title: Synthesis and anticancer activity of focused compound libraries from the natural product lead, oroidin.
abstract: Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42 μM in MCF-7 (breast) cells and 24 μM in A2780 (ovarian) cells and >50 μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of <5 μM were observed with 4l against HT29 (colon) and SW480 (colon); 5a against HT29; and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active.
authors: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors: Lauren
authors: L
authors: Dyson
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA.
authors: Anthony D
authors: AD
authors: Wright
authors: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors: Kelly A
authors: KA
authors: Young
authors: Department of Medical Oncology, Calvary Mater Newcastle Hospital, Edith Street, Waratah, NSW 2298, Australia.
authors: Jennette A
authors: JA
authors: Sakoff
authors: Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, NSW 2308, Australia. Electronic address: Adam.McCluskey@newcastle.edu.au.
authors: Adam
authors: A
authors: McCluskey
mesh_terms: D000818:Animals; D001688:Biological Products; D049109:Cell Proliferation; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D011758:Pyrroles; C077209:oroidin
keywords: Cytotoxic compound; Focused libraries; Natural product leads; Oroidin; Sponges; Synthesis