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Starting materials of phosphasugars, 1-phenyl-2-phospholene 1-oxides, were prepared from dienes and phenylphosphonous dichloride (dichlorophenylphosphine). Several substituted novel phosphasugars (3- or 4-halo-substituted)-1-phenyl-2-phospholene 1-oxides as well as 1-phenyl-2-phospholane 1-oxides were prepared from 2-phospholenes. The synthesized compounds were evaluated for their antitumor activities against the leukemia cell lines (U937 and K562) by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 2,3,4-Tribromo-3-methyl-1-phenylphospholane 1-oxide showed superior antitumor activity against U937 and K562 cell lines in a comparative evaluation with Glivec. The analysis by flow cytometry implied that 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide induced apoptosis to leukemia cell lines.

A novel phospha sugar analogue, 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (DBMPP), was prepared from 1-phenyl-3-methyl-2- phospholene 1-oxide and evaluated by in vitro MTT method forleukemia cells and microscopic observations forsolid tumor cells, e.g., stomach cancer cells. The evaluation revealed clearly that the synthesized phospha sugar analogue DBMPP has competent potentials and excellent anti-cancer activities that killed selectively and specifically the leukemia cells of cell lines of K562 and U937 but did not give any damages on healthy leukocyte. Moreover it was revealed that DBMPP killed solid cancer cells such as stomach cancer cells and melanoma of cell lines of MKN45 and G361. Therefore, DBMPP should exert anti-proliferative effects for different kinds of tumor cells based on the in vitro evaluations. The cell cycle analyses by flow cytometry for K562 and U937 cells clearly demonstrated that the mechanism of the anti-proliferative effect on the human tumor cells is apoptosis induced by DBMPP.

[Background] Sugar derivatives whose oxygen atom in the hemiacetal ring is replaced by a carbon, nitrogen, sulfur atom, and etc., are celled as pseudo sugars. The synthesis and bioassay of these pseudo sugars are well investigated and are known as potential bioactive materials. Phospha sugar, which is one of pseudo sugars, having a phosphorus atom instead of the oxygen atom in the hemiacetal ring, is little known. The synthesis and bioassay of phospha sugars are not well studied in detail. We synthesized the 2, 3, 4-tribromo-3-methyl-1-phenyl phospholane 1-oxide (TMPP) and 2, 3-dibromo-3-methyl-1-phenyl phospholane 1-oxide (DMPP) by the nucleophilic substitution reactions, and found their anti-leukemic activities. [Purpose] The aims of the present study were to evaluate the inhibition of proliferation and induction of apoptosis in leukemia cell treated with TMPP or DMPP, and define the target molecules for TMPP in leukemia cells. [Methods] The cells used in this study were human leukemia cell lines, K562, U937, and YRK2 cells. For proliferation analysis, MTT assays were performed in leukemia cells treated with TMPP. For cell cycle analysis, flow cytometory analysis was performed in leukemia cells treated with TMPP or DMPP by PI staining. For analysis of mitotic regulatory proteins (p27, p21, Skp2, Cdc25B, Cyclin D1, Survivin, and Aurora kinase B), Western blotting was performed in leukemia cells treated with TMPP. [Results] In leukemia cell lines, DMPP and TMPP significantly inhibited the cell proliferation, and TMPP more strongly inhibited the cell proliferation than DMPP. 10 μM TMPP significantly induced G2/M phase arrest, and 25 μM TMPP induced apoptosis in leukemia cells. In leukemia cells, 10 μM TMPP reduced protein of Aurora kinase B, Survivin, Cyclin D1, Skp2 KIS, and FoxM1, while increased protein expression of p21and p27 by western blot analysis. Moreover, 25 μM TMPP activated caspase-3 and caspase-9, cleaved PARP, and reduced Bcl-2. [Conclusions] In this study, we report in the first time the possibility of phospha sugar derivatives as anti-leukemic agents in therapy for leukemias, and analysis of their characterizations. DMPP significantly inhibited the proliferation, and induced apoptosis of leukemia cells. These results demonstrated that the FoxM1, which is an essential transcription factor for cell growth and regulates expression of the mitotic regulators, is one of the targets for DMPP. Therefore, DMPP or TMPP has possibility as new agents for FoxM1 in leukemia therapy.