Horiguchi T, Hayashi K, Tsubotani S, Iinuma S, Harada S, Tanida S
Discovery Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
J Antibiot (Tokyo). 1994 May;47(5):545-56. doi: 10.7164/antibiotics.47.545.
New naphthacenecarboxamide antibiotics, TAN-1518 A and B, were isolated from a culture broth of Streptomyces sp. AL-16012. Their structures were elucidated from their reactions and from spectroscopic analyses. The relaxation of supercoiled pBR322 DNA by calf thymus DNA topoisomerase I was inhibited by these metabolites as potently as by camptothecin. However, the decatenation of kinetoplast DNA by calf thymus DNA topoisomerase II was little affected by these agents. The major metabolite, TAN-1518 A, strongly suppressed the growth of various murine and human tumor cells, inducing apoptosis. Unlike camptothecin, TAN-1518 A did not stimulate cleavable complex formation in the nuclei of CHO-K1 cells and had weak activity in intercalating into DNA strands. This metabolite arrested the growth of human tumor cell lines in G1 phase of the cell cycle. These results suggest that TAN-1518 A and B are novel antitumor agents targeting topoisomerase I.
新型萘并四甲酰胺类抗生素TAN - 1518 A和B是从链霉菌属AL - 16012的培养液中分离得到的。通过化学反应和光谱分析确定了它们的结构。这些代谢产物对小牛胸腺DNA拓扑异构酶I介导的超螺旋pBR322 DNA松弛的抑制作用与喜树碱一样强。然而，这些药物对小牛胸腺DNA拓扑异构酶II介导的动质体DNA解连环作用影响很小。主要代谢产物TAN - 1518 A强烈抑制多种小鼠和人类肿瘤细胞的生长，诱导细胞凋亡。与喜树碱不同，TAN - 1518 A不会刺激CHO - K1细胞核中可裂解复合物的形成，并且插入DNA链的活性较弱。这种代谢产物使人类肿瘤细胞系的生长停滞在细胞周期的G1期。这些结果表明，TAN - 1518 A和B是靶向拓扑异构酶I的新型抗肿瘤药物。
