Novel human topoisomerase I inhibitors, topopyrones A, B, C and D. I. Producing strain, fermentation, isolation, physico-chemical properties and biological activity.
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.
Kanai
Y
Y
Institute of Biotechnology Applied to Soil Eumycetes, Akita, Japan.
Ishiyama
D
D
Senda
H
H
Iwatani
W
W
Takahashi
H
H
Konno
H
H
Tokumasu
S
S
Kanazawa
S
S
D000880:Anthraquinones / Q000737:chemistry; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001203:Ascomycota / Q000737:chemistry* / Q000378:metabolism; D001230:Aspergillus / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005285:Fermentation; D006367:HeLa Cells; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D010407:Penicillium / Q000737:chemistry* / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011753:Pyrones; D059004:Topoisomerase I Inhibitors; C417102:topopyrone A; C417105:topopyrone B; C417104:topopyrone C; C417103:topopyrone D