title: New tetromycin derivatives with anti-trypanosomal and protease inhibitory activities.
abstract: Four new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001(T) cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV M(pro), and PL(pro). The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with K(i) values in the low micromolar range.
authors.affiliation: Julius-von-Sachs Institute for Biological Sciences, University of Würzburg, Julius-von-Sachs-Platz 3, Würzburg 97082, Germany.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Pimentel-Elardo
authors.affiliation: Institute for Pharmacy and Food Chemistry, Am Hubland, Würzburg 97074, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Buback
authors.affiliation: Institute of Organic Chemistry, University of Würzburg, Am Hubland, Würzburg 97074, Germany.
authors.forename: Tobias A M
authors.initials: TAM
authors.lastname: Gulder
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Bugni
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Reppart
authors.affiliation: Institute of Organic Chemistry, University of Würzburg, Am Hubland, Würzburg 97074, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Ireland
authors.affiliation: Institute for Pharmacy and Food Chemistry, Am Hubland, Würzburg 97074, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Julius-von-Sachs Institute for Biological Sciences, University of Würzburg, Julius-von-Sachs-Platz 3, Würzburg 97082, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hentschel
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000302:isolation & purification / Q000494:pharmacology; D047089:Axinella / Q000382:microbiology; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L / Q000037:antagonists & inhibitors; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000302:isolation & purification* / Q000494:pharmacology; D018320:Leishmania major / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D011480:Protease Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects; D013302:Streptomyces / Q000737:chemistry; D014344:Trypanocidal Agents / Q000302:isolation & purification* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014764:Viral Proteins / Q000037:antagonists & inhibitors
chemical_list: D000981:Antiprotozoal Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011480:Protease Inhibitors; D014344:Trypanocidal Agents; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C446033:rhodesain; D002401:Cathepsin B; D056668:Cathepsin L; D000086782:Coronavirus 3C Proteases
references.citation: J Med Chem. 2010 Mar 11;53(5):1951-63
references.pmid: 20131843
references.citation: Int J Syst Evol Microbiol. 2009 Jun;59(Pt 6):1433-7
references.pmid: 19502329
references.citation: ChemMedChem. 2006 Oct;1(10):1126-41
references.pmid: 16933358
references.citation: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references.pmid: 4202581
references.citation: N Engl J Med. 2003 Dec 18;349(25):2431-41
references.pmid: 14681510
references.citation: Pharmacol Ther. 2007 Feb;113(2):354-68
references.pmid: 17098288
references.citation: Bioorg Med Chem Lett. 2006 May 15;16(10):2753-7
references.pmid: 16516467
references.citation: Acta Trop. 1993 Dec;55(4):257-61
references.pmid: 8147282
references.citation: Antimicrob Agents Chemother. 2006 Jul;50(7):2439-47
references.pmid: 16801424
references.citation: Trends Microbiol. 2007 Nov;15(11):491-9
references.pmid: 17997312
references.citation: Curr Pharm Biotechnol. 2009 Jan;10(1):86-105
references.pmid: 19149592
references.citation: Curr Top Med Chem. 2010;10(3):368-82
references.pmid: 20166949
references.citation: Science. 2003 Jun 13;300(5626):1763-7
references.pmid: 12746549
references.citation: Mar Drugs. 2010 Apr 22;8(4):1417-68
references.pmid: 20479984
references.citation: Curr Opin Microbiol. 2006 Jun;9(3):245-51
references.pmid: 16675289
references.citation: ChemMedChem. 2011 Feb 7;6(2):273-8
references.pmid: 21275051