- Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis
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Tropolones, such as β-thujaplicin, are small lead-like natural products that possess a variety of biological activities. While the β-substituted natural products and their synthetic analogs are potent inhibitors of human cancer cell growth, less is known about their α-substituted counterparts. Recently, we synthesized a series of α-substituted tropolones including 2-hydroxy-7-(naphthalen-2-yl)cyclohepta-2,4,6-trien-1-one (α-naphthyl tropolone). Here, we evaluate the antiproliferative mechanisms of α-naphthyl tropolone and the related α-benzodioxinyl analog. The α-substituted tropolones inhibit growth of lymphocytic leukemia cells, but not healthy blood cells, with nanomolar potency. Treatment of leukemia cell lines with the tropolone dose-dependently induces apoptosis as judged by staining with annexin V and propidium iodide and Western blot analysis of cleaved caspase 3 and 7. Moreover, pre-treatment of cells with the caspase inhibitor Z-VAD-FMK inhibited the apoptotic effects of the tropolone in two lymphocytic lines. Caspase inhibition also blocked elevated histone acetylation caused by the tropolone, indicating that its effects on histone acetylation are potentiated by caspases. In contrast, α-naphthyl tropolone upregulated p53 expression and phosphorylation of Akt and mTOR in a manner that was not rescued by caspase inhibition. The effects of tropolone were blocked by co-incubation with high levels of free extracellular iron but not by pre-loading with iron. Additionally, dose and time dependent reduction in ex vivo viability of cells from leukemia patients was observed. Taken together, we demonstrate that α-substituted tropolones upregulate DNA damage repair pathways leading to caspase-dependent apoptosis in malignant lymphocytes.
- Li, Jin,Falcone, Eric R.,Holstein, Sarah A.,Anderson, Amy C.,Wright, Dennis L.,Wiemer, Andrew J.
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- HINOKITIOL ANALOGUES, METHODS OF PREPARING AND PHARMACEUTICAL COMPOSITIONS THEREOF
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Disclosed are analogues of hinokitiol, methods for preparing them, and pharmaceutical compositions thereof. Also disclosed are methods for their use in treating iron-related diseases.
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Page/Page column 211
(2019/11/04)
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- COMPOSITIONS AND METHODS FOR INHIBITING INFLUENZA RNA POLYMERASE PA ENDONUCLEASE
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There are provided inter alia metalloenzyme inhibitors, such as inhibitors of influenza A RNA dependent RNA polymerase PA subunit endonuclease, and methods of synthesis and use of the same.
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Paragraph 0585
(2017/09/27)
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- An Improved Synthesis of 2,7-Dihydroxytropone (3-Hydroxytropolone)
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2,7-Dihydroxytropone is efficiently prepared from 2-methoxytropone by bromination with N-bromosuccinimide, reaction of the resultant 2-bromo-7-methoxytropone with acetyl trifluoroacetate in situ, and hydrolysis of the 2,7-diacetoxytropone thus obtained with aqueous acetic acid.The intermediacy of a 2-acetoxy-1-bromo-3-methoxytropylium salt in the acetoxylation step is suggested.
- Takeshita, Hitoshi,Mori, Akira
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p. 578 - 579
(2007/10/02)
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- 4,9-Dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine derivatives
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Aldose reductase inhibitors of the formula STR1 in which R1 is COOH and R2 is hydrogen, 8-halo or 6-hydroxy, or R1 is CON(R3)-CH2 COOH wherein R3 is lower alkyl and R2 is hydrogen or 8-halo are useful for treating diabetic complications.
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