TAN-1496 A, C and E, diketopiperazine antibiotics with inhibitory activity against mammalian DNA topoisomerase I.
Fungal metabolites with an epi-oligothiadiketopiperazine structure, TAN-1496 A, C and E, were isolated from the culture broth of Microsphaeropsis sp. FL-16144. Their molecular formulas were determined to be C22H28N2O9S2, C22H28N2O9S3 and C22H28N2O9S4, respectively. Structures were determined by comparing the NMR data with those of known diketopiperazine antibiotics, sirodesmins. These metabolites inhibited the relaxation of supercoiled pBR322 DNA by calf thymus topoisomerase I but did not affect the decatenation of kinetoplast DNA by calf thymus topoisomerase II at concentration up to 500 microM. They strongly suppressed the growth of various murine and human tumor cells and induced apoptosis. Moreover, various derivatives were synthesized to investigate the relationship of their functional groups and biological activities.
Funabashi
Y
Y
Discovery Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Horiguchi
T
T
Iinuma
S
S
Tanida
S
S
Harada
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005285:Fermentation; D006801:Humans; D051379:Mice; D003904:Mitosporic Fungi / Q000145:classification / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; C091114:TAN 1496 A; C091115:TAN 1496 C; C091116:TAN 1496 E; D059004:Topoisomerase I Inhibitors