41 Phoma sp.の生産する新規ヒトトポイソメラーゼI阻害物質、EK004-1,-2(口頭発表の部)

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In the course of a screening program for specific inhibitors of human topoisomerase I using a recombinant yeast, we have discovered two new active compounds in the culture broth of a fungus, Phoma sp. BAUA2861. We designated these compounds as topopyrone A (1) and B (2). The physico-chemical properties of 1 and 2 are summarized in Table 1. The molecular weight of 1 and 2 were deduced to be 372 from m/z 371 [M-H^-] in ESI-Neg. and the presence of one chlorine atom was indicated by a peak intensity ratio of isotope peaks. The molecular formulae of 1 and 2 were finally established as C_<18>H_9O_7Cl by HRFAB-MS. Treatment of 1 with an excess of diazomethane afforded the methyl derivative (3) whose HREI-MS gave the molecular formula C_<22>H_<17>O_7Cl. The ^1H and ^<13>C NMR data of 3 are summarized in Table 2. As a result of 2D correlation NMR experiment, these signals were assigned as shown in Fig. 2. Acetylation of 1 gave triacetate (5), which had no epoxide ring. These results indicated that epoxide ring of 3 was formed by addition of diazomethane with loss of N_2 to the ketone of 1. Methylation of 2 with diazomethane gave compound 4. From the result of 2D correlation NMR experiment, the ^1H and ^<13>C NMR data of 4 (Table 2) was assigned as shown in Fig. 3. The structures of 1 and 2 were thus elucidated as shown. Topopyrone A (1) and B (2) inhibited selectively recombinant yeast growth dependent on expression of human topoisomerase I with IC_<50> value of 1.22ng/ml and 0.15ng/ml, respectively. The activity and selectivity of 2 were comparable to those of camptothecin. The relaxation of supercoiled pBR322 DNA by human DNA topoisomerase I was inhibited by these compounds as potently as by camptothecin. 1 and 2 were cytotoxic to all the tumor cell line when tested in vitro, but slightly weaker than camptothecin. We also found that 2 has a potent inhibitory activity against herpes virus, especially varicella zoster virus (VZV). It inhibited VZV growth with EC_<50> value of 0.038μg/ml, which is 24-fold stronger than that of acyclovir (0.9μg/ml). 1 and 2 were inhibitory to Gram-positive bacteria including quinolone-resistant MRSA.
天然有機化合物討論会の論文
1999-09-01

41 Phoma sp.の生産する新規ヒトトポイソメラーゼI阻害物質、EK004-1,-2(口頭発表の部)

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