Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors

被引：8

作者：

Sobh, Eman A. ^{[1
,8
]}

Dahab, Mohammed A. ^{[2
,9
]}

Elkaeed, Eslam B. ^{[3
]}

Alsfouk, Aisha A. ^{[4
]}

Ibrahim, Ibrahim M. ^{[5
]}

Metwaly, Ahmed M. ^{[6
,7
]}

Eissa, Ibrahim H. ^{[2
,9
]}

机构：

[1] Menoufia Univ, Fac Pharm, Dept Pharmaceut Chem, Menoufia, Egypt

[2] Al Azhar Univ, Fac Pharm Boys, Pharmaceut Med Chem & Drug Design Dept, Cairo, Egypt

[3] AlMaarefa Univ, Coll Pharm, Dept Pharmaceut Sci, Riyadh, Saudi Arabia

[4] Princess Nourah Bint Abdulrahman Univ, Coll Pharm, Dept Pharmaceut Sci, Riyadh, Saudi Arabia

[5] Cairo Univ, Fac Sci, Biophys Dept, Cairo, Egypt

[6] Al Azhar Univ, Fac Pharm Boys, Pharmacognosy & Med Plants Dept, Cairo, Egypt

[7] City Sci Res & Technol Applicat SRTA City, Genet Engn & Biotechnol Res Inst, Biopharmaceut Prod Res Dept, Alexandria, Egypt

[8] Menoufia Univ, Fac Pharm, Pharmaceut Chem Dept, Menoufia, Egypt

[9] Al Azhar Univ, Fac Pharm Boys, Pharmaceut Med Chemistry& Drug Design Dept, Cairo 11884, Egypt

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2023年 / 38卷 / 01期

关键词：

Anti-proliferative; apoptosis; EGFR inhibitors; MD simulations; thieno[2; 3-d]pyrimidines; POTENTIAL VEGFR-2 INHIBITORS; TYROSINE KINASE INHIBITORS; RAPID COLORIMETRIC ASSAY; BIOLOGICAL EVALUATION; ANTICANCER EVALUATION; ACQUIRED-RESISTANCE; BINDING MODE; GROWTH; APOPTOSIS; DISCOVERY;

D O I：

10.1080/14756366.2023.2220579

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：

A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFR(WT) and EGFR(T790M), respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFR(WT) and EGFR(T790M) indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

引用

页数：21

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