Microwave-assisted synthesis, spectroscopic characterization, and biological evaluation of fused thieno[2,3-d]pyrimidines as potential anti-cancer agents targeting EGFRWT and EGFRT790M

• Published in: Molecular diversity Vol. 27; no. 2; pp. 901 - 917
• Main Authors: Aboelez, Moustafa O., Kamel, Moumen S., Belal, Amany, El Badry Abdel-Aziz, Ahmed, Abourehab, Mohammed A. S., Abdel-Ghany, H., A. El Hamd, Mohamed, El-Remaily, Mahmoud Abd El Aleem Ali
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-04-2023; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Cytotoxicity; Life Sciences; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Microwave; Pyrimidines; Anticancer agents; EGFR
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-022-10477-7

Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that is usually overexpressed in many types of cancers. In the present study, an effort was done in synthesis of new 3,4-diaminothieno[2,3-b] thiophene-2,5-dicarbonitrile derivatives
2–8
, assisted by a microwave device. Different spectroscopic instruments were used for their analysis and confirmed their chemical structures. The antimicrobial properties of the produced compounds were investigated and found to be promising. Next, they were tested for cytotoxicity against MCF-7, HepG-2, HCT-116, and A549 cell lines. Moreover, in vitro cytotoxicity evaluation against well-known standards, namely, gefitinib and erlotinib was achieved using MTT method. The obtained compounds (2–8) were found to be more effective against the two tested cancer cell lines than erlotinib. In MCF-7 and A549 cells, compound
3
was found to be 4.42 and 4.12 times more active than erlotinib, respectively. The activity of radical scavenging was inhibited by 78%. The most cytotoxic compounds were subsequently studied for their kinase inhibitory effect against EGFR
WT
and EGFR
T790M
using the HTRF assay. Compound
3
was shown to be the most powerful against both kinds of EGFR, with IC
50
values of 0.28 and 5.02. Furthermore, compound
2
demonstrated the highest antioxidant activity as it has a radical scavenging activity of 78%. Compounds
2,6,7
and
8
revealed to be the most safe compounds, none hepatotoxic, none carcinogenic, none immunotoxic, none mutagenic and none cytotoxic.
Graphical abstract