Saccharomonosporine A inspiration; synthesis of potent analogues as potential PIM kinase inhibitors

Abstract

Saccharomonosporine A was recently reported as a natural anti-cancer agent working through inhibition of a Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) kinase. Structural bioisosteres of this natural product were synthesized and tested against PIM kinase enzymes. They showed potent inhibitory activity against all the known PIM kinases (PIM-1, 2 and 3) with IC₅₀ values ranging from 0.22 to 2.46 μM. Compound 5 was the most potent pan-inhibitor with IC₅₀ values of 0.37, 0.41, and 0.3 μM, against PIM-1, 2, 3 respectively. Compounds 4–6 were tested for their cytotoxic activities against 3 cell lines: H1650, HT-29, and HL-60. Compound 5 exhibited significant cytotoxic activity against human colon adenocarcinoma HT-29 and the human promyelocytic leukemia HL-60, with IC₅₀ μM values of 1.4 and 1.7 respectively. Molecular docking and homology modeling studies were carried out to confirm the affinity of these synthesized compounds to the three different PIM kinases. Additionally, a number of in silico predictions, ADME/Tox, were adopted to evaluate their drug-likeness.