title: Cytotoxic Indolocarbazoles from Actinomadura melliaura ATCC 39691.
abstract: Actinomadura melliaura ATCC 39691, a strain isolated from a soil sample collected in Bristol Cove, California, is a known producer of the disaccharide-substituted AT2433 indolocarbazoles (6-9). Reinvestigation of this strain using new media conditions led to >40-fold improvement in the production of previously reported AT2433 metabolites and the isolation and structure elucidation of the four new analogues, AT2433-A3, A4, A5, and B3 (1-4). The availability of this broader set of compounds enabled a subsequent small antibacterial/fungal/cancer SAR study that revealed disaccharyl substitution, N-6 methylation, and C-11 chlorination as key modulators of bioactivity. The slightly improved anticancer potency of the newly reported N-6-desmethyl 1 (compared to 6) contrasts extensive SAR of monoglycosylated rebeccamycin-type topoisomerase I inhibitors where N-6 alkylation has contributed to improved potency and ADME. Complete 2D NMR assignments for the known metabolite BMY-41219 (5) and (13)C NMR spectroscopic data for the known analogue AT2433-B1 (7) are also provided for the first time.
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Shaaban
authors.forename: Sherif I
authors.initials: SI
authors.lastname: Elshahawi
authors.forename: Xiachang
authors.initials: X
authors.lastname: Wang
authors.forename: Jamie
authors.initials: J
authors.lastname: Horn
authors.affiliation: §School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, Maryland 21853, United States.
authors.forename: Madan K
authors.initials: MK
authors.lastname: Kharel
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.forename: Jon S
authors.initials: JS
authors.lastname: Thorson
mesh_terms: D000192:Actinomycetales / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002140:California; D002227:Carbazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D012988:Soil Microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D026121:Indole Alkaloids; D059004:Topoisomerase I Inhibitors; C061863:AT 2433-B1; C053339:rebeccamycin