyl carbon at δC 9.0 (C-29), two olefinic carbons at δC 131.7 (C-25) and 126.2 (C-24) and one carbonyl carbon 180.5 (C-28) which indicated a cycloart-24-en-28-oic acid as a skeleton[58,59]. Thus MS02 was a cycloartane-type triterpenoid bearing three hydroxyl groups. The 1 H-NMR data of MS02 revealed a pair of doublets of an AX system at δH 0.47 (d, J = 4.5 Hz, H-19a), 0.83 (d, J = 4.5 Hz, H-19b) which characteristic of typical resonances of a cyclopropyl methylene group in a cycloartane-type framework; one olefinic proton at δH 5.12 (t, J = 7.0 Hz, H-24); three oxygenated methine protons at δH 3.58 (brs, H-1), 4.54 (d, J = 5.0 & 12.0 Hz, H-3) and 3.59 (m, H-7); five tertiary methyl groups at δH 1.03-1.69 and one secondary methyl group δH 0.94 (d, J = 6.0 Hz, H-21). The HMBC spectrum (Fig. 4.2) designated correlations between oxygenated methine proton at δH 3.58 (H-1) and carbons at δC 71.2 (C-3) and 37.4 (C-5); between proton at δH 4.54 (H-3) and carbons at δC 55.5 (C-4) and 37.4 (C-5); between proton at δH 3.59 (H-7) and carbons at δC 37.4 (C-5); so, three hydroxyl group attached to C-1, C-3 and C-7, respectively. Moreover, these connectivities were also confirmed by correlations observed in the COSY spectrum between H-1 (δH 3.58) and H-2a (δH 1.82), H-2b (δH 1.88) and H-3 (δH 4.54); between H-5 (δH 2.78) and H-6a (δH 1.17), H-6b (δH 1.45) and H-7 (δH 3.59) and H-8 (δH 1.63). In addition, the NOESY spectral data of MS02 (Fig. 4.2) evinced the cyclopropyl methylene protons (H-19) which β-type were close in space to proton (H-1); the 14 methine proton (H-5) which α-type was close in space to protons (H-3, H-7). Thus, three hydroxyl groups of carbons C-1, C-3 and C-7 were α, β and β-type, respectively. Based on data of IR, UV, HR-ESI-MS, 1D, 2D-NMR and compared with previous published data[58,59]; the structure of MS02 was identified as 1α,3β,7β-trihydroxycycloart-24-en-28-oic acid, and named Markhacanasin A. Fig 4.2: The selected HMBC, COSY and NOESY correlations of 1 Fig 4.3: Chemical structures of MS02 4.3. Biological activity of compounds 4.3.1. Cytotoxic activity Results of cytotoxic activity of fraction from leaves of M. stipulata var. canaense V.S. Dang are presented in table 4.2 15 Table 4.2. The cytotoxic percentage (%) of fractions from leaves of M.stipulata var. canaense V.S. Dang at concentration of 100 µg/mL. No. Sample Cell line MCF-7 HeLa Hep G2 1 MSH 72.11 ± 1.96 52.60 ± 1.20 49.64 ± 2.27 2 MSH.I 19.95 ± 4.26 0.78 ± 4.78 2.00 ± 0.49 3 MSH.II 55,81 ± 2.16 35.49 ± 1.86 39.34 ± 1.73 4 MSH.III 86.84 ± 2.78 95.03 ± 0.79 92.71 ± 0.99 5 MSH.IV 95.83 ± 0.64 95.59 ± 1.62 90.91 ± 1.13 6 MSH.V 79.00 ± 0.06 92.75 ± 1.83 61.89 ± 2.13 7 MSE 28.98±4.00 6.72 ± 2.99 13.57 ± 6.22 8 MSE.I 35.57 ± 1.79 13.61 ± 2.48 23.65 ± 4.96 9 MSE.II 60.29 ± 1.94 37.48 ± 3.52 46.13 ± 1.78 10 MSE.III 41.36 ± 4.16 6.08 ± 2.21 12.50 ± 3.24 11 MSE.IV 21.67 ± 4.74 1.92 ± 1.01 -9.57 ± 4.30 12 MSE.V 5.98 ± 6.27 -7.33 ± 1.26 -7.88 ± 5.41 13 Camptothecin 51.85 ± 1.32 65.08 ± 2.59 51.85 ± 0.32 Results showed that the fraction MSH.IV, which had toxic activity on 3 cancer cell lines MCF-7, HeLa, Hep G2, were at the highest concentration of 100 µg / mL with the cytotoxic percentage. 