Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells

• Published in: Bioorganic chemistry Vol. 122; p. 105752
• Main Authors: Abdelgawad, Mohamed A., Mohamed, Fatma E.A., Lamie, Phoebe F., Bukhari, Syed N.A., Al-Sanea, Mohammad M., Musa, Arafa, Elmowafy, Mohammed, Nayl, A.A., Karam Farag, Ahmed, Ali, Sameeha M., Shaker, Mohamed E., Omar, Hany A., Abdelhameid, Mohammed K., Kandeel, Manal M.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.05.2022; Elsevier
• Subjects: Acridine; Amsacrine - chemistry; Amsacrine - pharmacology; And pseudo-pyrido-acridones; Antineoplastic Agents - chemistry; Apoptosis; Biochemistry & Molecular Biology; Cell Proliferation; Chemistry; Chemistry, Organic; DNA Topoisomerases, Type II - metabolism; FLT3 kinase; fms-Like Tyrosine Kinase 3; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Life Sciences & Biomedicine; Molecular Docking Simulation; Physical Sciences; Pyrido-dipyrimidines; Science & Technology; Topoisomerase II; Topoisomerase II Inhibitors; FLT3 kinase; Acridine; And pseudo-pyrido-acridones; Leukemia; Topoisomerase II; Pyrido-dipyrimidines; APOPTOSIS; GILTERITINIB; TYROSINE KINASE; TUMOR; FLT3 MUTATIONS; PSEUDO-RING; CHALLENGES; POLYPHARMACOLOGY; DNA; DERIVATIVES
• DOI: 10.1016/j.bioorg.2022.105752
• ISSN: 0045-2068

[Display omitted] •Pyrido-dipyrimidines and pseudo-pyrido-acridones as dual topoisomerase II/FLT3 inhibitors were designed and synthesized.•Compounds 19 and 20 inhibited topoisomerase II/FLT3 and had high potency against HL-60 cells.•Compound 20 induced late-stage apoptosis in HL-60 cells.•Compound 20 induced cell cycle arrest at the G2/M phase and upregulated several apoptosis biomarkers. Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.