Conformational Analysis of Diterpene Lactone Andrographolide towards Reestablishment of Its Absolute Configuration via Theoretical and Experimental ECD and VCD Methods

Muhamad Faid A Kadir(1), Agustono Wibowo(2), Fatimah Salim(3), El Hassane Anouar(4), Khalijah Awang(5), Moses Kiprotich Langat(6), Rohaya Ahmad(7*)

(1) Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia
(2) Faculty of Applied Sciences, Universiti Teknologi MARA, Pahang Branch, Jengka Campus, 26400 Bandar Tun Abdul Razak Jengka, Pahang Darul Makmur, Malaysia
(3) Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
(4) Department of Chemistry, College of Sciences and Humanities Studies in Al-Kharj, Prince Sattam bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
(5) Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
(6) Jodrell Laboratory, Natural Capital and Plant Health Department, Royal Botanic Gardens, Kew, Richmond, TW9 3DS, UK
(7) Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia
(*) Corresponding Author


Andrographolide, the major constituent from the terrestrial plant Andrographis paniculata is a much-studied bioactive ent-labdane diterpene lactone and has become an important medicinal intermediate. Its structure as determined by X-ray crystallography has been applied in molecular docking studies to explain biological activities. Nevertheless, recently there has been a number of conflicting reports concerning the stereochemistry at the C-14 and C-10 positions affecting the absolute configuration (AC) of the compound. Since a lack of information on the molecular flexibility of the molecule can lead to misleading conclusions on biological activity, a conformational analysis of the molecule in the solution state was necessary. The conformational analysis was performed by the Spartan14 package using the Merck Molecular Force Field (MMFF). The exciton chirality method in electronic circular dichroism spectroscopy (ECM-ECD) and vibrational circular dichroism (VCD) techniques were then jointly employed to re-establish the AC of andrographolide. Theoretical calculations were performed using TD-DFT methods by using the hybrid functionals B3LYP and CAM-B3LYP combined with 6-31G(d,p) basis set. Long-range exciton coupling of 2-naphthoyl chromophores at C-14 and C-19 led to the establishment of the AC to be 3R, 4R, 5S, 9R, 10R and 14S. Comparison between the theoretical VCD data of 14-S and 14-R stereoisomer confirmed a configuration of S at C-14 position instead of R.


andrographolide; conformational analysis; exciton coupling; vibrational circular dichroism; absolute configuration


[1] Anouar, E.H., and Weber J.-F.F., 2013, Time-dependent density functional theory study of UV/vis spectra of natural styrylpyrones, Spectrochim. Acta, Part A, 115, 675–682.

[2] Pescitelli, G., Di Bari, L., and Berova, N., 2011, Conformational aspects in the studies of organic compounds by electronic circular dichroism, Chem. Soc. Rev., 40 (9), 4603–4625.

[3] Bultinck, P., Cherblanc, F.L., Fuchter, M.J., Herrebout, W.A., Lo, Y.P., Rzepa, H.S., Siligardi, G., and Weimar, M., 2015, Chiroptical studies on brevianamide B: Vibrational and electronic circular dichroism confronted, J. Org. Chem., 80 (7), 3359–3367.

[4] Mishra, S.K., and Suryaprakash, N., 2017, Some new protocols for the assignment of absolute configuration by NMR spectroscopy using chiral solvating agents and CDAs, Tetrahedron: Asymmetry, 28 (10), 1220–1232.

[5] Petrovic G.A., Navarro-Vazquez, A., and Alonso-Gomez J.L., 2010, From relative to absolute configuration of complex natural products: Interplay between NMR, ECD, VCD, and ORD assisted by ab initio calculations, Curr. Org. Chem., 14 (15), 1612–1628.

[6] Batista, J.M., and da Silva Bolzani, V., 2014, Chapter 13. Determination of the absolute configuration of natural product molecules using vibrational circular dichroism, Stud. Nat. Prod. Chem., 41, 383–417.

[7] Salim, F., Yunus, Y.M., Anouar, E.H., Awang, K., Langat, M., Cordell, G.A., and Ahmad, R., 2019, Absolute configuration of alkaloids from Uncaria longiflora through experimental and theoretical approaches, J. Nat. Prod., 82 (11), 2933–2940.

[8] Smith, A.B., Toder, B.H., Carroll, P.J., and Donohue, J., 1982, Andrographolide: an X-ray crystallographic analysis, J. Crystallogr. Spectrosc. Res., 12 (4), 309–319.

[9] Fujita, T., Fujitani, R., Takeda, Y., Takaishi, Y., Yamada, T., Kido, M., Miura, I., 1984, On the diterpenoids of Andrographis paniculata: X-ray crystallographic analysis of andrographolide and structure determination of new minor diterpenoids, Chem. Pharm. Bull., 32 (6), 2117–2125.

