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Synthesis, structural characterisation, and preliminary evaluation of non-indolin-2-one-based angiogenesis inhibitors related to sunitinib (Sutent®)

Journal Article


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Abstract


  • The indolin-2-one fused-ring system and the 2,4-dimethylpyrrole unit represent key structural motifs in the anticancer drug sunitinib (Sutent®) and predecessor angiogenesis inhibitors that have undergone anticancer clinical trials (e.g. semaxanib, SU5416). In pursuit of novel anti-angiogenic scaffolds, we were interested in identifying whether the indolin-2-one group in these structures could be modified without losing activity. This paper describes novel condensation chemistry used to prepare a test series of (E)- and (Z)-alkenes related to SU5416 that retain the 2,4-dimethylpyrrole unit while incorporating ring-opened indolin-2-ones. Unique structural characteristics were identified in the compounds, such as intramolecular hydrogen bonds in the (Z)-alkenes, and several examples were shown to possess significant anti-angiogenic activity in a rat aorta in vitro model of angiogenesis. The work demonstrates that the indolin-2-one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class.

Authors


  •   Sudta, Pichit (external author)
  •   Kirk, Nicholas (external author)
  •   Bezos, Anna (external author)
  •   Gurlica, Anthony (external author)
  •   Mitchell, Rhys
  •   Weber, Thomas (external author)
  •   Willis, Anthony C. (external author)
  •   Prabpai, Samran (external author)
  •   Kongsaeree, Palangpon (external author)
  •   Parish, Christopher R. (external author)
  •   Suksamrarn, Sunit (external author)
  •   Kelso, Michael J.

Publication Date


  • 2013

Citation


  • Sudta, P., Kirk, N., Bezos, A., Gurlica, A., Mitchell, R., Weber, T., Willis, A. C., Prabpai, S., Kongsaeree, P., Parish, C. R., Suksamrarn, S. & Kelso, M. J. (2013). Synthesis, structural characterisation, and preliminary evaluation of non-indolin-2-one-based angiogenesis inhibitors related to sunitinib (Sutent®). Australian Journal of Chemistry: an international journal for chemical science, 66 (8), 864-873.

Scopus Eid


  • 2-s2.0-84882683064

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2085&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1067

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 864

End Page


  • 873

Volume


  • 66

Issue


  • 8

Place Of Publication


  • Australia

Abstract


  • The indolin-2-one fused-ring system and the 2,4-dimethylpyrrole unit represent key structural motifs in the anticancer drug sunitinib (Sutent®) and predecessor angiogenesis inhibitors that have undergone anticancer clinical trials (e.g. semaxanib, SU5416). In pursuit of novel anti-angiogenic scaffolds, we were interested in identifying whether the indolin-2-one group in these structures could be modified without losing activity. This paper describes novel condensation chemistry used to prepare a test series of (E)- and (Z)-alkenes related to SU5416 that retain the 2,4-dimethylpyrrole unit while incorporating ring-opened indolin-2-ones. Unique structural characteristics were identified in the compounds, such as intramolecular hydrogen bonds in the (Z)-alkenes, and several examples were shown to possess significant anti-angiogenic activity in a rat aorta in vitro model of angiogenesis. The work demonstrates that the indolin-2-one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class.

Authors


  •   Sudta, Pichit (external author)
  •   Kirk, Nicholas (external author)
  •   Bezos, Anna (external author)
  •   Gurlica, Anthony (external author)
  •   Mitchell, Rhys
  •   Weber, Thomas (external author)
  •   Willis, Anthony C. (external author)
  •   Prabpai, Samran (external author)
  •   Kongsaeree, Palangpon (external author)
  •   Parish, Christopher R. (external author)
  •   Suksamrarn, Sunit (external author)
  •   Kelso, Michael J.

Publication Date


  • 2013

Citation


  • Sudta, P., Kirk, N., Bezos, A., Gurlica, A., Mitchell, R., Weber, T., Willis, A. C., Prabpai, S., Kongsaeree, P., Parish, C. R., Suksamrarn, S. & Kelso, M. J. (2013). Synthesis, structural characterisation, and preliminary evaluation of non-indolin-2-one-based angiogenesis inhibitors related to sunitinib (Sutent®). Australian Journal of Chemistry: an international journal for chemical science, 66 (8), 864-873.

Scopus Eid


  • 2-s2.0-84882683064

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2085&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1067

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 864

End Page


  • 873

Volume


  • 66

Issue


  • 8

Place Of Publication


  • Australia