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. 2015 Nov 25;58(22):8896-906.
doi: 10.1021/acs.jmedchem.5b01187. Epub 2015 Nov 16.

Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells

Venumadhav Janganati  1   2 , Jessica Ponder  1   2 , Craig T Jordan  1   2 , Michael J Borrelli  1   2 , Narsimha Reddy Penthala  1   2 , Peter A Crooks  1   2
Affiliations

Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells

Venumadhav Janganati et al. J Med Chem. .

Abstract

Novel carbamate (7a-7h) and carbonate (7i, 7j, and 8) dimers of melampomagnolide B have been synthesized by reaction of the melampomagnolide-B-triazole carbamate synthon 6 with various terminal diamino- and dihydroxyalkanes. Dimeric carbamate products 7b, 7c, and 7f exhibited potent growth inhibition (GI50 = 0.16-0.99 μM) against the majority of cell lines in the NCI panel of 60 human hematological and solid tumor cell lines. Compound 7f and 8 exhibited anticancer activity that was 300-fold and 1 × 10(6)-fold more cytotoxic than DMAPT, respectively, at a concentration of 10 μM against rat 9L-SF gliosarcoma cells. Compounds 7a-7j and 8 were also screened against M9-ENL1 and acute myelogenous leukemia (AML) primary cell lines and exhibited 2- to 10-fold more potent antileukemic activity against M9-ENL1 cells (EC50 = 0.57-2.90 μM) when compared to parthenolide (EC50 = 6.0) and showed potent antileukemic activity against five primary AML cell lines (EC50 = 0.76-7.3 μM).

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Figures

Figure 1
Figure 1
The anticancer sesquiterpene lactones parthenolide (PTL) (1), dimethylaminoparthenolide (DMAPT) fumarate (2), melampomagnolide B (MMB) (3) and micheliolide (MCL) (4).
Figure 2
Figure 2
Dose-response curve for compounds 7f, 8 and PTL against rat gliosarcoma cells (9L-SF): Cell survival as a function of drug concentration for cells treated for 48 h with the indicated drug. Each datum point represents the mean plus standard error of the mean for three experiments. Drugs 7f and 8 were markedly more toxic than DMAPT, with drug 8 being one million-fold more toxic than DMAPT at a concentration of 10 μM.
Figure 3
Figure 3
Dose-response curves for PTL and MMB derivatives with AML cells. A) Dimers 7a-7j and 8 exhibited potent antileukemic activity with EC50 values in the range 0.57-2.9 μM against M9-ENL1 cells. B) Carbamate dimers were equally effective in the parthenolide-resistant primary sample AML01 relative to other primary cell samples, suggesting that these compounds may not be hindered by common mechanisms of drug resistance in relapsed AML patients.
Scheme 1
Scheme 1
Synthesis of carbamate and carbonate dimers of MMB (7a-7j)
Scheme 2
Scheme 2
Synthesis of MMB dicarbonate (8)
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References

    1. Knight DW. Feverfew: chemistry and biological activity. Nat. Prod. Rep. 1995;12:271–276. - PubMed
    1. Skalska J, Brookes PS, Nadtochiy SM, Hilchey SP, Jordan CT, Guzman ML, Maggirwar SB, Briehl MM, Bernstein SH. Modulation of cell surface protein free thiols: a potential novel mechanism of action of the sesquiterpene lactone parthenolide. PLoS One. 2009;4:e8115. - PMC - PubMed
    1. Nasim S, Crooks PA. Antileukemic activity of aminoparthenolide analogs. Bioorg. Med. Chem. Lett. 2008;18:3870–3873. - PubMed
    1. Hewamana S, Alghazal S, Lin TT, Clement M, Jenkins C, Guzman ML, Jordan CT, Neelakantan S, Crooks PA, Burnett AK, Pratt G, Fegan C, Rowntree C, Brennan P, Pepper C. The NF-kappaB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target. Blood. 2008;111:4681–4689. - PubMed
    1. Oka D, Nishimura K, Shiba M, Nakai Y, Arai Y, Nakayama M, Takayama H, Inoue H, Okuyama A, Nonomura N. Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-kappaB. Int. J. Cancer. 2007;120:2576–2581. - PubMed

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