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01.08.2010 | PRECLINICAL STUDIES | Ausgabe 4/2010

Investigational New Drugs 4/2010

Development and pharmacologic characterization of deoxybromophospha sugar derivatives with antileukemic activity

Zeitschrift:
Investigational New Drugs > Ausgabe 4/2010
Autoren:
Satoki Nakamura, Mitsuji Yamashita, Daisuke Yokota, Isao Hirano, Takaaki Ono, Michio Fujie, Kiyoshi Shibata, Taishi Niimi, Takuya Suyama, Kasthuraiah Maddali, Kazuhide Asai, Junko Yamashita, Yukiko Iguchi, Kazunori Ohnishi

Summary

Here, we synthesized two phospha sugar derivatives, 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP) and 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (DMPP) by reacting 3-methyl-1-phenyl-2-phospholene 1-oxide with bromine, and investigated their potential as antileukemic agents in cell lines. Both agents showed inhibitory effects on leukemia cell proliferation, with mean IC50 values of 6.25 μmol/L for TMPP and 23.7 μmol/L for DMPP, indicating that inhibition appeared to be dependent on the number of bromine atoms in the structure. Further, TMPP at 10 μmol/L and DMPP at 20 μmol/L induced G2/M cell cycle block in leukemia cells, and TMPP at 20 μmol/L induced apoptosis in these cells. TMPP treatment effected a reduction in both cell cycle progression signals (FoxM1, KIS, Cdc25B, Cyclin D1, Cyclin A, and Aurora-B) and tumor cell survival (p27 Kip1 and p21 Cip1 ), as well as induced the activation of caspase-3 and -9. Further, treatment with TMPP significantly reduced the viability of AML specimens derived from AML patients, but only slightly reduced the viability of normal ALDHhi progenitor cells. We also observed that FoxM1 mRNA was overexpressed in AML cells, and treatment with TMPP reduced FoxM1 mRNA expression in AML cells. Here, we report on the synthesis of TMPP and DMPP and demonstrate that these agents hinder proliferation of leukemia cells by FoxM1 suppression, which leads to G2/M cell cycle block and subsequent caspase-3-dependent apoptosis in acute leukemia cells. These agents may facilitate the development of new strategies in targeted antileukemic therapy.

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