Kanai Y, Ishiyama D, Senda H, Iwatani W, Takahashi H, Konno H, Tokumasu S, Kanazawa S
Institute of Biotechnology Applied to Soil Eumycetes, Akita, Japan.
J Antibiot (Tokyo). 2000 Sep;53(9):863-72. doi: 10.7164/antibiotics.53.863.
In the course of a screening program for specific inhibitors of human topoisomerase I using a recombinant yeast, we have discovered four new active compounds. All four compounds were isolated from the culture broth of a fungus, Phoma sp. BAUA2861, and two of them were isolated from the culture broth of a fungus, Penicillium sp. BAUA4206. We designated these compounds as topopyrones A, B, C and D. Topopyrones A, B, C and D selectively inhibited recombinant yeast growth dependent on expression of human topoisomerase I with IC50 values of 1.22, 0.15, 4.88 and 19.63 ng/ml, respectively. The activity and selectivity of topopyrone B were comparable to those of camptothecin. The relaxation of supercoiled pBR322 DNA by human DNA topoisomerase I was inhibited by these compounds, however they did not inhibit human DNA topoisomerase II. Topopyrones A, B, C and D were cytotoxic to all tumor cell lines when tested in vitro. Topopyrone B has potent inhibitory activity against herpesvirus, especially varicella zoster virus (VZV). It inhibited VZV growth with EC50 value of 0.038 microg/ml, which is 24-fold stronger than that of acyclovir (0.9 microg/ml). Topopyrones A, B, and C were inhibitory to Gram-positive bacteria.
在一项使用重组酵母筛选人拓扑异构酶I特异性抑制剂的过程中，我们发现了四种新的活性化合物。所有这四种化合物均从一种真菌——茎点霉属BAUA2861的培养液中分离得到，其中两种还从一种青霉属真菌BAUA4206的培养液中分离得到。我们将这些化合物命名为拓扑吡喃酮A、B、C和D。拓扑吡喃酮A、B、C和D选择性地抑制依赖于人拓扑异构酶I表达的重组酵母生长，其IC50值分别为1.22、0.15、4.88和19.63 ng/ml。拓扑吡喃酮B的活性和选择性与喜树碱相当。这些化合物抑制人DNA拓扑异构酶I对超螺旋pBR322 DNA的松弛作用，但不抑制人DNA拓扑异构酶II。在体外测试时，拓扑吡喃酮A、B、C和D对所有肿瘤细胞系均具有细胞毒性。拓扑吡喃酮B对疱疹病毒，尤其是水痘带状疱疹病毒（VZV）具有强大的抑制活性。它抑制VZV生长的EC50值为0.038 μg/ml，比阿昔洛韦（0.9 μg/ml）强24倍。拓扑吡喃酮A、B和C对革兰氏阳性菌有抑制作用。
