Selenylated Imidazo[1,2-a]pyridine Induces Cell Senescence and Oxidative Stress in Chronic Myeloid Leukemia Cells

Abstract

Imidazo[1,2-a]pyridines (IPs) have been studied regarding drug development. The objective of this work was to evaluate the antileukemic capacity of IP derivatives by screening their ability as a pro-oxidant. IP derivatives were synthesized and oral bioavailability and toxicity were analyzed in silico. Redox screening was performed on human Kasumi, KG-1, K562, and Jurkat leukemia cells. The IP derivative and the most responsive leukemic cell were selected for cytotoxicity, cell proliferation, cell senescence, and oxidative stress assays. The predictive toxicity analysis showed a possible effect on the reproductive system, but without mutagenic, carcinogenic, or irritability effects. MRK-107 against K562 cells was the compound that showed the best redox profile. MRK-107 did not induce cell death in K562 and monocyte cells. However, this compound was able to decrease cell proliferation and increase cell senescence after 48 and 72 h. Furthermore, MRK-107 induced oxidative stress in K562 cells after 72 h, increasing lipid peroxidation and decreasing reduced glutathione (GSH) contents. This study demonstrated that MRK-107-induced senescence with the involvement of oxidative stress is a possible mechanism of action, addressing this compound as a potential antitumor drug against chronic myeloid leukemia.

The Mechanism of Anti-Tumor Activity of 6-Morpholino- and 6-Amino-9-Sulfonylpurine Derivatives on Human Leukemia Cells

“…Chronic myeloid leukemia (CML) is characterized by continuous activation of the BCR-ABL1 tyrosine kinase fusion gene, leading to activation of oncogenic signaling pathways. Although tyrosine kinase inhibitors are currently available for the treatment of CML, there continues to be interest in developing drugs with improved efficacy [ 25 ]. Newly synthesized derivatives of 6-chloro/morpholino/amino-9-sulfonylpurine have shown promising ability to inhibit growth in various human carcinoma, leukemia, and lymphoma cells [ 19 ].…”

Design, synthesis and identification of novel molecular hybrids based on naphthoquinone aromatic hydrazides as potential trypanocide and leishmanicidal agents

“…Among the potential medicinal chemistry tools that can circumvent this issue, there is the molecular hybridization strategy for drug discovery. This approach is based on the design of new chemical entities by the fusion of bioactive molecular fragments derived from known bioactive molecules (Burkner et al 2023, Pedroso et al 2023, Lourenço et al 2023, Wang et al 2023. Usually, it is essential to verify the synergistic characteristics of the two fragments in order to plan the new target molecular entity (Dong et al 2023, Fershtat & Makhova 2017, Fraga 2009, Langdon et al 2010, Lazar et al 2004, Wang et al 2023, Viegas-Junior et al 2007).…”

Urea Hydrogen Peroxide and Ethyl Lactate, an Eco-Friendly Combo System in the Direct C(sp2)–H Bond Selenylation of Imidazo[2,1-b]thiazole and Related Structures

“…Considering the biological relevance of organoselenium compounds and therapeutic properties of imidazoheteroarenes, molecular hybridization of these structures could lead to molecules (e.g., compound viii–xi , Figure ) with interesting biological properties. , There are several interesting methods in the literature to access such a hybrid structure. In this regard, different strategies are available in the literature for their synthesis, involving transition-metal catalysis, transition-metal-free catalytic approach, photoinduced transformation, solvent-free approach, etc. ,,, Therefore, continuous search for an alternative and greener approach involving benign solvents for the synthesis of such hybrid structure is a topic of interest.…”