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

0
0

Issued Date

2016

Resource Type

Article

File Type

application/pdf

ISSN

0960894X

DOI

10.1016/j.bmcl.2016.02.033

Other identifier(s)

2-s2.0-85006067081

Rights Holder(s)

มหาวิทยาลัยศรีนครินทรวิโรฒ

Bibliographic Citation

Bioorganic and Medicinal Chemistry Letters. Vol 26, No.7 (2016), p.1813-1816

Suggested Citation

Kirk N.S., Bezos A., Willis A.C., Sudta P., Suksamrarn S., Parish C.R., Ranson M., Kelso M.J. Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters. Vol 26, No.7 (2016), p.1813-1816. doi:10.1016/j.bmcl.2016.02.033 Retrieved from: https://hdl.handle.net/20.500.14740/5946

Title

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

Author(s)

Kirk N.S.
 Bezos A.
 Willis A.C.
 Sudta P.
 Suksamrarn S.
 Parish C.R.
 Ranson M.
 Kelso M.J.

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. © 2016 Elsevier Ltd

Subject(s)

5,7 dimethyl 2 aryl 3 h pyrrolizin 3 one
 Acrylic acid derivative
 Angiogenesis inhibitor
 Arylacetic acid derivative
 Phenylacetic acid
 Phenylacetic acid derivative
 Potassium salt
 Reagent
 Semaxanib
 Sunitinib
 Unclassified drug
 Angiogenesis inhibitor
 Indole derivative
 Pyrrole derivative
 Semaxanib
 Animal tissue
 Antiangiogenic activity
 Aortic ring (slice)
 Article
 Carbon nuclear magnetic resonance
 Controlled study
 Crystal structure
 Drug synthesis
 Evaluation study
 Nonhuman
 One pot synthesis
 Proton nuclear magnetic resonance
 Rat
 Structure activity relation
 Thin layer chromatography
 Angiogenesis
 Animal
 Aorta
 Chemistry
 Drug effects
 Human
 Methylation
 Molecular model
 Physiology
 Synthesis
 Umbilical vein endothelial cell
 Angiogenesis Inhibitors
 Animals
 Aorta
 Human Umbilical Vein Endothelial Cells
 Humans
 Indoles
 Methylation
 Models, Molecular
 Neovascularization, Physiologic
 Pyrroles
 Rats

View online Resources

Research Projects

Organizational Units

Journal Issue

URI

https://hdl.handle.net/20.500.14740/5946

Collections

Scopus: Year 1983-2021

Endorsement

Review

Supplemented By

Referenced By