Synthesis, Antiproliferative Evaluation and QSAR Analysis of Novel Halogen- and Amidino-Substituted Benzothiazoles and Benzimidazoles

被引:1
作者
Rep Kaulic, Valentina [1 ]
Racane, Livio [2 ]
Leventic, Marijana [3 ]
Subaric, Domagoj [4 ]
Rastija, Vesna [4 ]
Glavas-Obrovac, Ljubica [3 ]
Raic-Malic, Silvana [1 ]
机构
[1] Univ Zagreb, Fac Chem Engn & Technol, Dept Organ Chem, Marulicev Trg 20, Zagreb 10000, Croatia
[2] Univ Zagreb, Fac Text Technol, Dept Appl Chem, Prilaz Baruna Filipovica 28, Zagreb 10000, Croatia
[3] Univ Josip Juraj Strossmayer Osijek, Fac Med Osijek, Dept Med Chem Biochem & Lab Med, Josipa Huttlera 4, Osijek 31000, Croatia
[4] Josip Juraj Strossmayer Univ Osijek, Fac Agrobiotechn Sci Osijek, Vladimira Preloga 1, Osijek 31000, Croatia
关键词
benzothiazoles; benzimidazoles; anticancer; QSAR; cell cycle perturbation; mitochondrial membrane potential; ANTITUMOR AGENT; DESCRIPTORS; DERIVATIVES; VALIDATION; PARAMETERS; BINDING; DESIGN; POTENT; MITOCHONDRIAL; PREDICTION;
D O I
10.3390/ijms232415843
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Syntheses of 6-halogen-substituted benzothiazoles were performed by condensation of 4-hydroxybenzaldehydes and 2-aminotiophenoles and subsequent O-alkylation with appropriate halides, whereas 6-amidino-substituted benzothiazoles were synthesized by condensation of 5-amidino-2-aminothiophenoles and corresponding benzaldehydes. While most of the compounds from non-substituted and halogen-substituted benzothiazole series showed marginal antiproliferative activity on tested tumor cell lines, amidino benzazoles exhibited stronger inhibitory activity. Generally, imidazolyl benzothiazoles showed pronounced and nonselective activity, with the exception of 36c which had a strong inhibitory effect on HuT78 cells (IC50 = 1.6 mu M) without adverse cytotoxicity on normal BJ cells (IC50 >100 mu M). Compared to benzothiazoles, benzimidazole structural analogs 45a-45c and 46c containing the 1,2,3-triazole ring exhibited pronounced and selective antiproliferative activity against HuT78 cells with IC50 < 10 mu M. Moreover, compounds 45c and 46c containing the methoxy group at the phenoxy unit were not toxic to normal BJ cells. Of all the tested compounds, benzimidazole 45a with the unsubstituted phenoxy central core showed the most pronounced cell growth inhibition on THP1 cells in the nanomolar range (IC50 = 0.8 mu M; SI = 70). QSAR models of antiproliferative activity for benzazoles on T-cell lymphoma (HuT78) and non-tumor MDCK-1 cells elucidated the effects of the substituents at position 6 of benzazoles, demonstrating their dependence on the topological and spatial distribution of atomic mass, polarizability, and van der Waals volumes. A notable cell cycle perturbation with higher accumulation of cells in the G(2)/M phase, and a significant cell increase in subG0/G1 phase were found in HuT78 cells treated with 36c, 42c, 45a-45c and 46c. Apoptotic morphological changes, an externalization of phosphatidylserine, and changes in the mitochondrial membrane potential of treated cells were observed as well.
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页数:35
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