95.83 ± 0.64%, 95.59 ± 1.62%, 90.91 ± 1.13% Results of cytotoxic activity of fraction from leaves of S.binhchauesis V.S. Dang are presented in table 4.3 16 Table 4.3. The cytotoxic percentage (%) of fractions from leaves of S. binhchauesis V.S. Dang at concentration of 100 µg/mL. No. Sample Cell line MCF-7 HeLa Hep G2 1 SBH.I 12.92 ± 4.62 10.77 ± 0.45 0.71 ± 4.98 2 SBH.II 34.48 ± 3.22 12.91 ± 2.46 17.63 ± 5.64 3 SBH.III 44.41 ± 0.85 19.64 ± 0.94 20.14 ± 4.48 4 SBH.IV 41.94 ± 3.19 24.30 ± 1.19 17.37 ± 4.05 5 SBH.V 29.12 ± 3.15 18.83 ± 2.87 -3.02 ± 3.88 6 SBE.I 68.51 ± 1.71 56.31 ± 3.52 33.37 ± 3.39 7 SBE.II 60.56 ± 1.07 83.26 ± 5.56 53.79 ± 1.20 8 SBE.III 44.09 ± 1.47 44.57 ± 3.83 44.07 ± 0.61 9 SBE.IV 32.55 ± 5.50 35.89 ± 1.89 14,72 ± 8.33 10 SBE.V 1.31 ± 6.09 -4.97 ± 6.57 -12.43 ± 2.03 13 Camptothecin* 51.85 ± 1.32 65.08 ± 2.59 51.85 ± 0.32 *concentration at 0.01 µg/mL with MCF-7, 0.07 µg/mL with HepG2, and 1.00 µg/mL with HeLa Results showed that the fraction SBE.II, which had toxic activity on 3 cancer cell lines MCF-7, HeLa, Hep G2, were at the highest concentration of 100 µg / mL with the cytotoxic percentage 60.56 ± 1.07%, 83.26 ± 5.56%, 53.79 ± 1.20%. Results of cytotoxic activity of compound are presented in table 4.4 and table 4.5. 17 Table 4.4: The cytotoxic percentage (%) of compounds at concentration of 100 µg / mL. No. Sample Cell line MCF-7 HeLa Hep G2 NCI-H460 Jurkat 1 MS02* 92.72 ± 0.11 85.92 ± 3.99 91.25 ± 1.91 94.52 ± 1.67 91.84 ± 1.21 2 MS03 29.58 ± 3.06 6.66 ± 2.08 10.31 ± 1.59 -1.10 ± 3.13 21.54±3.78 3 MS04 5.06 ± 2.03 - - - - 4 MS05 72.16±0.34 - - - - 5 MS07 27.67 ± 1.57 86.36±3.69 29.50 ± 1.84 - - 6 MS08 43.38 ± 2.11 26.19 ± 1.25 5.57 ± 1.02 - - 7 MS10 71.39 ± 0.09 - 71.20 ± 2.46 - - 8 MS13 77.41 ± 0.82 - - - - 9 MS14 5.06 ± 2.03 - - - - 10 MS16 75.08 ± 2.81 63.72 ± 1.74 66.76 ± 1.68 - - 11 MS17 19.69 ± 3.18 12.76 ± 2.36 -4.43 ± 3.21 - - - Not test * Concentration at 50 µg/mL The results showed that the compounds MS03, MS04, MS08, MS17 do not show cytotoxic activity at concentrations of 100 µg /ml. Compounds MS05, MS07 show only cytotoxic activity on 1 cancer cell line. Compounds MS02 and MS16 exhibit high cytotoxic activity on cancer cell lines MCF-7, HeLa, Hep G2. Especially, MS02 showed high activity on 5 cell lines at a concentration of 50 µg/mL. Table 4.5: IC50 of compounds No. Sample Cell line (IC50, µg/mL) MCF-7 HeLa Hep G2 NCI-H460 Jurkat 1 MS02 16.51 ± 29.55 ± 25.26 ± 24.21 ± 14.72 ± 18 0.22 1.64 1.06 0.38 0.38 2 MS05 53.38 ± 0.56 - - - - 3 MS13 61.88 ± 0.90 - - - - 4 MS16 48.51 ± 1.78 63.30 ± 0.27 57.94 ± 4.82 - - 5 Camptothecin 0.005 ± 0.001 0.089 ± 0.088 0.079 ± 0.023 0.003 ± 0.000 0.005 ± 0.001 The results showed that MS02 showed good inhibition of cancer cell lines with IC50 values from 14 -28 µg/mL. 4.3.2. Inhibiting activity of α-glucosidase enzyme Results of α-glucosidase inhibiting activity of fraction from leaves of M.stipulata var. canaense V. S. Dang are presented in table 4.6 Table 4.6: Results of α-glucosidase inhibiting activity of fraction from leaves of M.stipulata var. canaense V. S. Dang No. Sample IC50 (µg/mL) 1 MSHI 527.530 2 MSHII - 3 MSHIII 141.785 4 MSHIV 145.908 5 MSHV - 6 MSEI - 7 MSEII 71.436 8 MSEIII 51.339 9 MSEIV 93.333 10 MSEV 70.909 19 Results of Inhibiting activity of α-glucosidase enzyme of compounds from leaves of M.stipulata var. canaense V. S. Dang are presented in table 