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Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Journal Article


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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 10 μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors.

Authors


  •   Kirk, Nicholas (external author)
  •   Bezos, Anna (external author)
  •   Willis, Anthony C. (external author)
  •   Sudta, Pichit (external author)
  •   Suksamrarn, Sunit (external author)
  •   Parish, Christopher R. (external author)
  •   Ranson, Marie
  •   Kelso, Michael J.

Publication Date


  • 2016

Citation


  • Kirk, N. S., Bezos, A., Willis, A. C., Sudta, P., Suksamrarn, S., Parish, C. R., Ranson, M. & Kelso, M. J. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (7), 1813-1816.

Scopus Eid


  • 2-s2.0-85006067081

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1817&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/794

Number Of Pages


  • 3

Start Page


  • 1813

End Page


  • 1816

Volume


  • 26

Issue


  • 7

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 10 μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors.

Authors


  •   Kirk, Nicholas (external author)
  •   Bezos, Anna (external author)
  •   Willis, Anthony C. (external author)
  •   Sudta, Pichit (external author)
  •   Suksamrarn, Sunit (external author)
  •   Parish, Christopher R. (external author)
  •   Ranson, Marie
  •   Kelso, Michael J.

Publication Date


  • 2016

Citation


  • Kirk, N. S., Bezos, A., Willis, A. C., Sudta, P., Suksamrarn, S., Parish, C. R., Ranson, M. & Kelso, M. J. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (7), 1813-1816.

Scopus Eid


  • 2-s2.0-85006067081

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1817&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/794

Number Of Pages


  • 3

Start Page


  • 1813

End Page


  • 1816

Volume


  • 26

Issue


  • 7