- Dimeric small molecule agonists of EphA2 receptor inhibit glioblastoma cell growth
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EphA2 receptor kinase could become a novel target for anti-glioblastoma treatment. Doxazosin previously identified acts like the endogenous ligand of EphA2 and induces cell apoptosis. Through lead structure modification a derivative of Doxazosin possessing unique dimeric structure showed an improvement in the activity. In the current study, we expanded the dimeric scaffold by lead optimization to explore the chemical space of the conjoining moieties and a slight variation to the core structure. 27 new derivatives were synthesized and examined with EphA2 overexpressed and wild type glioblastoma cell lines for cell proliferation and EphA2 activation. Three new compounds 3d, 3e, and 7bg showed potent and selective activities against the growth of EphA2 overexpressed glioblastoma cells. Dimer 3d modification replaces the long alkyl chain with a short polyethylene glycol chain. Dimer 7bg has a relatively longer polyethylene glycol chain in comparison to compound 3d and the length is more similar to the lead compound. Whereas dimer 3e has a rigid aromatic linker exploring the chemical space. The diversity of the linkers in the active suggest additional hydrogen binding sites has a positive correlation to the activity. All three dimers showed selective activity in EphA2 overexpressed cells, indicating the activity is correlated to the EphA2 targeting effect.
- Hanna, Jovana,Li, Yaxin,Orahoske, Cody M.,Petty, Aaron,Salem, Fatma M.,Su, Bin,Wang, Bingcheng,Zhang, Wenjing
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- NOVEL ANTITUMOUR AGENTS AND METHODS OF THEIR USE
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Antitumor compounds based on the α1-adrenoceptor antagonist, doxazosin, as well as compositions and methods of use. The disclosed compounds induce apoptosis in cancer cells.
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Page/Page column 30
(2008/06/13)
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- Pharmacological exploitation of the alpha1-adrenoreceptor antagonist doxazosin to develop a novel class of antitumor agents that block intracellular protein kinase B/Akt activation.
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The alpha1-adrenoreceptor antagonist doxazosin induces apoptosis in malignant cells with moderate potency via an alpha1-adrenoreceptor-independent mechanism. Here, we demonstrate that the ability of doxazosin to induce apoptosis in PC-3 prostate cancer cells was, in part, attributable to the inhibition of protein kinase B (PKB)/Akt activation. The separation of the effect of doxazosin on apoptosis from its original pharmacological activity provides molecular underpinnings to develop novel antitumor agents. Replacement of the (2,3-dihydro-benzo[1,4]dioxane)-carbonyl moiety of doxazosin with aryl-sulfonyl functions dramatically improves the potency in facilitating Akt deactivation and inducing apoptosis. The optimal compounds, 33 and 44, were effective in apoptosis induction at low micromolar concentrations irrespective of androgen dependency and p53 functional status. Both agents were active in suppressing the growth of a panel of 60 cancer-cell lines with IC50 values of 2.2 and 1.5 microM, respectively. Together, these in vitro efficacy data suggest the translational potential of these agents in prostate cancer treatment.
- Shaw, Yeng-Jeng,Yang, Ya-Ting,Garrison, Jason B,Kyprianou, Natasha,Chen, Ching-Shih
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p. 4453 - 4462
(2007/10/03)
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- A modified synthesis of iodoazidoaryl prazosin.
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The antihypertension agent iodoazidoaryl prazosin (IAAP) has been made using a convergent route involving addition of an acylated piperazine 7 to 2-chloroquinazoline 5. IAAP has been shown to function as a multidrug resistance (MDR) reversal agent and bind to P-glycoprotein, a transmembrane transport protein. A study is also reported involving palladium-catalyzed substitution with amine heterocycles. With N,N-bis(2,6-diisopropyl)dihydroimidazolium chloride (10) as the ligand (2 mol %) for palladium(II) acetate (2 mol %) in THF at room temperature, morpholine added to 5 in 81% yield.
- Andrus, Merritt B,Mettath, Sashikumar N,Song, Chun
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p. 8284 - 8286
(2007/10/03)
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