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Prediction Of Anticancer Activities Of Kaempferol-3- O-Methylether And Kaempferol-3-0-(2,4-0-Diacetyl- Alpha-L-Rhamnopyranoside) Isolating From Plant Rhizome Zingiber Zerumbet Sm Using QSDAR Models From ¹³C-NMR and ¹⁵O-NMR Simulation Spectra Data

Pham Van Tat³*, Bui Thi Phuong Thuy¹, Tran Duong², Phung Van Trung⁴, Hoang Thi Kim Dung⁴ and Pham Nu Ngoc Han³

¹FacuJty of Chemistry, Hue University of Science, Viet Nam

²FacuIty of Chemistry, Hue University of Education, Viet Nam

³Faculty of Science and Engineering, Hoa Sen University, Viet Nam

⁴Institute of Chemical Technology, Vietnam Academy of Science and Technology, Viet Nam

Submission: November 21, 2017; Published: December 06, 2017

*Corresponding author: Pham Van Tat, Faculty of Science and Engineering, Hoa Sen University, Ho Chi Minh City, Viet Nam; Email: vantat@gmail.com

How to cite this article: Pham V T, Bui T P T, Tran D, Phung V T, Hoang T K D, Pham N N H. Prediction Of Anticancer Activities Of Kaempferol-3-O-Methylether And Kaempferol-3-O-(2,4-O-Diacetyl-Alpha-L-Rhamnopyranoside) Isolating From Plant Rhizome Zingiber Zerumbet Sm Using QSDAR Models From 13C-NMR and 15O-NMR Simulation Spectra Data. Organic & Medicinal Chem IJ. 2017; 4(4): 555644.DOI:10.19080/OMCIJ.2017.05.555644

Abstract

In this work, the quantitative spectrum data - activity relationship (QSDAR_MLR) models for a set of anticancer flavonoids were developed from the simulated-spectral data ¹³C-NMR and ¹⁵O-NMR. The quality of best model QSDARMLR resulting from the chemical-shift data of atoms O₁,O₁₁ C₂, C₃, C₆, C₇ va 'C₂' was shown in the values R²_train of 0.9057 and R²_test of 0.7137. The atomic sites C, C and C_ were used to design the new flavonoid derivatives. The neural network model QSDAR_ANN I(7)-HL(9)-O(1) presented to be a better model in values R²_train of 0.993 and R²_pred of 0.971. The models QSDAR_MLR and QSDAR_ANN were explored to predict the anticancer activities of flavonoids in test group and two new compounds kaempferol-3-O-methylether and kaempferol-3-O-(2,4-O-diacetyl-alpha-L-rhamnopyranoside) isolating from Rhizome Zingiber Zerumbet Sm in Viet Nam [1]. The predicted activities resulting from those models turn out to be good agreement with experimental data.

Keywords: QSDAR_MLR and QSDAR_ANN Model; Anticancer Activities Hela Cell Line

Abbrevations: QSDAR: Quantitative Structure Activity Relationship; NMR: Nuclear Magnetic Resonance; LOO: Leave-One-Out

Introduction

Natural products from plants are of interest in searching for new anti-cancer drugs and can have a direct effect on HeLa cell line and reduce side effects. Recently, we have isolated a few flavonoids from Rhizome Zingiber Zerumbet Sm and tested in vitro activities pointed out the relatively strong impacts for cancer cells HeLa [1,2]. Flavonoids are polyphenolic compounds in most plants [3-5]. The flavonoids from Rhizome Zingiber Zerumbet Sm were also tested the biological activities in some different cancer cells [6]. The flavonoids presented their activities and role of food within flavonoids in the cancer inhibition are widely studied [7-10]. The derivatives flavonoids are present in all parts of high plants and are found in many everyday vegetables and fruits [1,2]. Flavonoids are known to be a group of compounds that have antioxidant effects or prevent the oxidation of free radicals produced during metabolism, such as OH o, ROO o ... [3,4]. Flavonoids in the natural foods have the potential to form complexes with metal ions, which act as catalysts that inhibit oxidative reactions. Therefore, flavonoids have the effect of protecting the body, preventing atherosclerosis, stroke, aging, liver degeneration, radiation damage and prevention: osteoporosis, hypertension, cardiovascular, high cholesterol and some cancers [11,12].