4.7. Table 4.7: Results of α-glucosidase inhibiting activity of compounds No. Sample IC50 (µg/mL) 1 MS09 - 2 MS10 82.862 3 MS13 103.763 4 MS14 159.411 5 Acarbose 134.125 The results showed that MS10, MS13, MS14 showed α-glucosidase inhibiting activity, in which MS10 compound has IC50 quite good with IC50 = 82,862 µg / ml. 4.4. General comment The chemical composition of the M. stipulata var. canaense V.S. Dang is mainly triterpenoid and flavonoid. The cycloartane-based triterpen was found on M. lutea. However, the cycloartane of M. stipulata var. canaense V.S. Dang is somewhat aglycon cycloart-24-en triterpen (MS01 - MS05), while in Markhamia lutea species is cycloart -23-en and cycloart-25-en. Beside, hydroxy group mounted at C-7 (MS02, MS04, MS05) have brought about a new structural. In addition, this is the first time discovered in the genus Markhamia glycolipid group in the form of derivatives of glycerol (MS16) and phytosphingolipid (MS17). The chemical composition of the Stereospermum binhchaunesis V.S. Dang is coumarin, iridoid, triterpenoid, and flavonoid. This is the first time to detect flavonoid compounds (SB01, SB02, SB03, SB04) and flavanoids (SB05, SB06 ), while other species S. acuminatissimum, S. kunthianum, S. personnatum, 20 S. suaveolens, and S. zenkeri, quinone is very common, bringing about new chemical composition in Stereospermum. Cytotoxic activity on the cancer cell line of some compounds isolated from M. stipulata var. canaense V.S. Dang with a concentration of 100 µg/mL, showed that the compounds MS02, MS05, MS13, MS16 have cyctotoxic activity. Especially, compound MS02 has high cytotoxic activity on cancer cell lines MCF-7, HeLa, Hep G2, NCI-H460, Jurkat with IC50, respectively: 16.51 ± 0.22, 29.55 ± 1.64; 25.26 ± 1.06; 24.21 ± 0.38; 14.72 ± 0.38 (µg/mL). From the results of the cytotoxic activity test of cycloartane compounds from M. stipulata var. canaense V.S. Dang has suggested some initial comments on the relationship between chemical structure and cytotoxic activity: Among the isolated cycloartane compounds (MS01-MS05), the MS02 exhibits activity strong on 5 cancer cell lines, Which has a hydroxy group at C-7. While MS03 has weak activity, there is hydroxy group on C-22 instead of C-7, MS05 is active but lower than MS02 when there is both hydroxy group at C-7 and hydroxy group at C-24 and C-25, and MS01 is also less active than MS02 without hydroxy group at the C-7 position and on the branch line (HeLa, 34.74 µg/mL) [109]. This showed that triterpenes compounds with cycloart-24-en-28-oic acid framework with hydroxy groups on the branch wire reduced the inhibitory activity of cancer cells, while the hydroxy group at C-7 enhanced active. Compounds MS10, MS13, and MS14 exhibited moderate α-glucosidase inhibiting activity (IC50 values from 82.862 µg/mL to 159.411 µg/mL). This again shows that flavonoid compounds often have strong α-glucosidase inhibiting activity, consistent with studies published in the world [110, 111,112]. 