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. Epub 2022 Jul 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / metabolism
  • Phenanthridines / pharmacology
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-pim-1

Substances

  • Antineoplastic Agents
  • Phenanthridines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-pim-1