3(A-3) 脂肪細胞分化誘導阻害物質ミコフェノール酸及び誘導体の分子標的(口頭発表の部)

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Mycophenolic acid (MPA) (1), known as an inhibitor of inosine monophosphate dehydrogenase (IMPDH) was found to inhibit the differentiation of 3T3-L1 pre-adipocytes1) into mature adipocytes. Inhibition of IMPDH could be abrogated by the addition of guanosine or guanosine derivatives in the case of 1 as an inducer of differentiation in erythroleukemia cell lines such as HL-60 or K562 cells.5),6),7) However, the inhibitory activity of 1 did not affect by the addition of guanosine or any other derivatives, XMP, GMP and GTP. This finding suggested that 1 inhibits 3T3-L1 cell differentiation via the molecular target except IMPDH. To confirm this possibility, we performed the structure-activity relationship study synthesizing various analogs of MPA (Fig. 1). The SAR study suggested also that the target molecule of 1 is not IMPDH8) but a different specific factor. We therefore focused our attention on the issue if MPA inhibits the function of peroxisome proliferatior-activated receptor gamma (PPARγ), one of the key nuclear receptor on adipocyte differentiation. Mycophenolic acid (1) was found to inhibit the function of PPARγ activated by pioglitazon under the reporter assay conditions (Fig. 2). The 1:1 specific interaction between MPA and immobilized PPARγ was detected based on surface plasmon resonance (SPR) as shown in Fig. 3. The results indicated that MPA is at least a partial antagonist of PPARγ. The alcohol analog of MPA (6) was found to be an inhibitor having a higher affinity toward PPARγ. We next focused our attention on design and synthesis of HDAC (histone deacetylase) inhibitor. Hydroxamic acid analog of MPA, namely MPAHA (13) was successfully found to be an inhibitor of HDAC, whereas 1 did not show inhibition of HDAC (Fig. 4). In conclusion, IMPDH is not the only molecular target8),9) toward MPA (1), and 1 could be an attractive leading compound to develop useful bioprobes or medicines having molecular targets except IMPDH.
天然有機化合物討論会の論文
2004-10-01

3(A-3) 脂肪細胞分化誘導阻害物質ミコフェノール酸及び誘導体の分子標的(口頭発表の部)

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