Saccharomonosporine A Inspiration; Synthesis of Potent Analogues As Potential PIM Kinase Inhibitors

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 May 2

PMID 35493904

Authors

Asmaa M AboulMagd

Hossam M Hassan

Ahmed M Sayed

Usama Ramadan Abdelmohsen

Hamdy M Abdel-Rahman

Affiliations

Soon will be listed here.

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 IC values ranging from 0.22 to 2.46 μM. Compound 5 was the most potent -inhibitor with IC 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 IC 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 predictions, ADME/Tox, were adopted to evaluate their drug-likeness.

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