Thieno[2,3-d]pyrimidin-4(3H)-one Derivatives of Benzimidazole as Potential Anti- Breast Cancer (MDA-MB-231, MCF-7) Agents

Abstract

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.

Recent Advances in the Anticancer Applications of Benzimidazole Derivatives

“…[70,71] In this trend, various thieno [2,3d]pyrimidine-based-N,N-disubstituted-benzimidazole derivatives were synthesized to estimate their cytotoxicity proficiency against MDA-MB-231 and MCF-7 cell lines. [72] The results show that almost all the benzimidazoles demonstrated a short range of activity towards MDA-MB-231, MCF-7, and fibroblast 3T3 cells. In contrast, some displayed comparatively proper viability against MCF-7 and 3T3 cell lines.…”

“…According to scientific explorations, mutations can influence EGFR (or other receptor tyrosine kinases) expression, thereby leading to over‐expression which is responsible for different categories of cancer [70,71] . In this trend, various thieno[2,3‐d]pyrimidine‐based‐ N , N ‐disubstituted‐benzimidazole derivatives were synthesized to estimate their cytotoxicity proficiency against MDA‐MB‐231 and MCF‐7 cell lines [72] . The results show that almost all the benzimidazoles demonstrated a short range of activity towards MDA‐MB‐231, MCF‐7, and fibroblast 3T3 cells.…”

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…The 1 H ‐benzimidazole‐2‐one‐thieno[2,3‐ d ]pyrimidin‐4(3 H )‐one hybrid 49 (IC 50 : 29.0 and 74.0 nM, MTT assay) exhibited pronounced activity against MCF‐7 and MDA‐MB‐231 breast cancer cell lines, demonstrating its potential as a novel antibreast cancer candidate. [ 105,106 ]…”

“…[104] The mechanistic study revealed that hybrid 48 and MDA-MB-231 breast cancer cell lines, demonstrating its potential as a novel antibreast cancer candidate. [105,106]…”

Design, Cytotoxicity and Antiproliferative Activity of 4-Amino-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylates against MFC-7 and MDA-MB-231 Breast Cancer Cell Lines

“…As the discussed PTKs are therapeutical targets in cancer treatment, and on the basis of the above-mentioned thienopyrimidines’ inhibitory properties, we set ourselves the objective to design and synthesize 4-amino-thieno [2,3-d]pyrimidines in order to study both their activity against human cancer cell lines and their effects on normal cell lines. This investigation is a continuation of our foregoing study of the cytotoxicity effects of thienopyrimidines on human cancer cell lines (MDA-MB-231, MCF-7, HT-29, HeLa, HepG2) as well as towards normal human cells [ 28 , 29 ].…”