2. Academic Validation
  3. Synthesis and biological evaluation of 1H-pyrrolo[3,2-g]isoquinolines

Synthesis and biological evaluation of 1H-pyrrolo[3,2-g]isoquinolines

  • Bioorg Med Chem. 2024 Feb 15:100:117619. doi: 10.1016/j.bmc.2024.117619.
Mathilde Defois 1,  Béatrice Josselin 2,  Pierre Brindeau 3,  Andreas Krämer 4,  Stefan Knapp 4,  Fabrice Anizon 1,  Francis Giraud 5,  Sandrine Ruchaud 6,  Pascale Moreau 7
Affiliations

Affiliations

  • 1 Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France.
  • 2 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, 29680 Roscoff, France.
  • 3 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France.
  • 4 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.
  • 5 Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France. Electronic address: [email protected].
  • 6 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France. Electronic address: [email protected].
  • 7 Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France. Electronic address: [email protected].
PMID: 38320389 DOI: 10.1016/j.bmc.2024.117619
Abstract

A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC50 = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography.

Keywords

Cellular activity; Haspin; Indoles; Isoquinolines; Kinase inhibition; Pyrroles.

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