New naphthacenecarboxamide antibiotics, TAN-1518 A and B, have inhibitory activity against mammalian DNA topoisomerase I.
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.
Horiguchi
T
T
Discovery Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Hayashi
K
K
Tsubotani
S
S
Iinuma
S
S
Harada
S
S
Tanida
S
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004273:DNA, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005285:Fermentation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D013302:Streptomyces / Q000737:chemistry / Q000145:classification; D013754:Tetracyclines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D013754:Tetracyclines; D059004:Topoisomerase I Inhibitors; C088527:TAN 1518 A; C088528:TAN 1518 B