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Article history: Bioassay-guided fractionation of the fruit powder of graviola (Annona muricata) yielded three novel com-
Received 14 February 2014 pounds: muricins J, K, and L. The compounds are all C35 Annonaceous acetogenins with a mono-tetrahy-
Revised 28 March 2014 drofuran ring and four hydroxyls. Their structures were elucidated by spectral methods and chemical
Accepted 31 March 2014
modication after isolation via chromatographic techniques and HPLC purication. These three acetoge-
Available online 18 April 2014
nins demonstrated an antiproliferative against human prostate cancer PC-3 cells.
2014 Published by Elsevier Ltd.
Keywords:
Annona muricata
Acetogenin
Muricin
Cytotoxicity
Human prostate cancer
Graviola (Annona muricata) is an evergreen fruit tree, indige- carcinoma cell lines, colon adenocarcinoma cell lines, liver cancer
nous to the warmest tropical areas in South and North America. cell lines, human lymphoma cell lines, and multi-drug resistant
The bark, leaves, roots, fruit, and seeds of graviola are all regarded human breast adenocarcinoma.2,7,8,1113 Studies on the pharmaco-
as natural medicine in the indigenous tropics. The bark, leaves, and logical mechanisms underlying the aforementioned functions indi-
roots have been used to manage a wide range of human diseases cate that Annonaceous acetogenins induce cytotoxicity by
including inammatory conditions, rheumatism, neuralgia, diabe- inhibiting the mitochondrial complex I of the electron transport
tes, hypertension, insomnia, cystitis, parasitic infections, and chain, involved in ATP synthesis.6 Mitochondrial complex I could
cancer. The fruit is edible and sold in local markets. The fruit pulp be a potential target in cancer therapeutics because cancer cells
is ideal for making drinks and sherbets and can be eaten out of have a higher demand for ATP than normal cells. These compounds
hand. The fruit and fruit juice are often consumed for cooling are hence regarded as promising anti-cancer agents worthy of fur-
fevers, increasing mothers milk supply after childbirth, and as an ther animal studies, with attempts of incorporation into new che-
astringent for diarrhea and dysentery. The crushed seeds are used motherapeutic drugs. A recent study analyzing the anti-tumor
against internal and external parasites, head lice, and worms.1 efcacy of graviola extract revealed a direct anti-tumorigenic effect
Graviola belongs to the family Annonaceae, members of which on breast cancer cells by down-regulating the expression of the
were found to contain a unique set of derivatives of C35 or C37 epidermal growth factor receptor (EGFR).14 In vitro and in vivo
long chain fatty acids derived from the polyketide pathway2 and studies involving various prostate cancer (PC) cell lines have
characteristic of this family. These phytochemicals have been sep- reported graviola extracts as inhibitors of multiple signaling path-
arately reported to possess signicant antitumorous properties. ways that regulate metabolism, cell cycle, survival, and metastatic
They are selectively toxic to various types of cancer cells, including properties of PC cells.11,15
multi-drug resistant cancer cell lines, at very low dosages.310 In previous studies of graviola-derived Annonaceous acetoge-
Current research on graviola is also focused on Annonaceous ace- nins, the stems, leaves, and seeds were found to contain more than
togenins. Specic acetogenins in graviola and/or extracts of gravi- 40 acetogenins,16 and more acetogenins continue to be discov-
ola have been reported to be selectively toxic in vitro to the ered.7,13 Graviola products, namely capsules and tinctures, are
following types of tumor cells: lung carcinoma cell lines, human becoming more widely available in the U.S. market, and now
breast solid tumor lines, prostate adenocarcinoma, pancreatic offered under several different manufacturer labels in health food
stores. The therapeutic dosage of graviola leaf is reported to be
Corresponding author. Tel.: +1 313 577 3444; fax: +1 313 577 8616. 23 g, taken 3 or 4 times daily.11,15 We have previously reported
E-mail address: kzhou@wayne.edu (K. Zhou). that the extract of graviola fruit has signicant activity against
http://dx.doi.org/10.1016/j.bmcl.2014.03.099
0960-894X/ 2014 Published by Elsevier Ltd.
