Utilization of cyanopyridine in design and synthesis of first-in-class anticancer dual acting PIM-1 kinase/HDAC inhibitors.

Autor: Bass AKA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt., Nageeb EM; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt., El-Zoghbi MS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt., Mohamed MFA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt., Badr M; Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt., Abuo-Rahma GEA; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt. Electronic address: gamal.aborahma@mu.edu.eg.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 Feb; Vol. 119, pp. 105564. Date of Electronic Publication: 2021 Dec 16.
DOI: 10.1016/j.bioorg.2021.105564
Abstrakt: Herein, we report design and synthesis of twenty-one dual PIM-1/HDAC inhibitors utilizing 3-cyanopyridines as a novel cap moiety linked with aliphatic /aromatic linker bearing carboxylic acid 3a-g, hydroxamic acid 4a-g or 2-aminoanilide moieties 5a-g as zinc-binding group. Most of the target hybrids revealed promising growth inhibition according to one dose NCI protocol against 60 cancer cell lines. Meanwhile, hydroxamic acids 4b, 4d and 4e displayed strong and broad-spectrum activity against nine tumor subpanels tested (GI 50 0.176-8.87 μM); 4d displayed strong antiproliferative activity with GI 50  ≤ 3 μM against different cancer cell lines (GI 50 range from 0.325 to 2.9 μM). Furthermore, 4a, 4d-4g and 5f manifested a high inhibitory activity against HDACs 1 and 6 isozymes; 4g, displayed potent HDAC 1 and 6 inhibitory activity (45.01 ± 2.1 and 19.78 ± 1.1 nM) more than the reference SAHA (51.54 ± 2.4 and 21.38 ± 1.2 nM, respectively), while 4f was more potent (30.09 ± 1.4 nM) than SAHA against HDAC 1 and less potent (30.29 ± 1.7 nM) than SAHA against HDAC 6. Hybrids 4b, 4d, 4e and 4f exhibited potent PIM-1 inhibitory activity; 4d showed comparable activity to quercetin (IC 50 of 343.87 ± 16.6 and 353.76 ± 17.1 nM, respectively); it exhibited pre G1 apoptosis and arrest cell cycle at G2/M phase. Moreover, it revealed good binding into pocket of HDACs 1,6 and PIM-1 kinase enzymes with good correlation with biological results. Moreover, 4b, 4d and 4e had reasonable drug-likeness properties according to Lipinski's rule. However, multitarget inhibitor of PIM-1/HDAC is a promising strategy in anticancer drug discovery; the most potent hybrids require further in vivo and clinical investigations.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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