The experimental results in this work have been studied the relationships between the structure and anti-cancer activity of flavonoids kaempferol-3-O-methylether and kaempferol-3- O-(2,4-O-diacetyl-alpha-L-rhamnopyranoside) isolating from Rhizome Zingiber Zerumbet Sm in Viet Nam using spectrum data ¹³C-NMR and ¹⁵O-NMR on atoms carbon and oxygen [1]. The statistical techniques were supported for building QSDAR_MLR and QSDAR_ANN model to predict the anticancer activities of these flavonoids [13-18]. In this work, we report the use of semi- empirical quantum calculations TNDO MO and construction of quantitative structure activity relationship (QSDAR) models for 32 flavone and isoflavone derivatives [19-22]. The anti-cancer activities GI₅₀/of flavonoids in test group and two new flavonoids kaempferol-3-O-methylether and kaempferol- 3-O-(2,4-O-diacetyl-alpha-L-rhamnopyranoside) isolating from Rhizome Zingiber Zerumbet Sm in Viet Nam resulting from QSDAR models are compared with those from experimental data [1].

Isolation of Kaempferols From Plant

Chemicals and equipment: We used the chemicals and the equipments for isolating and purifying two flavonoids kaempferol-3-O-methylether and kaempferol-3-O-(2,4-O- Diacetyl-Alpha-L-Rhamnopyranoside) before determining the flavonoid structures by ^JH-NMR and ¹³C-NMR spectrum [26]. The following materials are used to isolate the flavonoids as

a) Silica gel with the particle size in range 0.04 to 0.06 mm was used for ordinary and Rp18 phase chromatography

b) Thin-layer chromatography was implemented by the thin plate DC-Alufolien F254 (Merck) for the ordinary phase and Rp18 F254s (Merck) for the reverse-phase chromatography.

c) Solvents used for the isolation processes: hexane, petroleum ether, chloroform, methanol, ethyl acetate, ethanol, acetone, distilled water.

d) UV handheld lamps, 254 and 365 nm UVITEC effect.

e) Vacuum Evaporators Buchi - 111 and Water Bath cooker JULABO 461.

f) Infrared heating equipment SCHOTT.

g) Chromatography column with diameter range 2 to 5.5 cm.

h) Analytical Balances AND HR 200.

Isolation process of kaempferols: To isolate and purify kaempferol compounds from plant Rhizome Zingiber Zerumbet Sm we used the techniques of thin-layer and column chromatography [22]. After isolating the compounds their structures were identified by the different spectrum as

i) Melting temperature carried out on Electrothermal 1A 9000 series, using unadjusted capillary

j) Column chromatography with silica gel for ordinary- phase, reverse-phase chromatography Rp 18 and sephadex techniques combined with thin-layer chromatography

k) Substances were detected by ultraviolet light at wavelengths 254 nm and 365 nm or reagent used is liquid H₂SO₄/EtOH or FeCl₃/EtOH.

l) Nuclear magnetic resonance spectrum (NMR) ^JH-NMR (500 MHz) and ¹³C-NMR (125 MHz) implemented on Bruker AM500 FT-NMR Spectrometer.

Prediction of biological activity for new substances: The predictability of the models QSDAR_MLR and QSDAR_ANN 1(7)-HL(9)-O(1) [2 3] were evaluated carefully by the leave- one-out (LOO) technique using their predictive values R2pred [23,17,18,24-26]. The compounds of test group and two flavonoids kaempferols isolated from plant Rhizome Zingiber Zerumbet Sm were employed for evaluating predictability of these QSDAR models [1]. The predicted in vitro activities of new isolated kaempferols were compared to experimental in vitro activity on Hela cell line. The plant Rhizome Zingiber Zerumbet Sm and kaempferols are exhibited in Figure 1 [1].

Conclusion

The use of computational methods constructed successfully the QSDAR_MLR and QSDAR_ANN I(7)-HL(9)-O(1) model with relationships between the spectrum data ¹³C-NMR and ¹⁵O-NMR and anti-cancer activities GI₅₀ (^M) of flavonoids. These QSDAR models pointed out the important sites O₁, O , C₂, C₃, C₆, C₇ va C₂' on flavonoids which effect an in vitro activity on Hela cell line. The QSDAR models established in this work can be used for in vitro activity assessment of two kaempferols isolating from plant Rhizome Zingiber Zerumbet Sm [1]. This work established the different models QSDAR and isolated two flavonoids from plant Rhizome Zingiber Zerumbet Sm that may prove to be useful for guiding the rational search of new therapeutic agents for cancer diseases [1].