Bioactive pimarane diterpenes from Icacina trichantha

CYTOTOXIC PIMARANE DITERPENES FROM ICACINA TRICHANTHA Ming Zhao1, Michael M. Onakpa1,2, Wei-Lun Chen1, Tanja Göedecke1, Steven M. Swanson1, Isaac U. Asuzu2, Chun-Tao Che1 1 Department

of Medicinal Chemistry and Pharmacognosy, and WHO Collaborating Center for Traditional Medicine, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612 2 Department of Veterinary Physiology and Pharmacology, Faculty of Veterinary Medicine, University of Nigeria, Nsukka, Nigeria

The tuber of Icacina trichantha Oliv. (Icacinaceae) is a Nigerian traditional medicine for the treatment of constipation and malaria as well as induction of emesis in emergency treatment of poisoning.1 The antidiabetic activity has also been demonstrated.2

21 OCH3

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6 Eleven pimarane-type diterpenes were isolated from an 80% MeOH extract, 18 19 including a new, rearranged 17-nor-pimarane (1), 17-nor-pimaranes (2 - 4), 17nor-9β-pimaranes (5 - 8), and 9β-pimaranes (9 - 11). (1) Icacintrichantholide* (2) Icacintrichanthol A* (3) Icacintrichanthol B* 3 Compounds 1 - 6 and 9 are new structures (*), whereas icacenone (7), humirianthenolide C (8),4 icacinol (10),5 and humirianthol (11)6 are known. All structures were elucidated by means of NMR and HRMS analyses. While the relative stereochemistry was established by NOESY, the absolute configuration of 10 and 11 was confirmed by X-ray crystallographic analysis,7 and that of the new compounds was assumed based on spectral comparisons with 10 and 11. Compounds 7 - 11 displayed cytotoxic activity in the human melanoma MDA- (4) Icacintrichanthol C* (5) 2-Dehydroxyicacenone* (6) Icacinolide* HO

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MB-435 cells (IC50 = 0.7 - 6.4 µM); 8, 10, and 11 were also active in the human colon cancer HT-29 cells (IC50 = 3.0 - 4.9 µM).

HO OH

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The 17-nor-pimarane, 17-nor-9β-pimarane, and 9β-pimarane diterpenes are rare in nature. Our preliminary screening results have suggested the cytotoxic potential of some of these compounds. Further search for promising cytotoxic candidates from these classes of natural products is in progress.

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(7) Icacenone

NMR Results of 1 Key NOESY Correlations

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(8) Humirianthenolide C

(9) 17-Hydroxyicacinol*

IC50 6.4 µM (MDA-MB-435) IC50 0.7 µM (MDA-MB-435) IC50 5.6 µM (MDA-MB-435) 13.3 µM (HT-29) 18.3 µM (HT-29) 3.0 µM (HT-29)

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H-1H COSY

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HMBC

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References

(1) (2) (3) (4) (5) (6) (7)

I.U. Asuzu and I.I. Abubakar, Phytother. Res. 9, 21-25, 1995. M. M. Onakpa and I.U. Asuzu, Asian Pacific J Trop Biomed 3, 628-633, 2013. P. On’Okoko et al., Phytochemistry 24, 2452-2453, 1985. M. Zoghbi et al., Phytochemistry 20, 1669-1673, 1981. P. On’Okoko et al., Tetrahedron 41, 745-748, 1985. I.B Graebner et al., Phytochemistry 53, 955-959, 2000. M.M. Onakpa et al., Chem. Biodiversity, 2014 (in press).

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(10) Icacinol IC50 1.3 µM (MDA-MB-435) 4.2 µM (HT-29)

Acknowledgement

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(11) Humirianthol IC50 1.7 µM (MDA-MB-435) 4.9 µM (HT-29)

M. Onakpa was a recipient of Fulbright research fellowship to carry out the study at UIC.