Isocryptolepine, an indoloquinoline alkaloid from Cryptolepis sanguinolenta promotes LDL uptake in HepG2 cells


About 31 percent of deaths worldwide result from atherosclerotic cardiovascular disease. Hyperlipidemia remains the major risk factor for this disease and therefore, it is necessary to identify antihyperlipidemic compounds for drug development. The crude ethanolic extract of Cryptolepis sanguinolenta (Lindl.) Schltr., Apocynaceae, has demonstrated antihyperlipidemic properties. However, the chemical constituents responsible for this action are unknown. Hence, to identify chemical constituent(s) of C. sanguinolenta with anti-hyperlipidemic effect, five indoloquinoline alkaloids were isolated and evaluated in 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate labeled low density lipoprotein uptake assay using HepG2 cells. The minor alkaloid, isocryptolepine, showed strong activity in promoting low lipid lipoprotein uptake by 1.85-fold. Isocryptolepine may, therefore, serve as a lead compound for future studies in the development of novel antihyperlipidemic drugs.


  1. Ajayi, A.F., Akhigbe, R.E., Adewumi, O.M., Okeleji, L.O., Mujaidu, K.B., Olaleye, S.B., 2012. Effect of ethanolic extract of Cryptolepis sanguinolenta stem on in vivo and in vitro glucose absorption and transport: mechanism of its antidiabetic activity. Indian J. Endocrinol. Metab. 16 (Suppl. 1), S91–S96.

    PubMed  PubMed Central  Google Scholar 

  2. Benjamin, E.J., Blaha, M.J., Chiuve, E.S., Cushman, M., Das, S.R., Deo, R., Ferranti, S.D., Floyd, J., Fornage, M., Gillespie, C., Isasi, C.R., Jiménez, M.C., Jordan, L.C., Judd, S.E., Lackland, D., Lichtman, J.H., Lisabeth, L., Liu, S., Longenecker, C.T., Mackey, R.H., Matsushita, K., Mozaffarian, D., Mussolino, M.E., Nasir, K., Neu-mar, R.W., Palaniappan, L., Pandey, D.K., Thiagarajan, R.R., Reeves, M.J., Ritchey, M., Rodriguez, C.J., Roth, G.A., Rosamond, W.D., Sasson, C., Towfighi, A., Tsao, C.W., Turner, M.B., Virani, S.S., Voeks, J.H., Willey, J.Z., Wilkins, J.T., Wu, J.H., Alger, H.M., Wong, S.S., Muntner, P., 2017. Heart Disease and stroke statistics - 2017 update: a report from the American Heart Association. Circulation, 25, (accessed 27.03.18, Epub ahead of print).

  3. Bierer, D.E., Fort, D.M., Mendez, C.D., Luo, J., Imbach, P.A., Dubenko, L.G., Jolad, S.D., Gerber, R.E., Litvak, J., Lu, Q., Zhang, P.S., Reed, M.J., Waldeck, N., Bruening, R.C., Noamesi, B.K., Hector, R.F., Carlson, T.J., King, S.R., 1998. Ethnobotanical-directed discovery oftheantihyperglycemic properties of cryptolepine: its isolation from Cryptolepis sanguinolenta, synthesis, and in vitro and in vivo activities. J. Med. Chem. 41, 894–901.

    CAS  Article  PubMed Central  Google Scholar 

  4. Boye, G.L., Ampofo, O., 1990. Medicinal plants in Ghana. In: Wagner, H., Farnsworth, N.R. (Eds.), Economic and Medicinal Plants Research. Academic Press, London, pp. 32–33.

    Google Scholar 

  5. Catapano, L.A., Graham, I., De Backer, G., Wiklund, O., Chapman, M.J., Drexel, H., Hoes, W.A., Jennings, S.C., Landmesser, U., Pedersen, T.R., Reiner, Z., Riccardi, G., Task-inen, M.R., Tokgozoglu, L., Verschuren, M.W.M., Vlachopoulos, C., Wood, A.D., Zamorano, L.J., Cooney, M.T., ESC Scientific Document Group, 2016. ESC/EAS guidelines for the management of dyslipidaemias. Eur. Heart J. 37, 2999–3058.

    Article  PubMed Central  Google Scholar 

  6. Collins, W.E., 2012. Plasmodium knowlesi: a malaria parasite of monkeys and humans. Ann. Rev. Entomol. 57, 107–121.

    CAS  Article  Google Scholar 

  7. Cooper, M.M., Lovell, J.M., Joule, J.A., 1996. Indole-β-nucleophilic substitution. Part 9: nitrogen nucleophiles. Syntheses of hydroxycryptolepine, cryptolepine, and quindoline. Tet. Lett. 37, 4283–4286.

    CAS  Article  Google Scholar 

  8. Dwuma-Badu, D., Ayim, J.S.K., Fiagbe, N.I.Y., Knapp, J.E., Schiff, P.L., Slatkin, D.J., 1978. Constituents of West-African medicinal plants: quindoline from Cryptolepis sanguinolenta. J. Pharm. Sci. 67, 433–434.

