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ABSTRACT: New synthetic routes to (±)-α-lycorane and (±)-1-deoxylycorine were exploited. The endo-cycloadduct of 3,5-dibromo-2-pyrone with styrene-type dienophile provided the pivotal intermediate for the syntheses of the titled natural products.
Organic Letters 12/2012; · 5.86 Impact Factor
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ABSTRACT: (±) trans-Dihydronarciclasine, isolated from Chinese medicinal plant Zephyranthes candida, has been shown to possess quite potent anti-tumoral effect against selected human cancer cell lines. However, little is known about the anti-tumoral effect of (±) trans-dihydronarciclasine in acute myeloid leukemia (AML). This study was performed to investigate the effect of a novel synthetic (±) trans-dihydronarciclasine (code name; HYU-01) in AML. The HYU-01 inhibited the proliferation of various AML cell lines including HL-60 as well as primary leukemic blasts in a dose-dependent manner. To investigate the mechanism of the anti-proliferative effect of HYU-01, cell-cycle analysis was attempted in HL-60 cells, resulting in G1 arrest. The expression levels of CDK2, CDK4, CDK6, cyclin E, and cyclin A were decreased in a time-dependent manner. In addition, HYU-01 up-regulated the expression of the p27, and markedly enhanced the binding of p27 with CDK2, 4, and 6, ultimately resulting in the decrease of their kinase activities. Furthermore, HYU-01 induced the apoptosis through the induction of proapoptotic molecules and reduction of antiapoptotic molecules in association with the activation of caspase-3, -8, and -9. These results suggest that HYU-01 may inhibit the proliferation of HL-60 cells, via apoptosis, as well as G1 block in association with the induction of p27.
Apmis 10/2012; 120(10):836-45. · 1.99 Impact Factor
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Rae-Kwon Kim,
Min-Jung Kim,
Chang-Hwan Yoon,
Eun-Jung Lim,
Ki-Chun Yoo,
Ga-Haeng Lee,
Young-Heon Kim,
Hyeonmi Kim,
Yeung Bae Jin,
Yoon-Jin Lee, Cheon-Gyu Cho,
Yeong Seok Oh,
Myung Chan Gye,
Yongjoon Suh,
Su-Jae Lee
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ABSTRACT: Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs are able to repopulate the tumor. Compounds that target GSCs might be helpful in overcoming resistance to anticancer treatments in human brain tumors. In this study, we showed that 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, suppressed the maintenance of the GSC population in both a glioma cell line and patient-derived glioma cells. Treatment of GSCs with BHP effectively inhibited sphere formation and suppressed the CD133(+) cell population. Treatment with BHP also suppressed expression of the stemness-regulating transcription factors Sox2, Notch2, and β-catenin in sphere-cultured glioma cells. Treatment of GSCs with BHP significantly suppressed two fundamental characteristics of cancer stem cells: self-renewal and tumorigenicity. BHP treatment dramatically inhibited clone-forming ability at the single-cell level and suppressed in vivo tumor formation. BHP markedly inhibited both phosphoinositide 3-kinase/Akt and Ras/Raf-1/extracellular signal-regulated kinase signaling, which suggests that one or both of these pathways are involved in BHP-induced suppression of GSCs. In addition, treatment with BHP effectively sensitized GSCs to chemotherapy and radiotherapy. Taken together, these results indicate that BHP targets GSCs and enhances their sensitivity to anticancer treatments and suggest that BHP treatment may be useful for treating brain tumors by eliminating GSCs.
Molecular pharmacology 05/2012; 82(3):400-7. · 4.53 Impact Factor
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Jin Sun Yoon,
Young Woong Won,
Seo Ju Kim,
Suk Joong Oh,
Eun Shil Kim,
Byoung Kook Kim, Cheon Gyu Cho,
Jung Hye Choi,
Byeong Bae Park,
Min Ho Lee,
Young Yiul Lee
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ABSTRACT: Substituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2-pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5 × 10(-6) M to 5 × 10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up-regulated. Furthermore, pyrone 9 suppressed NF-κB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9-treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice.
Investigational New Drugs 04/2012; · 3.36 Impact Factor
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ABSTRACT: At the end of the tether: Aryl hydrazides that have carbonyl groups tethered at the para position of the aromatic ring undergo an intramolecular Fischer indolization reaction to give the corresponding indolophanes. Strategic insertion of a double bond in the tether enables a tandem aromatic [3,3] sigmatropic rearrangement reaction to occur to give tricyclic benzo[cd]indoles.
Angewandte Chemie International Edition 03/2012; 51(10):2496-9. · 13.45 Impact Factor
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ABSTRACT: A new synthetic route to (±)-pancratistatin was devised utilizing β-silyl styrene as a dienophile in the cycloaddition with 3,5-dibromo-2-pyrone. The TMS group incorporated in the cycloadduct permitted a facile elimination process for the eventual installation of the C(1)-OH function. Subsequent transformations including Curtius rearrangement and Bischler-Napieralski reactions completed the total synthesis of (±)-pancratistatin.
