title: Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors.
abstract: Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that non-indoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of non-indoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib; the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to semaxanib at 10μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors.
authors.affiliation: Illawarra Health and Medical Research Institute, School of Chemistry, University of Wollongong, NSW 2522, Australia.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirk
authors.affiliation: Cancer and Vascular Biology Group, Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Bezos
authors.affiliation: Single Crystal X-ray Diffraction Unit, Research School of Chemistry, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Willis
authors.affiliation: Division of Chemistry, Phetchaburi Rajabhat University, Phetchaburi 76000, Thailand; Department of Chemistry, Srinakharinwirot University, Bangkok 10110, Thailand.
authors.forename: Pichit
authors.initials: P
authors.lastname: Sudta
authors.affiliation: Department of Chemistry, Srinakharinwirot University, Bangkok 10110, Thailand.
authors.forename: Sunit
authors.initials: S
authors.lastname: Suksamrarn
authors.affiliation: Cancer and Vascular Biology Group, Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
authors.affiliation: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, NSW 2522, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
authors.affiliation: Illawarra Health and Medical Research Institute, School of Chemistry, University of Wollongong, NSW 2522, Australia. Electronic address: mkelso@uow.edu.au.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008745:Methylation; D008958:Models, Molecular; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D000077210:Sunitinib
keywords: 3H-Pyrrolizin-3-one; Angiogenesis inhibitor; Knoevenagel; SU5416; Semaxanib; Sunitinib