[10] Chantrapromma, S., Boonnak, N., Pitakpornpreecha, T., Yordthong, T., Kumar, C.S.C., and Fun, H.K., 2018, Absolute configuration of andrographolide and its proliferation of osteoblast cell lines, Crystallogr. Rep., 63 (3), 416–421.

[11] Jayakumar, T., Hsieh, C.Y., Lee, J.J., and Sheu, J.R., 2013, Experimental and clinical pharmacology of Andrographis paniculata and its major bioactive phytoconstituent andrographolide, Evid. Based Complement. Altern. Med., 2013, 846740.

[12] Hossain, M.S., Urbi, Z., Sule, A., and Rahman, K.M.H., 2014, Andrographis paniculata (Burm. f.) Wall. ex Nees: A review of ethnobotany, phytochemistry, and pharmacology, Sci. World J., 2014, 1–28.

[13] Berova, N., Ellestad, G.A., and Harada, N., 2010, “Characterization by circular dichroism spectroscopy” in Comprehensive Natural Products II: Chemistry and Biology, Eds. Mander, L., and Liu, H.W., Elsevier Science, United Kingdom, 91–146.

[14] Berova, N., Polavarapu, P.L., Nakanishi, K., and Woody, R.W., 2012, Comprehensive Chiroptical Spectroscopy: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules, John Wiley & Sons, Inc., Hoboken, New Jersey, United States.

[15] Li, X., Burrell, C.E., Staples, R.J., and Borhan, B., 2012, Absolute configuration for 1, n-Glycols: A nonempirical approach to long-range stereochemical determination, J. Am. Chem. Soc., 134 (22), 9026–9029.

[16] Tanaka, H., Inoue, Y., Nakano, T., and Mori, T., 2017, Absolute configuration determination through the unique intramolecular excitonic coupling in the circular dichroisms of o,p′-DDT and o,p′-DDD. A combined experimental and theoretical study, Photochem. Photobiol. Sci., 16 (4), 606–610.

[17] Autschbach, J., 2009, Computing chiroptical properties with first-principles theoretical methods: Background and illustrative examples, Chirality, 21 (1E), E116–E152.

[18] Taniguchi, T., 2017, Analysis of molecular configuration and conformation by (electronic and) vibrational circular dichroism: Theoretical calculation and exciton chirality method, Bull. Chem. Soc. Jpn., 90 (9), 1005–1016.

[19] Pescitelli, G., Di Bari, L., and Barova, N., 2014, Application of electronic circular dichroism in the study of supramolecular systems, Chem. Soc. Rev., 43 (15), 5211–5233.

[20] Nicu, V.P., and Jan Baerends, E., 2011, On the origin dependence of the angle made by the electric and magnetic vibrational transition dipole moment vectors, Phys. Chem. Chem. Phys., 13 (36), 16126.

[21] Person, R.V., Monde, K., Humpf, H., Berova, N., and Nakanishi, K., 1995, A new approach in exciton-coupled circular dichroism (ECCD)-Insertion of an auxiliary stereogenic center, Chirality, 7 (3), 128–135.

[22] Berova, N., Nakanishi, K., and Woody, R.W., 2000, Circular Dichroism. Principles and Applications, 2nd Ed., John Wiley & Sons, Inc., New York, US.

[23] García-Sánchez, E., Ramírez-López, C.B., Talavera-Alemán, A., León-Hernández, A., Martínez-Muñoz, R.E., Martínez-Pacheco, M.M., Gómez-Hurtado, M.A., Cerda-García-Rojas, C.M., Joseph-Nathan, P., and del Río, R.E., 2014, Absolute configuration of (13R)- and (13S)-labdane diterpenes coexisting in Ageratina jocotepecana, J. Nat. Prod., 77 (4), 1005–1012.

[24] Hoffmann, S.V., Fano, M., and Van de Weert, M., 2016, “Circular dichroism spectroscopy for structural characterization of proteins” in Analytical Techniques in the Pharmaceutical Sciences. Advances in Delivery Science and Technology, Eds. Müllertz, A., Perrie, Y., and Rades, T., Springer, New York, NY, 223–251.

[25] Joseph-Nathan, P., Gordillo-Román, B., 2015, Vibrational circular dichroism absolute configuration determination of natural products, Prog. Chem. Org. Nat. Prod., 100, 311–452.


Article Metrics

Abstract views : 2097 | views : 1478 | views : 613

Copyright (c) 2020 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


Indonesian Journal of Chemistry (ISSN 1411-9420 / 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Analytics View The Statistics of Indones. J. Chem.