    CAS  Article  PubMed Central  Google Scholar 

  9. Gui, Y.Z., Yao, S., Yan, H., Hu, L., Yu, C.Y., Gao, F., Xi, C., Li, H.H., Ye, Y., Wang, Y.P., 2016. A novel small molecule liverXreceptortranscriptional regulator, nagilactone B, suppresses atherosclerosis inapoE-deficient mice. Cardiovasc. Res. 112, 502–514.

    CAS  Article  PubMed Central  Google Scholar 

  10. Iwu, M.M., 1993. Handbook of African Medicinal Plants, first ed. CRC Press, Florida.

    Google Scholar 

  11. LaRosa, J.C., Grundy, S.M., Waters, D.D., Shear, C., Barter, P., Fruchart, J.-C., Gotto, A.M., Greten, H., Kastelein, J.J.P., Shepherd, J., Wenger, N.K., Treating to New Targets (TNT) Investigators, 2005. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352, 1425–1435.

    CAS  Article  PubMed Central  Google Scholar 

  12. Lavrado, J., Moreira, R., Paulo, A., 2010. Indoloquinolines as scaffolds for drug discovery. Curr. Med. Chem. 17, 2348–2370.

    CAS  Article  PubMed Central  Google Scholar 

  13. Lu, Y.J., Ou, T.M., Tan, J.H., Hou, J.Q., Shao, W.Y., Peng, D., Sun, N., Wang, X.D., Wu, W.B., Bu, X.Z., Huang, Z.S., Ma, D.L., Wong, K.Y., Gu, L.Q., 2008. 5-N-Methylated quindoline derivatives as telomeric G-quadruplex stabilizing ligands: effects of 5-N positive charge on quadruplex binding affinity and cell proliferation. J. Med. Chem. 51, 6381–6392.

    CAS  Article  PubMed Central  Google Scholar 

  14. Mattar, M., Obeid, O., 2009. Fish oil and the management of hypertriglyceridemia. Nutr. Health 20, 41–49.

    CAS  Article  PubMed Central  Google Scholar 

  15. Paulo, A., Houghton, P.J., 2002. Chemotaxonomic analysis of the genus Cryptolepis. Biochem. Syst. Ecol. 31, 155–166.

    Article  Google Scholar 

  16. Pousset, J.L., Martin, M.T. Jossang, A., Bodo, B., 1995. Isocryptolepine from Cryptolepis sanguinolenta. Phytochemistry 39, 735–736.

    CAS  Article  Google Scholar 

  17. Sahebkar, A., Serban, M.C., Gluba-Brzózka, A., Mikhailidis, D.P., Cicero, A.F., Rysz, J., Banach, M., 2016. Lipid-modifying effects of nutraceuticals: an evidence-based approach. Nutrition 32, 1179–1192.

    CAS  Article  PubMed Central  Google Scholar 

  18. Sharaf, M.H.M., Schiff, P.L., Tackie, A.N., Phoebe, C.H., Martin, G.E., 1996. Two new indoloquinoline alkaloids from Cryptolepis sanguinolenta: cryptosanguinolentine and cryptotackieine. J. Heterocycl. Chem. 33, 239–243.

    CAS  Article  Google Scholar 

  19. Stephan, Z.F., Yurachek, E.C., 1993. Rapid fluorometric assay of LDL receptor activity by DiI-labeled LDL J. Lipid Res. 34, 325–330.

    CAS  Google Scholar 

  20. Tousek, J., Van Miert, S., Pieters, L., Van Baelen, G., Hostyn, S., Maes, B.U.W., Lemiere, G., Dommisse, R., Marek, R., 2008. Structural and solvent effects on the 1C and 15N NMR chemical shifts of indoloquinoline alkaloids: experimental and DFT study. Magn. Reson. Chem. 46, 42–51.

    CAS  Article  PubMed Central  Google Scholar 

  21. Wang, Y., Ye., J., Li, J., Chen, C., Huang, J., Liu, P., Huang, H., 2016. Polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proproteinconvertase subtilisin/kexintype9 (PCSK9). Cardiovasc. Diabetol. 15,

  22. Wright, C.W., Phillipson, J.D., Awe, S.O., Kirby, G.C., Warhurst, D.C., Quertin-Leclerq, J., Angenot, L., 1996. Antimalarial activity of cryptolepine and some other anhydronium bases. Phytother. Res. 10, 361–363.

    CAS  Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Li-Jiang Xuan.

Additional information

Authors’ contribution

MOA, YW, and LXJ and contributed to the concept and experimental designs. MOA and WQW took part in the extraction and characterization of test compounds. HHL and YW conducted the DiI-LDL uptake assay. LXJ, YW, WS, and MOA interpreted the results. MOA prepared the manuscript and all authors contributed to its critical reading and approval for submission.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aggrey, M.O., Li, H., Wang, W. et al. Isocryptolepine, an indoloquinoline alkaloid from Cryptolepis sanguinolenta promotes LDL uptake in HepG2 cells. Rev. Bras. Farmacogn. 28, 654–657 (2018).

Download citation


  • Antihyperlipidemia
  • Atherosclerosis
  • DiI-LDL uptake
  • HepG2 cells
  • Isocryptolepine
  • SAR