Aims:
The purpose was the synthesis of some new thienopyrimidines derivative of 1,3-disubstituted
benzimidazoles and the evaluation of their cytotoxicity towards MDA-MB-231 and MCF-7 cell lines as well 3T3 cells.
Background:
An overexpression or mutational activation of TK receptors EGFR and HER2/neu are characteristic for
tumors. It has been found that some thieno[2,3-d]pyrimidines exhibit better inhibitory activity against epidermal growth
factor receptor (EGFR/ErbB-2) tyrosine kinase in comparison to aminoquinazolines. Breast cancer activity towards MDAMB-231 and MCF-7 cell lines by inhibiting EGFR was revealed by a novel 2-arylbenzimidazole. This motivated the
synthesis of new thienopyrimidines possessing benzimidazole fragment in order to evaluate their cytotoxicity to the above
mentioned cell lines.
Objective:
The objectives were the design and synthesis of a novel series thieno[2,3-d]pyrimidines bearing biologically
active moieties as 1,3-disubstituted-benzimidazole heterocycle structurally similar to diaryl ureas in order to evaluate their
cytotoxicity against MDA-MB-231, MCF-7 breast cancer cell lines.
Methods:
N,N-disubstituted benzimidazole-2-one carbonitriles were synthesized by Aza-Michael addition and used as
precursors to generate some of the new thieno[2,3-d]pyrimidines in acidic medium. The interaction of chloroethyl-2-
thienopyrimidines and 2-amino-benzimidazole resp. benzimidazol-2-one nitriles under solid-liquid transfer catalysis
conditions lead to obtaining of new thienopyrimidines. MTT assay for cells survival was performed in order to establish
the cytotoxicity of the tested compounds. Fluorescence study was used to elucidate some aspect of mechanism.
Results:
The effect of nine of the synthesized compounds was investigated towards MDA-MB-231 and MCF-7 cells as
well as to 3T3 cells. Thieno[2,3-d]pyirimidine-4-one 16 (IC50 – 0.058 μM) and 21 (IC50 – 0.029 μM) possess high
cytotoxicity against MDA-MB-231 cells after 24h. The most toxic against breast cancer MCF-7 cells was compounds 21
(IC50 – 0.074 μM), revealing lower cytotoxicity towards mouse fibroblast 3T3 cells with IC50 – 0.20 μM. SAR analisys
was performed. Fluorescence study of the treatment of MDA-MB cells with compound 21 was carried out in order to
clarify some aspects of mechanism of action.
Conclusion:
The relationship between cytotoxicity of compounds 14 and 20 against MCF-7 and 3T3 cells can suggest a
similar mechanism of action. The antitumor potential of the tested compounds proves the necessity for further
investigation to estimate the exact inhibition pathway in the cellular processes. The fluorescence study of the treatment of
MDA-MB cells with compound 21 showed a rapid process of apoptosis.
Snake venom phospholipases A2. A fluorescence study of their binding to phospholipid vesicles correlation with their anticoagulant activities.