21 CONCLUSIONS AND RECOMMENDATIONS Conclusions - By chromatography and modern spectroscopic methods, 28 compounds were isolated and indentified from two species of Ca Na (M. stipulata var canaense V.S. Dang) and Binh Chau (Stereospermum binhchaunesis V.S. Dang): + From the leaves of M. stipulata var canaense V.S. Dang in Ninh Thuan were isolated and indentified 17 compounds. Including 5 new and 12 known compounds:  5 new compounds: 1α,3β,7β-trihydroxycycloart-24-en-28-oic acid (markhacanasin A, MS02), 1α,3β,22-trihydroxycycloart-24-en-28-oic acid (markhacanasin B, MS03), 1α,3β,7β,24(S),25-pentahydroxycycloartane-28-oic acid (markhacanasin C, MS04), 1α,3β,7β,24(R),25-pentahydroxycycloartane-28-oic acid (24-epi markhacanasin C, MS05), 1-O-β-D-glucopyranosyl-(2S,3S,4R,10Z)-2-[(2’R)-2’- hydroxytetracosanoylamino]-octadec-10-en-1,3,4-triol (markhasphingolipid A, MS17).  12 known compounds: acid mollic (MS01), acid oleanolic (MS06), acid ursolic (MS07), acid 6β,19α-dihydroxyursolic (MS08), apigenin (MS09), luteolin (MS10), 4’,7-dimethylapigenin (MS11), naringenin (MS12), apigenin 7-O-β-D- glucopyranoside (MS13), luteolin 7-O-β-D-glucopyranoside (MS14), tectoquinone (MS15), 2,3-dihydroxypropyl palmitate (MS16). + From the leaves of Stereospermum binhchaunesis V.S. Dang in Ba Ria-Vung Tau were isolated and indentified 11 compounds, including: chrysin 5,7-dimethyl ether (SB01), kaempferol (SB02), luteolin (SB03), luteolin 7-O-β-D- glucopyranoside (SB04), naringenin 7-O-β-D-glucopyranoside (SB05), eriodictyol 22 7-O-β-D-glucopyranoside (SB06), lupeol (SB08), acid oleanoic (SB09), bergapten (SB10), 5,7-dihyroxychoromone (SB11), specioside (SB07). - Tested cytotoxic activity on 11 compounds. The results show that: + Compound 24-epi markhacanasin C (MS05) and apienin 7-O-β-D- glucopyranoside (MS13) has cytotoxic activity on breast cancer line (MCF-7) with IC50, respectively: 53.38 ± 0.56; 61.88 ± 0.90 (µg/mL). + Compound 2,3-dihydroxypropyl palmitate (MS16) has cytotoxic activity on 3 cell lines of breast cancer (MCF-7), cervical cancer (HeLa), liver cancer (Hep G2) with IC50, respectively: 48.51 ± 1.78; 63.30 ± 0.27; 57.94 ± 4.82 (µg/mL). + The new compound Markhacanasin A (MS02) has cytotoxic activity on all 5 cell lines of breast cancer (MCF-7), cervical cancer (HeLa), liver cancer (Hep G2), cancer lung (NCI H460), leukemia (Jurkat), with IC50, respectively: 16.51 ± 0.22; 29.55 ± 1.64; 25.26 ± 1.06; 24.21 ± 0.38; 14.72 ± 0.38 (µg/mL). - Tested on α-glucosidase inhibiting activity on 4 compounds MS09, MS10, MS13, MS14. The results showed that luteolin (MS10), apigenin 7-O-β-D- glucopyranoside (MS13), and luteolin 7-O-β-D-glucopyranoside (MS14) have α- glucosidase inhibiting activity with IC50, respectively: 82.862; 103.763; 159.411 (µg/mL). Recommendations Continuing study the chemical composition of other extraction and other parts of M. stipulata var. canaense V.S. Dang and Stereopermum binhchaunesis V.S. Dang to search for compounds that inhibit cancer cell lines and inhibit enzyme α-glucosidase. Testing some other biological activities such as inhibiting the activity of enzyme xanthine oxidase, tryptophan hydroxylase, ... 23 NEW FINDINGS OF THE THESIS 1. From the leaves of Markhamia stipulata var. canaense V.S. Dang has isolated and determined the structure of 17 compounds, including 5 new compounds: Markhacanasin A, Markhacanasin B, Markhacanasin C, epi-Markhacanasin C and Markhasphingolipid A. For the first time discovered in the genus Markhamia there is a cycloartane triterpenoid with aglycon part cycloart-24-en triterpen while in Markhamia lutea species cycloart -23-en and cycloart-25-en. It was first discovered in the genus Markhamia that contains glycolipid compounds in the form of glycerol derivatives and phytosphingolipid. 