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A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity
Author(s) -
Bayrak Nilüfer,
Yıldırım Hatice,
Yıldız Mahmut,
Radwan Mohamed O.,
Otsuka Masami,
Fujita Mikako,
Ciftci Halil I.,
Tuyun Amaç Fatih
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13651
Subject(s) - chemistry , plastoquinone , imatinib mesylate , tyrosine kinase , imatinib , chronic myelogenous leukemia , k562 cells , cytotoxic t cell , dna fragmentation , kinase , stereochemistry , cytotoxicity , biochemistry , apoptosis , leukemia , biology , signal transduction , cancer research , in vitro , programmed cell death , myeloid leukemia , immunology , thylakoid , chloroplast , gene
Herein, we report the synthesis and cytotoxic effects of novel chlorinated plastoquinone analogs ( ABQ1–17 ) against different leukemic cells. Compounds ABQ3 , ABQ11 , and ABQ12 demonstrated a pronounced antiproliferative effect against chronic myelogenous leukemia (CML) K562 cell line with IC 50 values of 0.82 ± 0.07, 0.28 ± 0.03, and 0.98 ± 0.22 μM, respectively. Among them, ABQ11 showed approximately three times higher selectivity than imatinib on CML. ABQ11 ‐treated CML cells induced significant apoptosis at low concentration. Inhibitory effect of ABQ11 against eight different tyrosine kinases, including ABL1, was investigated. ABQ11 inhibited ABL1 with IC 50 value of 13.12 ± 1.71 μM, indicating that the moderate inhibition of ABL1 kinase is just an in‐part mechanism of its outstanding cellular activity. Molecular docking of ABQ11 into ABL1 kinase ATP‐binding pocket revealed the formation of some key interactions. Furthermore, DNA cleavage assay showed that ABQ11 strongly disintegrated DNA at 1 μM concentration in the presence of iron (II) complex system, assuming that the major mechanism for the anticancer effects of ABQ11 is DNA cleavage. In silico ADMET prediction revealed that ABQ11 is a drug‐like small molecule with a favorable safety profile. Taken together, ABQ11 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from imatinib.