59(P27) ガマ毒bufadienolideの構造と抗腫瘍活性(ポスター発表の部)

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The toad poison bufadienolides having novel steroidal A/B cis and C/D cis structure with α-pyrone ring at C17-position exhibit a variety of biological activities. To carry out the systematic studies on the biological activities of the bufadienolides, we investigated their cytotoxcities against cell line of human liver cancer PLC/PRF/5 and other cancer cells which are HepG2, HeLa-S3, KB, PC-3 cell including some resistance cells. Our research was extended to studies on relationship the bufadienolides structure and antineoplastic activity. Natural bufadienolide exhibited a potent cytotoxicity against PLC cell than their isomers and related compounds. For cytotoxycities against PLC cell, 16 compounds showed comparatively potent active (IC50 10^<-4>〜10^<-3>μg/ml)(Table 1). Hellebrigenin having 19-CHO group was most active (IC50 1.6×10^<-4>μg/ml). Next, bufalin-3-acetate, gamabufotalin, bufalin, scillarenin, bufotalin, telocinobufagin et. al showed strong cytotoxicities. The 14 β-hydroxy derivatives showed the higher activites than 14β, 15β-epoxy, 14α, 15α-epoxy and α-pyrone ring opening compounds. Therefore, we classified the bufadienolides, cardenolides and their derivatives into the five groups, A〜E, and discussed relationship between structure and activity on each group. The most important factors were found to be the α-pyrone ring, 14β-OH or 14β, 15β-epoxy, 19-CHO, 11α-OH and 16β-OAc groups (Fig. 2 and 3). We also found that the D-ring structure and 3-substituent structure contributed much to the activites for PLC cell. On the base of activities, we attempted to approch to structure/activity correlation by computable calculation. We first calculated to find possible pharmacophores given 16 compounds having potent cytotoxicity against PLC and resistance PLC cell using DISCO(Distance Comparisions). A pharmacophore moldel was established, as indicated in Fig. 4. Then, we determained the structure/activity relationship 80 compounds by CoMFA (Comparative Molecular Field Analysis). Finally, we discussed about the antineoplastic activities of bufadienolides such as cell line of the HepG2, HeLa-S3, KB, PC-3 and P388 cells, including some resistance cell in the comparion with PLC/PRF/5 activities. As the interesting antineoplastic compounds, scillarenin (5), bufalin-3-O-[N-(tert-butoxycarbonyl)hydraidolsuccinate (8), bufalin-3-suberate (10) and its CH3 ester (15), Δ^2/Δ^3-bufalin (81), and Δ^<14>-bufalin (45) were found (Table 2). Also, in the difference of activities of bufadienolides between the original cancer cells and the Resistance cancer cells, the drastic change was not fouund.
天然有機化合物討論会の論文
1996-09-02

59(P27) ガマ毒bufadienolideの構造と抗腫瘍活性(ポスター発表の部)

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