Development and pharmacologic characterization of deoxybromophospha sugar derivatives with antileukemic activity.
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 IC(50) values of 6.25 micromol/L for TMPP and 23.7 micromol/L for DMPP, indicating that inhibition appeared to be dependent on the number of bromine atoms in the structure. Further, TMPP at 10 micromol/L and DMPP at 20 micromol/L induced G2/M cell cycle block in leukemia cells, and TMPP at 20 micromol/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 ALDH(hi) 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.
Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu city, Shizuoka, 431-3192, Japan. satonaka@hama-med.ac.jp
Satoki
S
Nakamura
Mitsuji
M
Yamashita
Daisuke
D
Yokota
Isao
I
Hirano
Takaaki
T
Ono
Michio
M
Fujie
Kiyoshi
K
Shibata
Taishi
T
Niimi
Takuya
T
Suyama
Kasthuraiah
K
Maddali
Kazuhide
K
Asai
Junko
J
Yamashita
Yukiko
Y
Iguchi
Kazunori
K
Ohnishi
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003498:Cyclic P-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008875:Middle Aged; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*
C552032:2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide; C548839:2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide; D000970:Antineoplastic Agents; D003498:Cyclic P-Oxides; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D009943:Organophosphorus Compounds; C013194:phospholenes; D053148:Caspase 3; D053453:Caspase 9