- Novel Multiple Type Molecular Targeted Antitumor Agents: Preparation and Preclinical Evaluation of Low-Molecular-Weight Phospha Sugar Derivatives
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Phospha sugar derivatives of 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide and 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide were synthesized from 2-phospholenes and evaluated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide method against leukemia cell lines, and then characterized by cell cycle analysis, Western blot analysis, and molecular docking simulation. Phospha sugar derivatives were revealed to be potential antitumor agents against leukemia cell lines such as U937 and K562. Cell cycle analysis indicated that phospha sugar derivatives induced apoptoses. Western blot analyses against U937 showed that phospha sugar derivatives regulate many mitotic regulators in cell cycle. Results of molecular docking simulation suggested that phospha sugar derivatives enter the pockets present in cell cycle and apoptosis-related proteins.
- Makita, Reiko,Yamashita, Mitsuji,Yamaoka, Mayumi,Fujie, Michio,Nakamura, Satoki,Oshikawa, Tatsuo,Yamashita, Junko,Yamada, Manabu,Asai, Kazuhide,Suyama, Takuya,Kondo, Mitsuru,Hasegawa, Hiroko,Okita, Yoshimitsu,Hirakawa, Kazutaka,Toda, Mitsuo,Ohnishi, Kazunori,Sugimura, Haruhiko
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- Research on phospha sugar analogues to develop novel multiple type molecular targeted antitumor drugs against various types of tumor cells
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The synthesis and antitumor activity evaluation of new branched phospha sugars, especially deoxybromophospha sugar derivatives or bromophospholanes of 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (DBMPP: 3) and 2,3,4-tribromo-3-methyl-1- phenylphospho
- Makita, Reiko,Yamashita, Mitsuji,Fujie, Michio,Yamaoka, Mayumi,Kiyofuji, Keita,Yamada, Manabu,Yamashita, Junko,Tsunekawa, Kenji,Asai, Kazuhide,Suyama, Takuya,Toda, Mitsuo,Tanaka, Yasutaka,Sugimura, Haruhiko,Magata, Yasuhiro,Ohnishi, Kazunori,Nakamura, Satoki
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p. 213 - 223
(2013/07/11)
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- Research and development of phospha sugar anti-cancer agents with anti-leukemic activity
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We have synthesized three deoxybromophospha sugar analogues, 4-bromo-3-methyl-l-phenyl-2-phospholene 1-oxide (MBMPP (2)), 2,3-dibromo-3-methyl-l-phenylphospholane 1-oxide (DBMPP (3)), and 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TBMPP (4)), by the reaction of 3-methyl-l-phenyl-2-phospholene 1-oxide (lb) and/or 2 with bromine, and investigated their potentials as anti-leukemic agents against human leukemia cell lines of K562 and U937. Cells' growth inhibition was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) in vitro assay. All agents showed inhibitory effects on leukemia cell proliferation, indicating that inhibition appeared to be dependent on number of bromine substituent in the heterocyclic structure. Further, the phospha sugar derivatives did not show any inhibitory effects on normal cell proliferation. These agents may facilitate the development of new strategies in molecular targeting anti-leukemic therapy.
- Yamashita, Junko,Suyamab, Takuya,Asai, Kazuhide,Yamada, Manabu,Niimi, Taishi,Fujie, Michio,Nakamura, Satoki,Ohnishi, Kazunori,Yamashita, Mitsuji
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- Preparation and characterization of novel 4-bromo-3,4-dimethyl-1-phenyl-2- phospholene 1-oxide and the analogous phosphorus heterocycles or phospha sugars
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4-Bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (3c) was first synthesized from 3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (2c) by a bromo-radical substitution reaction occurred at C-4 position by N-bromosuccinimide and 2,2′-azobisisobutyronitrile. The novel phospha sugar analogue 3c exerted high anti-proliferative effect on U937 cells evaluated by MTT in vitro methods and was much more efficient than that of Gleevec, which is known as a molecule targeting chemotherapeutical agent. The substitution of 2-phospholenes at C-3 and C-4 position with methyl groups as well as 4-bromo substituent suggests a good anti-proliferative effect.
- Yamada, Manabu,Yamashita, Mitsuji,Suyama, Takuya,Yamashita, Junko,Asai, Kazuhide,Niimi, Taishi,Ozaki, Nobuhisa,Fujie, Michio,Maddali, Kasthuraiah,Nakamura, Satoki,Ohnishi, Kazunori
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experimental part
p. 5943 - 5946
(2010/11/18)
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