Unusual Sesquiterpenes: Gorgonenes and Further Bioactive Secondary Metabolites Derived from Marine and Terrestrial Bacteria Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität zu Göttingen vorgelegt von Md. Hafizur Rahman aus Satkhira, Bangladesh Göttingen 2008 Referent: Prof. Dr. Hartmut Laatsch Korreferent: Prof. Dr. A. Zeeck Tag der mündlichen Prüfung: 29. Oktober 2008 Die vorliegende Dissertation wurde im Institut für Organische und Biomolekulare Chemie der Universität Göttingen in der Zeit vom August 2004 bis Oktober 2008 un- ter der Leitung von Herrn Prof. Dr. Hartmut Laatsch durchgeführt. Dedicated to my beloved parents Md Fazlur Rahman and Mrs. Fazilatunnessa Contents I Contents 1 Introduction....................................................................................................... 1 1.1 History of the use of natural products for medical applications..........................2 1.2 Approaches for the search of new natural products ............................................4 1.3 Antibiotic screening.............................................................................................6 1.4 Natural Products from Marine Bacteria...............................................................6 1.5 Therapeutic areas influenced by natural products ...............................................9 1.6 Natural products against infectious diseases; bacterial pathogens ......................9 1.7 Antifungal compounds from natural sources.....................................................10 1.8 Antibacterial compounds from natural sources .................................................11 1.9 Potential antiparasitic drugs originated from natural products..........................13 1.10 Marine derived anticancer drugs .......................................................................14 1.11 Antiviral compounds from natural sources .......................................................15 1.12 Sequiterpenes from marine microorganism.......................................................17 2 Objectives of the present investigation........................................................... 18 3 General techniques.......................................................................................... 20 3.1 Collection of strains...........................................................................................20 3.2 Pre-screening .....................................................................................................20 3.3 Chemical screening............................................................................................20 3.4 Pharmacological and biological assays .............................................................22 3.5 Cultivation and scale-up ....................................................................................22 3.6 Isolation methods...............................................................................................23 3.7 Partial identification and dereplication..............................................................23 3.8 Description of Strain Codes...............................................................................25 4 Investigation of selected marine and terrestrial Streptomycetes..................... 25 4.1 Terrestrial Streptomyces sp. ADM 14 ...............................................................25 4.1.1 1-Hydroxy-4-methoxynaphthalene-2-caboxylic acid........................................27 4.1.2 5'-Methyl-thioadenosine ....................................................................................28 4.1.3 5,7,9,11-Tetrahydroxy-4,6,8,10-tetramethyl-tridec-2-enoic acid......................30 4.2 Streptomyces sp. B7880.....................................................................................33 4.2.1 ζ-Pyrromycinone; Galirubinone C.....................................................................33 4.2.2 Cinerubin B; Ryemycin B .................................................................................35 II Contents 4.2.3 Cinerubin A/ Spartanamicin B ..........................................................................37 4.2.4 Cinerubin X.......................................................................................................38 4.3 Terrestrial Streptomyces sp. ACT 7619.............................................................39 4.3.1 Dinactin .............................................................................................................40 4.3.2 Bonactin.............................................................................................................41 4.3.3 4,10-Dihydroxy-10-methyl-dodec-2-en-1,4-olide.............................................42 4.4 Terrestrial Streptomycete GW 6311..................................................................43 4.4.1 β-Indomycinone.................................................................................................43 4.4.2 Saptomycin A....................................................................................................44 4.5 Terrestrial Streptomyces sp. GT 2005/079 ........................................................45 4.5.1 N-(7-Hydroxy-6-methyl-octyl)-acetamide ........................................................48 4.5.2 N-(7-Hydroxy-octyl)-acetamide ........................................................................50 4.5.3 N-(6-Hydroxy-6-methyl-heptyl)-acetamide ......................................................53 4.5.4 Homononactic acid amide .................................................................................56 4.5.5 2-Phenylbenzoxazole-4-carboxylic acid............................................................59 4.5.6 2-(3-Chloro-2-hydroxy phenyl) benzoxazole-4-carbxylic acid.........................61 4.6 Terrestrial Actinomycete N 435 ........................................................................63 4.6.1 Cyclo(dehydroalanyl-isoleucyl).........................................................................64 4.6.2 Cis-Cyclo(leucyl-tyrosyl) ..................................................................................65 4.6.3 Ramthacin B......................................................................................................69 4.7 Streptomyces sp. B7857.....................................................................................71 4.7.1 Bacteriogorgonene A.........................................................................................73 4.7.2 Bacteriogorgonene B.........................................................................................78 4.7.3 Bacteriogorgonene C.........................................................................................81 4.8 Terrestrial Streptomycete GW5127..................................................................84 4.8.1 13-Deoxy-1,3-dihydrodaunomycinone..............................................................85 4.8.2 4-Acetyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one..........................................87 4.8.3 N-[2-(3-Hydroxy-4-methoxy-phenyl)-ethyl]-acetamide ...................................90 4.8.4 4-(2-Hydroxyethyl)-2-methoxy-phenol.............................................................92 4.8.5 β-Rubromycin....................................................................................................93 Contents III 4.8.6 γ-Rubromycin ....................................................................................................95 4.9 Terrestrial Streptomyces sp. GW 18/1811.........................................................96 4.9.1 Komodoquinone B.............................................................................................97 4.9.2 Feudomycinone C..............................................................................................98 4.9.3 α-Hydroxyacetovanillone ..................................................................................99 4.9.4 N-Acetylhomocysteine thiolactone..................................................................103 4.9.5 Lysolipin I........................................................................................................105 5 Fungal metabolites ........................................................................................ 107 5.1 Bikaverin .........................................................................................................107 6 Plant Metabolites from Tephrosia sp............................................................ 110 6.1 Spinoflavanone B............................................................................................110 6.2 Caliphione A....................................................................................................113 6.3 Tephcalostan....................................................................................................117 6.4 Tephcalostan A................................................................................................118 6.5 Tephcalostan B and C......................................................................................121 6.6 Milletone..........................................................................................................124 6.7 Glabranine .......................................................................................................127 6.8 Betulinic acid and Betulinic acid methyl ester ................................................129 6.9 Stigmasterol and γ-Sitosterol...........................................................................131