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. 2020 Jul 15:198:112363.
doi: 10.1016/j.ejmech.2020.112363. Epub 2020 Apr 23.

Synthesis and anticancer activity of thiourea derivatives bearing a benzodioxole moiety with EGFR inhibitory activity, apoptosis assay and molecular docking study

Samir Y Abbas  1 , Reem A K Al-Harbi  2 , Marwa A M Sh El-Sharief  3
Affiliations

Synthesis and anticancer activity of thiourea derivatives bearing a benzodioxole moiety with EGFR inhibitory activity, apoptosis assay and molecular docking study

Samir Y Abbas et al. Eur J Med Chem. .

Abstract

New thiourea derivatives bearing a benzodioxole moiety were synthesized via the reaction of 5-isothiocyanatobenzodioxole with amino compounds such as aromatic amines, sulfa drugs, heterocyclic amines, hydrazines and hydrazides. The anticancer activity of the synthesized thiourea derivatives was examined against HCT116, HepG2 and MCF-7 cancer cell lines. Most of thiourea derivatives revealed significant cytotoxic effect, in some cases greater than the doxorubicin. As example, IC50 values of N1,N3-disubstituted-thiosemicarbazone 7 were 1.11, 1.74 and 7.0 μM for HCT116, HepG2 and MCF7, respectively; IC50 values of doxorubicin were 8.29, 7.46 and 4.56 μM, respectively. The anticancer mechanisms were studied via EGFR inhibition and apoptosis assessments, as well as molecular docking.

Keywords: Anticancer activity; Benzo[d][1,3]; Benzodioxole; Cytotoxic; Dioxol-5-yl; Thiourea.

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Conflict of interest statement

Declaration of competing interest According to the WHO report published in 2018, the major cause of the death is cancer the number of cancer cases will increase to 22 million by 2030. Chemotherapeutic drugs such as doxorubicin, thiotepa, cisplatin, paclitaxel and chlorambucil failed to asset the growth of cancer cells completely. The traditional chemotherapy is facing the lacking of selectivity towards tumor cells and the resistance of cancer cells to drugs that are structurally and mechanistically distinct. Accordingly, there is an emergent need to develop some newer versatile chemotherapeutic agents. Continuous exploration and discover of anti-cancer drugs with low toxicity and high efficiency are still important directions in anti-cancer drug research and development. As a part of our extensive research program to assemble novel bioactive compounds with potent antiproliferative effects on tumor cells, we have employed benzo[d] [1,3]dioxol-5-yl isothiocyanate to synthesize various thiourea derivatives incorporating two benzo[d] [1,3]dioxol-5-yl moieties. It can be concluded that employing benzo[d] [1,3]dioxol-5-yl isothiocyanate to synthesize various bis-benzo[d] [1,3]dioxol-5-yl thiourea derivatives afforded compounds having potent antitumor properties. Some of them showed a broad spectrum activity against all the tested cell lines, even more potent than doxorubicin. The biologically active compounds were safe toward normal cells. The results of annexin V-FITC apoptosis assay indicate that the tested compounds induced apoptosis in HepG2 cell line. In cell cycle analysis, the results showed that cells were strongly arrested in Pre-G1 phase by all the tested compounds. Also, the tested compounds induced apoptosis at G2-M phase. Moreover, the comparison of the Bax and Bcl2 values for the tested compounds with values of control stated that the tested compounds shifted the cells towards undergoing apoptosis.

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