The long-term objective of this proposal is to develop a novel class of anti-cancer agents based on the plant derived compound parthenolide (PTL). Previous studies have demonstrated that PTL has potent cytotoxic activity against a broad range of malignancies, including cancers of the breast, lung, prostate, colon, liver, kidney, pancreas, brain, and bone. In addition to solid tumor studies, several groups including our own have focused on human leukemia (or related hematologic malignancies). We have demonstrated that PTL is highly cytotoxic to primary human leukemia specimens, but non-toxic to normal blood-forming tissues. Thus, the collective evidence suggests that PTL has broad potential as an anti-cancer agent. However, despite the remarkable properties of this compound, clinical development has been very limited, likely due to the poor pharmacological properties of PTL. Indeed, to our knowledge the only PTL-based compound to reach clinical trial stage work is dimethylamino parthenolide (DMAPT), which we previously developed as an orally bioavailable PTL analog. Thus, going forward we believe that applying novel strategies to create more pharmacologically useful forms of PTL-based agents is a high priority. In the course of performing various chemical modifications of PTL, it was demonstrated that the C-10 methyl group can be hydroxylated by reaction with a suitable oxidizing agent. This reaction changes the geometry of the C-9-C-10 double bond from Z to E to afford a hydroxymethyl 1(10)-cis-parthenolide analogue, a compound previously described as melampomagnolide B (MM-B). Intriguingly, the biological activity of MM-B is identical to PTL, retaining strong specificity for leukemia cells. The presence of the C-10 hydroxymethyl group now creates the opportunity for designing an entirely new class of PTL analog. Thus, in the present application we propose to develop and test novel MM-B-based products. Specifically, the aims of the study will be to 1) synthesize novel water-soluble MM-B prodrugs, 2) perform pharmacological and biological efficacy studies, and 3) perform molecular and cellular characterization of the mechanism of action of MM-B. Taken together these studies will create and validate an entirely new type of anti-cancer agent. In addition, by characterizing the molecular mechanism of action of this novel PTL derivative, it should be possible to further refine strategies for the selective eradication of cancer cells.

Public Health Relevance

The goal of this project is to identify new and better ways to treat leukemia. We propose to develop new drugs derived from the naturally occurring compound parthenolide, which has shown significant activity as an anti-leukemia agent. Our studies will synthesize and test novel orally-available parthenolide derivatives

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Fu, Yali
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University of Kentucky
Schools of Pharmacy
United States
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Albayati, Zaineb A F; Janganati, Venumadhav; Chen, Zheng et al. (2017) Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia. Bioorg Med Chem 25:1235-1241
Janganati, Venumadhav; Ponder, Jessica; Thakkar, Shraddha et al. (2017) Succinamide derivatives of melampomagnolide B and their anti-cancer activities. Bioorg Med Chem 25:3694-3705
Bommagani, Shobanbabu; Ponder, Jessica; Penthala, Narsimha R et al. (2017) Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells. Eur J Med Chem 136:393-405
Pei, Shanshan; Minhajuddin, Mohammad; D'Alessandro, Angelo et al. (2016) Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells. J Biol Chem 291:21984-22000
Penthala, Narsimha Reddy; Janganati, Venumadhav; Alpe, Terri L et al. (2016) N-[11CH3]Dimethylaminoparthenolide (DMAPT) uptake into orthotopic 9LSF glioblastoma tumors in the rat. Bioorg Med Chem Lett 26:5883-5886
Janganati, Venumadhav; Ponder, Jessica; Jordan, Craig T et al. (2015) Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells. J Med Chem 58:8896-906
Karmakar, A; Xu, Y; Mustafa, T et al. (2015) Nanodelivery of Parthenolide Using Functionalized Nanographene Enhances its Anticancer Activity. RSC Adv 5:2411-2420
Bommagani, Shobanbabu; Penthala, Narsimha R; Parkin, Sean et al. (2015) Crystal structure of (E)-13-(pyrimidin-5-yl)parthenolide. Acta Crystallogr E Crystallogr Commun 71:1536-8
Penthala, Narsimha Reddy; Zong, Hongliang; Ketkar, Amit et al. (2015) Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents. Eur J Med Chem 92:212-20
Nakshatri, H; Appaiah, H N; Anjanappa, M et al. (2015) NF-?B-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT. Cell Death Dis 6:e1608

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