Synthesis of new pyrazolo[4,3-a]phenanthridine Pim-1 inhibitors and evaluation of their cytotoxic activity towards the MOLM-13 acute myeloid leukemia cell line

  • Bioorg Med Chem Lett. 2022 Oct 1:73:128914. doi: 10.1016/j.bmcl.2022.128914.
Etienne Auvert  1 ,  Reidun Aesoy  2 ,  Francis Giraud  1 ,  Lars Herfindal  2 ,  Fabrice Anizon  3 ,  Pascale Moreau  4
Affiliations
  • 1. Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France.
  • 2. Centre for Pharmacy, Department of Clinical Science, University of Bergen, Bergen, Norway.
  • 3. Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France. Electronic address: [email protected].
  • 4. Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France. Electronic address: [email protected].
PMID: 35917834 DOI: 10.1016/j.bmcl.2022.128914
Abstract

We synthesized new analogues of the anti-AML agent VS-II-173. We studied the effect of the substitution at the 1- and 5-positions of the pyrazolo[4,3-a]phenanthridine scaffold on Pim-1 kinase inhibition and cytotoxicity against AML MOLM-13 cells. We found that compounds 20 and 21, substituted at the 1-position exhibited stronger Pim-1 inhibition together with a high potency toward MOLM-13 cells, associated with Apoptosis induction and selectivity over non-cancerous NRK cells.

Keywords
Acute myeloid leukemia; Antiproliferative activity; Pim kinase inhibitors; Pyrazolo[4,3-a]phenanthridine.
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