Organic Letters 11/2011; 13(21):5890-2. · 5.86 Impact Factor
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Soo-Jung Woo,
Min-Jung Kim,
Rae-Kwon Kim,
Chang-Hwan Yoon,
Eun-Jung Lim,
Sungkwan An,
Yongjoon Suh,
Ji-Young Song,
In Gyu Kim, Cheon-Gyu Cho,
Su-Jae Lee
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ABSTRACT: Radiation resistance can be overcome by a combination treatment with chemical modifiers. Here, we showed that treatment with 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, in combination with ionizing radiation enhances the sensitivity of human cervical cancer cells to ionizing radiation through overproduction of reactive oxygen species (ROS). The combined treatment with BHP and ionizing radiation caused a decrease in clonogenic survival and an increase in apoptotic cell death in cervical cancer cells. The combined treatment promoted conformational activation of Bax and led to mitochondrial apoptotic cell death. The combination treatment also induced a marked increase in intracellular ROS level. Inhibition of ROS attenuated the radiosensitizing effect of BHP, concurrent with a decrease in Bax activation, a decrease in mitochondrial cell death, and an increase in clonogenic survival. These results indicate that BHP synergistically enhances sensitivity of human cervical cancer cells to ionizing radiation through elevation of intracellular ROS and that ROS-dependent Bax activation is critically involved in the increase in apoptotic cell death induced by the combined treatment with BHP and ionizing radiation.
Anti-cancer drugs 08/2011; 23(1):43-50. · 2.23 Impact Factor
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Annalen der Chemie und Pharmacie 12/2010; 2011(3):455 - 457. · 3.10 Impact Factor
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ABSTRACT: A new synthetic route to the key framework of aspidosperma alkaloid was devised from the cycloadduct of 3-(2-nitrophenyl)-5-bromo-2-pyrone via intramolecular imino Diels-Alder reaction.
Organic Letters 04/2010; 12(9):2012-4. · 5.86 Impact Factor
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ABSTRACT: A new efficient synthetic route to (+/-)-galanthamine was devised by using a tandem C3-selective Stille coupling-IMDA cascade of 3,5-dibromo-2-pyrone as a key strategy.
Organic Letters 04/2010; 12(9):2016-8. · 5.86 Impact Factor
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ABSTRACT: Aryl hydrazides underwent the Fischer indolization reactions, while the N-carbamate group(s) remained intact to directly provide N-Cbz-indoles. This new method allowed the synthesis of various N-Cbz-carbazoles and N,N'-bis-Cbz-pyrrolo[2,3-f]indoles.
Organic Letters 11/2009; 11(23):5454-6. · 5.86 Impact Factor
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ABSTRACT: We have devised a new unified synthetic protocol to (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a- epi-crinamine from the Diels-Alder cycloadduct of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone with TBS vinyl ether. The requisite 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone was prepared from the C3-selective Stille coupling reaction of 3,5-dibromo-2-pyrone. Also noted is that the vinyl bromide can be used as a handle for further derivatization.
The Journal of Organic Chemistry 08/2008; 73(16):6258-64. · 4.45 Impact Factor
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ABSTRACT: The regioselective synthesis and Diels-Alder cycloaddition of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone provided a new synthetic route to crinine. The vinyl bromide group can be used as a handle for further derivatization.
Organic Letters 03/2008; 10(4):601-3. · 5.86 Impact Factor
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ABSTRACT: 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10(-6) M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10(-6) M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-beta1, TGF-beta receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-beta1, suggesting that TGF-beta1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10(-7), 10(-6)and 10(-5) M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-beta1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.
International Journal of Oncology 03/2008; 32(2):387-96. · 2.40 Impact Factor
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ABSTRACT: The regioselective synthesis and Diels-Alder cycloaddition of 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone provided a new efficient synthetic route to joubertinamine (9.6% total yield over 10 steps).
Organic Letters 09/2007; 9(17):3391-2. · 5.86 Impact Factor
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ABSTRACT: N,N'-Diaryl hydrazides tethered with a polyether group at the meta positions undergo [5,5]-sigmatropic (benzidine) rearrangement reactions to furnish 4,4'-diamino-biphenyls (benzidines) strapped with a polyether unit at the 2,2'-positions.
Organic Letters 09/2007; 9(16):3185-6. · 5.86 Impact Factor
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Angewandte Chemie International Edition 02/2007; 46(13):2303-5. · 13.45 Impact Factor
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ABSTRACT: We devised a practical synthetic route to azobenzenophanes via successive Cu- and Pd-catalyzed coupling reaction of aryl hydrazide and aryl halide followed by Cu(I)-mediated oxidation reaction.
The Journal of Organic Chemistry 02/2007; 72(2):679-82. · 4.45 Impact Factor
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ABSTRACT: Readily prepared from the regioselective Pd-catalyzed coupling reactions of 3,5-dibromo-2-pyrone, 3-bromo-2-pyrone-5-carboxylates undergo tandem uninterrupted sequential Diels-Alder cycloaddition reactions with allyl vinyl ethers in a highly regio- and stereoselective fashion to provide a series of novel tetracyclolactones in good yields.
The Journal of Organic Chemistry 09/2006; 71(17):6701-4. · 4.45 Impact Factor
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ABSTRACT: [Structure: see text] An efficient one-step synthetic protocol for 3-methyl-5-bromo-2-pyrone was developed using the C3-selective Pd-catalyzed coupling reaction of 3,5-dibromo-2-pyrone with Me3Al-dimethylaminoethanol complex. A subsequent seven-step reaction sequence provided a cyclohexenyl bromide, which served as the key intermediate for the synthesis of the keto analogue of phomactin A, in 31% overall yield.
Organic Letters 08/2006; 8(15):3343-5. · 5.86 Impact Factor
