Synthesis of novel amidines via one-pot three component reactions: Selective topoisomerase I inhibitors with antiproliferative properties

Abstract

Novel series of amidines were synthesized via the interaction between alicyclic amines, cyclic ketones, and a highly electrophilic 4-azidoquinolin-2(1H)-ones without any catalyst or additive. All the obtained products were elucidated based on NMR spectroscopy, mass spectrometry, and elemental analysis. The reaction conditions were optimized using cyclohexanone (2), piperidine (3a), and 4-azido-quinolin-2(1H)-one (1a) under an air atmosphere. The new compounds 4a-l and 5a-c were tested for antiproliferative activity against four cancer cell lines using doxorubicin as a reference drug. The most potent derivatives were compounds 4b, 4d, 4e, 4i, and 5c, with GI50 ranging from 1.00 µM to 1.50 µM. Compound 5c was the most effective derivative against the four cancer cell lines, outperforming doxorubicin. The compounds 4b, 4d, 4e, 4i, and 5c were studied further as topoisomerase I and IIα inhibitors. The compounds tested showed selective inhibition of topo I over topo IIα. Finally, docking studies explain why these compounds prefer topo I over topo IIα.

New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

“…Appendix A (Supplementary File) contains detailed information about the different biological assays for Cell viability (Mahmoud et al., 2022; Mekheimer et al., 2022), antiproliferative assay (El‐Sheref et al., 2022; Obaid Arhema Frejat et al., 2022), EGFR inhibitory assay (Mohamed et al., 2021), CDK assays (Mohammed et al., 2021) and apoptosis assays (Abou‐Zied et al., 2019; Cory & Adams, 2002; Giaccia & Kastan, 1998; Hisham et al., 2019; Nagata, 1997).…”

“…Antiproliferative assay 7a-q were investigated for antiproliferative activity against four cancer cell lines (El-Sheref et al, 2022;Obaid Arhema Frejat et al, 2022): A-549 (epithelial cancer cell line), MCF-7 (breast cancer cell line), Panc-1 (pancreas cancer cell line), and HT-29 (colon cancer cell line). The reference drug was doxorubicin, and the results of determining the IC 50 of each compound are shown in Table 1.…”