Serge Fotso ___________________________________________________ Highly Cytotoxic Kettapeptin, Bhimamycins Possessing Unusual Chromophores and Further New Secondary Metabolites from Terrestrial and Marine Bacteria CH 3 O OH H C O CH 3 OH 3 CH CH CH O 3 3 3 NH HN CH3 N CH HO 3 O O O N O MeO O H CH N 3 O N N OH H3C HN O H3C H3C OH O O O CH3 O N O O CH OH O CH3 HO 3 OH Dissertation Highly Cytotoxic Kettapeptin, Bhimamycins Possessing Unusual Chromophores and Further New Secondary Metabolites from Terrestrial and Marine Bacteria Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität zu Göttingen vorgelegt von Serge Fotso aus Yaoundé (Kamerun) Göttingen 2005 D7 Referent: Prof. Dr. H. Laatsch Korreferent: Prof. Dr. A. Zeeck Tag der mündlichen Prüfung: 02.11.2005 Die vorliegende Arbeit wurde in der Zeit von Oktober 2001 bis September 2005 im Institut für Organische Chemie der Georg-August-Universität zu Göttingen unter der Leitung von Herrn Prof. Dr. H. Laatsch angefertigt. Herrn Prof. Dr. H. Laatsch danke ich für die Möglichkeit zur Durchführung dieser Arbeit sowie die ständige Bereitschaft, auftretende Probleme zu diskutieren. Für meine Eltern und meine Verlobte I 1 Introduction...................................................................................................... 1 1.1 New drugs from the Sea............................................................................. 1 2 Aim of the present work................................................................................. 14 3 General techniques......................................................................................... 15 3.1 Collection of strains ................................................................................. 15 3.2 Pre-screening............................................................................................ 15 3.3 Chemical screening.................................................................................. 15 3.4 Pharmacological and Biological Assays.................................................. 17 3.5 Cultivation and scale-up.......................................................................... 18 3.6 Isolation methods..................................................................................... 19 3.7 Partial identification and dereplication .................................................... 19 4 Terrestrial Streptomyces................................................................................. 21 4.1 Terrestrial Streptomyces sp. GW 2/1332. ................................................ 21 4.1.1 Griseorhodin A......................................................................................... 21 4.2 Terrestrial Streptomyces sp. GW 15/1817 ............................................... 22 4.2.1 Roxaticin.................................................................................................. 23 4.3 Terrestrial Streptomyces sp. GW 3/1122 ................................................. 25 4.3.1 Furanonaphthoquinone ............................................................................ 26 4.4 Terrestrial Streptomyces sp. GW 24/1229 ............................................... 29 4.4.1 β-Rubromycin .......................................................................................... 30 4.4.2 γ-Rubromycin........................................................................................... 31 4.5 Terrestrial Streptomyces sp. GW 22/1326 ............................................... 31 4.5.1 ε−Rhodomycinone ................................................................................... 32 4.5.2 Dihydrotetrodecamycin............................................................................ 34 4.5.3 Cosmomycin A (Rhodilunancin A) ......................................................... 36 4.6 Terrestrial Streptomyces sp. GW 28/1828 ............................................... 37 4.6.1 Resistomycin............................................................................................ 38 4.6.2 N-Acetyldopamine................................................................................... 39 4.7 Terrestrial Streptomyces sp. GW 10/580 ................................................. 41 4.7.1 Phenazin-1-carboxylic acid...................................................................... 42 4.7.2 Feigrisolide B........................................................................................... 43 4.7.3 Feigrisolide A........................................................................................... 44 4.7.4 Feigrisolide C........................................................................................... 46 II 4.8 Terrestrial Streptomyces GW 9/2335 ...................................................... 49 4.8.1 5-Deoxy-enterocin ................................................................................... 50 4.8.2 Irumamycin .............................................................................................. 52 4.8.3 X-14952B................................................................................................. 53 4.8.4 KSM-2690 B............................................................................................ 54 4.8.5 P-371-A2.................................................................................................. 57 4.9 Terrestrial Streptomyces sp.US80............................................................ 59 4.9.1 17-Hydroxyventuricidin A....................................................................... 60 4.10 Terrestrial Streptomyces sp. GW 37/3236 ............................................... 62 4.10.1 Bisanhydro-13-dihydrodaunomycinone .................................................. 63 4.10.2 7-Deoxydaunomycinol............................................................................. 65 4.10.3 Daunomycinol.......................................................................................... 65 4.10.4 Daunomycinone ....................................................................................... 67 4.10.5 Baumycin C1........................................................................................... 67 4.10.6 11-Deoxybisanhydro-13-dihydrodaunomycinone ................................... 69 4.10.7 6,9,11-Trihydroxy-4-methoxy-5,12-naphthacenedione........................... 70 4.10.8 13-O-Acetyl-bisanhydro-13-dihydrodaunomycinone.............................. 70 4.10.9 4,13-O-Diacetyl-bisanhydro-4-O-demethyl-13-dihydrodaunomycinone 73 4.10.10 2-Acetylamino-3-hydroxy-benzamide..................................................... 74 4.11 Terrestrial Streptomyces sp. GW 4284 .................................................... 76 4.11.1 Juglomycin A and B................................................................................. 77 4.11.2 Juglomycin J............................................................................................ 79 4.11.3 Oviedomycin............................................................................................ 82 4.11.4 Juglorubin ................................................................................................ 86 4.11.5 Juglorescein.............................................................................................. 89 4.11.6 GTRI-O2 .................................................................................................. 94 4.12 Terrestrial Streptomyces sp. GW 21/1313 ............................................... 94 4.12.1 4-Hydroxy-2-(5-hydroxymethyl-furan-2-ylmethylene)-5-methyl-furan-3- one ..................................................................................................... 95 4.12.2 Isolation from 50 L fermenter.................................................................. 98 4.12.3 5-Hydroxymethylfurfural......................................................................... 99 4.12.4 Krishnanone A......................................................................................... 99 4.12.5 Krishnanone B....................................................................................... 101 III 4.12.6 Perlolyrin................................................................................................ 103 4.12.7 Rhadanone A.......................................................................................... 104 4.12.8 Rhadanone B.......................................................................................... 107 4.13 Terrestrial Streptomyces sp. GW 99/1572 ............................................. 108 4.13.1 Kettapeptin............................................................................................. 109 4.13.2 Crystal Structure Analysis ..................................................................... 115 4.14 Terrestrial Streptomyces sp. GW 32/698 ............................................... 118 4.14.1 Chrysophanol ......................................................................................... 119 4.14.2 3,8-Dihydroxy-1-methylanthraquinone-2-carboxylic acid .................... 119 4.14.3 Aloesaponarin II..................................................................................... 121 4.14.4 Bhimamycin A....................................................................................... 123 4.14.5 Bhimamycin B....................................................................................... 125 4.14.6 Bhimamycin C......................................................................................