80279-24-9Relevant articles and documents
Biosynthesis of the Enterotoxic Pyrrolobenzodiazepine Natural Product Tilivalline
Dornisch, Elisabeth,Pletz, Jakob,Glabonjat, Ronald A.,Martin, Florian,Lembacher-Fadum, Christian,Neger, Margit,H?genauer, Christoph,Francesconi, Kevin,Kroutil, Wolfgang,Zangger, Klaus,Breinbauer, Rolf,Zechner, Ellen L.
, p. 14753 - 14757 (2017/11/14)
The nonribosomal enterotoxin tilivalline was the first naturally occurring pyrrolobenzodiazepine to be linked to disease in the human intestine. Since the producing organism Klebsiella oxytoca is part of the intestinal microbiota and the pyrrolobenzodiaze
A tricyclic pyrrolobenzodiazepine produced by Klebsiella oxytoca is associated with cytotoxicity in antibiotic-associated hemorrhagic colitis
Tse, Herman,Gu, Qiangshuai,Sze, Kong-Hung,Chu, Ivan K.,Kao, Richard Y.-T.,Lee, Kam-Chung,Lam, Ching-Wan,Yang, Dan,Shing-Chiu Tai, Sherlock,Ke, Yihong,Chan, Elaine,Chan, Wan-Mui,Dai, Jun,Leung, Sze-Pui,Leung, Suet-Yi,Yuen, Kwok-Yung
, p. 19503 - 19520 (2017/12/01)
Cytotoxin-producing Klebsiella oxytoca is the causative agent of antibiotic-associated hemorrhagic colitis (AAHC). Recently, the cytotoxin associated with AAHC was identified as tilivalline, a known pentacyclic pyrrolobenzodiazepine (PBD) metabolite produced by K. oxytoca. Although this assertion of tilivalline’s role in AAHC is supported by evidence from animal experiments, some key aspects of this finding appear to be incompatible with toxicity mechanisms of known PBD toxins. We therefore hypothesized that K. oxytoca may produce some other uncharacterized cytotoxins. To address this question, we investigated whether tilivalline alone is indeed necessary and sufficient to induce cytotoxicity or whether K. oxytoca also produces other cytotoxins. LC-MS- and NMR-based metabolomic analy-ses revealed the presence of an abundant tricyclic PBD, provisionally designated kleboxymycin, in the supernatant of toxigenic K. oxytoca strains. Moreover, by generating multiple mutants with gene deletions affecting tilivalline biosynthesis, we show that a tryptophanase-deficient, tilivalline-negative K. oxytoca mutant induced cytotoxicity in vitro similar to tilivalline-positive K. oxytoca strains. Furthermore, synthetic kleboxymycin exhibited greater than 9-fold higher cytotoxicity than tilivalline in TC50 cell culture assays. We also found that the biosynthetic pathways for kleboxymycin and tilivalline appear to overlap, as tilivalline is an indole derivative of kleboxymycin. In summary, our results indicate that tilivalline is not essential for inducing cytotoxicity observed in K. oxytoca-associated AAHC and that kleboxymycin is a tilivalline-related bacterial metabolite with even higher cytotoxicity.
Stereoselective synthesis of tilivalline
Nagasaka, Tatsuo,Koseki, Yuji
, p. 6797 - 6801 (2007/10/03)
Tilivalline 1, a metabolite from Klebsiella pneumoniae var. ocytoca, was easily synthesized in five steps from (S)-proline and 3-(benzyloxy)isatoic anhydride 4g. This synthesis is based on modified Curtius reactions of 3- substituted phthalic anhydrides 11 to 3-substituted isatoic anhydrides 4, conversion of lactams 6 to the acyliminium precursors 7 and stereoselective introduction of indole from the less hindered side of 7.
New methods and reagents in organic synthesis. 92. A stereoselective synthesis of tilivalline and its analogs
Mori, Shigehiro,Ohno, Tomoyasu,Harada, Hiroshi,Aoyama, Toyohiko,Shioiri, Takayuki
, p. 5051 - 5070 (2007/10/02)
Tilivalline (1a), a metabolite from Klebsiella pneumoniae var. oxytoca, and its derivatives 1 have been efficiently and stereoselectively synthesized from diphenyl phosphorazidate, the 2-oxazoline 2, the L-proline derivatives 5, and indole; the key step is a Mannich type intramolecular cyclization accompanied with completely stereoselective introduction of indole. Furthermore, 11-substituted 5H- pyrrolo[2,1-c][1,4]benzodiazepin-5-ones (16) have been also synthesized from the acetal amide 9a and various nucleophiles by the use of this new Mannich type cyclization.
STEREOSELECTIVE SYNTHESIS OF TILIVALLINE
Nagasaka, Tatsuo,Koseki, Yuji,Hamaguchi, Fumiko
, p. 1871 - 1872 (2007/10/02)
Tilivalline (1b) was easily synthesized by converting lactam 3b to the acyliminium precursor 5b followed by stereoselectively introducing indole from the less hindered side of 5b.
NEW METHOD AND REAGENTS IN ORGANIC SYNTHESIS. 65. A STEREOSELECTIVE SYNTHESIS OF TILIVALLINE
Mori, Shigehiro,Aoyama, Toyohiko,Shioiri, Takayuki
, p. 6111 - 6114 (2007/10/02)
Tilivalline (1), a metabolite from Klebsiella, has been efficiently and stereoselectively synthesized from diphenyl phosphorazidate (DPPA), the 2-oxazoline 2, the L-proline derivative 5, and indole; the key step is a Mannich type intramolecular cyclization accompanied with simultaneous and completely stereoselective introduction of indole.
TILIVALLINE, A NEW PYRROLOBENZODIAZEPINE METABOLITE FROM KLEBSIELLA.
Mohr, Nikolaus,Budzikiewicz, Herbert
, p. 147 - 152 (2007/10/02)
From Klebsiella pneumoniae (+)(11S,11aS)-(1,2,3,10,11,11a-hexahydro-9-hydroxy-11-(3'-indolyl)-5H-pyrrolobenzodiazepin-5-one (1) has been isolated for which the name tilivalline is suggested.Structure elucidation and synthesis are reported.