2774 S. Sun et al. / Bioorg. Med. Chem. Lett. 24 (2014) 27732776
Table 1
NMR data ( values) of compounds 13 (400 MHz for 1H and 100 MHz for 13
C, in CDCl3)
7. Chang, F. R.; Wu, Y. C. J. Nat. Prod. 2001, 64, 925. 18. Fang, X. P.; Rieser, M. J.; Gu, Z. M.; Zhao, G. X.; McLaughlin, J. L. Phytochem. Anal.
8. Liaw, C. C.; Chang, F. R.; Lin, C. Y.; Chou, C. J.; Chiu, H. F.; Wu, M. J.; Wu, Y. C. J. 1993, 4, 49.
Nat. Prod. 2002, 65, 470. 19. Fujimoto, Y.; Murasaki, C.; Shimada, H.; Nishioka, S.; Kakinuma, K.; Singh, S.;
9. Chen, Y.; Chen, J. W.; Xu, S. S.; Wang, Y.; Li, X.; Cai, B. C.; Fan, N. B. Bioorg. Med. Singh, M.; Gupta, Y. K.; Sahai, M., et al Chem. Pharm. Bull. 1994, 42, 1175.
Chem. Lett. 2012, 22, 2717. 20. Gu, Z. M.; Fang, X. P.; Zeng, L.; Kozlowski, J. F.; McLaughlin, J. L. Bioorg. Med.
10. Chen, Y.; Chen, J. W.; Li, X. J. Nat. Prod. 2011, 74, 2477. Chem. Lett. 1994, 4, 473.
11. Torres, M. P.; Rachagani, S.; Purohit, V.; Pandey, P.; Joshi, S.; Moore, E. D.; 21. Shi, G.; Gu, Z. M.; He, K.; Wood, K. V.; Zeng, L.; Ye, Q.; MacDougal, J. M.;
Johansson, S. L.; Singh, P. K.; Ganti, A. K.; Batra, S. K. Cancer Lett. 2012, 323, 29. McLaughlin, J. L. Bioorg. Med. Chem. 1996, 4, 1281.
12. Rieser, M. J.; Gu, Z. M.; Fang, X. P.; Zeng, L.; Wood, K. V.; McLaughlin, J. L. J. Nat. 22. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J. L. Nat.
Prod. 1996, 59, 100. Prod. Rep. 1996, 13, 275.
13. Chang, F. R.; Liaw, C. C.; Lin, C. Y.; Chou, C. J.; Chiu, H. F.; Wu, Y. C. Planta Med. 23. Born, L.; Lieb, F.; Lorentzen, J. P.; Moeschler, H.; Nonfon, M.; Sollner, R.;
2003, 69, 241. Wendisch, D. Planta Med. 1990, 56, 312.
14. Dai, Y.; Hogan, S.; Schmelz, E. M.; Ju, Y. H.; Canning, C.; Zhou, K. Nutr. Cancer 24. Liu, X. X.; Alali, F. Q.; Pilarinou, E.; McLaughlin, J. L. Phytochemistry 1999, 50,
2011, 63, 795. 815.
15. Torres, M. P.; Rachagani, S.; Purohit, V.; Pandey, P.; Joshi, S.; Moore, E. D.; 25. Wu, F. E.; Gu, Z. M.; Zeng, L.; Zhao, G. X.; Zhang, Y.; McLaughlin, J. L.;
Johansson, S. L.; Singh, P. K.; Ganti, A. K.; Batra, S. K. Cancer Lett. 2012, 323, 29. Sastrodihardjo, S. J. Nat. Prod. 1995, 58, 830.
16. Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. 26. Liaw, C. C.; Yang, Y. L.; Chen, M.; Chang, F. R.; Chen, S. L.; Wu, S. H.; Wu, Y. C. J.
17. Rupprecht, J. K.; Hui, Y. H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237. Nat. Prod. 2008, 71, 764.