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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Kirk, Nicholas S.¹  Bezos, Anna²  Willis, Anthony C.³  Sudta, Pichit^4,5  Suksamrarn, Sunit⁵  Parish, Christopher R.²  Ranson, Marie⁶  Kelso, Michael J.¹ 

[1] Univ Wollongong, Sch Chem, Illawarra Hlth & Med Res Inst, Wollongong, NSW 2522, Australia

[2] Australian Natl Univ, John Curtin Sch Med Res, Dept Canc Biol & Therapeut, Canc & Vasc Biol Grp, Canberra, ACT 2601, Australia

[3] Australian Natl Univ, Res Sch Chem, Single Crystal Xray Diffract Unit, Canberra, ACT 2601, Australia

[4] Phetchaburi Rajabhat Univ, Div Chem, Phetchaburi 76000, Thailand

[5] Srinakharinwirot Univ, Dept Chem, Bangkok 10110, Thailand

[6] Univ Wollongong, Sch Biol Sci, Illawarra Hlth & Med Res Inst, Wollongong, NSW 2522, Australia

关键词: Angiogenesis inhibitor;    Knoevenagel;    3H-Pyrrolizin-3-one;    Semaxanib;    SU5416;    Sunitinib;   

DOI  :  10.1016/j.bmcl.2016.02.033

来源: Elsevier

【 摘 要 】

Sunitinib (Sutent (R)) 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 mu g/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.

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