2. From the leaves of Stereospermum binhchaunesis V.S. Dang has isolated and determined the structure of 11 compounds, of which 10 were first isolated from Stereospermum. For the first time discovered in the genus Stereospermum has group of flavonoid compounds. 3. Evaluated cytotoxic activity of 11 compounds. The results showed that there are 4 compounds with cytotoxic activity: Markhacanasin A, 24-epi markhacanasin C, apienin 7-O-β-D-glucopyranoside, 2,3-dihydroxypropyl palmitate. Espcially, the new compound Markhacanasin A has cytotoxic activity on all 5 cell lines of breast cancer (MCF-7), cervical cancer (HeLa), liver cancer (Hep G2), lung cancer (NCI) H460), blood cancer (Jurkat), with IC50, respectively: 16.51 ± 0.22, 29.55 ± 1.64, 25.26 ± 1.06, 24.21 ± 0.38, 14.72 ± 0.38 (µg/mL). 24 PUBLICATIONS WITHIN THE SCOPE OF THESIS PUBLICATIONS WITHIN THE SCOPE OF THESIS 1. Ngô Trọng Nghĩa, Phan Nhật Minh, Bùi Trọng Đạt, Đặng Văn Sơn,Trần Công Luận, Mai Đình Trị, Nguyễn Tấn Phát, Các acid triterpen từ lá thiết đinh Cà ná Markhamia stipulata var. canaense V.S. Dang, (2017), Tạp chí hóa học, số 55 (5E34), 311 -314. 2. Ngô Trọng Nghĩa, Phan Nhật Minh, Bùi Trọng Đạt, Đặng Văn Sơn,Trần Công Luận, Mai Đình Trị, Nguyễn Tấn Phát, Các flavonoid từ lá thiết đinh cà ná Markhamia stipulata var. Canaense V.S. Dang, (2018), Tạp chí hóa học, số 56(3E12), 182-185. 3. Ngo Trong Nghia , Nguyen Nu Dan Phuong , Pham Nguyen Kim Tuyen , Ngo Quoc Luan , Phan Nhat Minh , Bui Trong Dat , Tran Cong Luan , Mai Dinh Tri , Nguyen Tan Phat, Phytochemical constituents of n-hexane extract from the leaves of markhamia stipulata var. Canaense v.s. Dang, (2018), Tạp chí hóa học, 56 (4E), 96-99. 4. Ngo Trong Nghia, Truong Ngoc Bao Hien, Phan Nhat Minh, Le Tien Dung, Dang Van Son, Tran Cong Luan, Mai Dinh Tri, Nguyen Tan Phat, Flavonoids and iridoid from the leaves of Stereospermum binhchauensis v.s. Dang, (2018), Tạp chí hóa học, 56, (4E1), 100-103. 5. Ngo Trong Nghia, Bui Thi Thanh Thuy, Phan Nhat Minh, Dang Van Son, Tran Cong Luan, Mai Dinh Tri, Nguyen Tan Phat, Phytochemical constituents of n-hexane extract from the leaves of Stereospermum binhchauensis V.S. Dang, (2018), Tạp chí học, 56 (6E1). 6. Trong Nghia Ngo, Nhat Minh Phan, Trong Dat Bui, Van Son Dang, Cong Luan Tran, Dinh Tri Mai, Tan Phat Nguyen (2017), Cytotoxic cycloartane triterpenoids from the leaves of Markhamia stipulata var. canaense, Phytochemsitry letters, 22, 251 -254. 25 7. Trong Nghia Ngo, Cong Thin Vo, Nguyen Kim Tuyen Pham, Nhat Minh Phan, Trong Dat Bui, Quoc Luan Ngo, Van Son Dang, Cong Luan Tran, Dinh Tri Mai Tan Phat Nguyen (2019), Markhacanasin C, cycloartane triterpenoid from the leaves of Markhamia stipulata var. canaense V.S. Dang, Natural Products Research, 33(2), 174-179. 8. Trong Nghia Ngo, Nu Dan Phuong Nguyen, Ngoc Thien Ly Nguyen, Nguyen Kim Tuyen Pham, Nhat Minh Phan, Trong Dat Bui, Van Son Dang, Cong Luan Tran, Dinh Tri Mai & Tan Phat Nguyen (2019), Markhasphingolipid A, new phytosphingolipid from the leaves of Markhamia stipulata var. canaense V. S

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