Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAF(V600E) dual inhibitors

Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAF(V600E) and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAF(V...

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Published inBioorganic chemistry Vol. 104
Main Authors Al-Wahaibi, Lamya H., Gouda, Ahmed M., Abou-Ghadir, Ola F., Salem, Ola I. A., Ali, Asmaa T., Farghaly, Hatem S., Abdelrahman, Mostafa H., Trembleau, Laurent, Abdu-Allah, Hajjaj H. M., Youssif, Bahaa G. M.
Format Journal Article
LanguageEnglish
Published SAN DIEGO Elsevier 01.11.2020
Subjects
Biochemistry & Molecular Biology
Chemistry
Chemistry, Organic
Life Sciences & Biomedicine
Physical Sciences
Science & Technology
Antiproliferative
MECHANISM
ANTICANCER AGENTS
DOCKING
INDOLE-2-CARBOXAMIDES
PIPERAFIZINE-A
EGFR
BRAF(V600E)
(-)-PHENYLAHISTIN
BIOLOGICAL EVALUATION
Pyrazino-indole
TARGETS
CYTOTOXICITY
Apoptosis
SCAFFOLD
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Summary:Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAF(V600E) and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAF(V600E), a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their anti proliferative activity against a panel of four human cancer cell lines. Compounds 20-23, 28-31, and 33 showed promising antiproliferative activities. These compounds were further tested for their inhibitory potencies against EGFR and BRAF(V600E) kinases with erlotinib as a reference drug. Compounds 23 and 33 exhibited equipotency to doxorubicin against the four cell lines and efficiently inhibited both EGFR (IC50 = 0.08 and 0.09 mu M, respectively) and BRAF(V600E) (IC50 = 0.1 and 0.29 mu M, respectively). In cell cycle study of MCF-7 cell line, compounds 23 and 33 induced apoptosis and exhibited cell cycle arrest in both Pre-G1 and G2/M phases. Molecular docking analyses revealed that the new compounds can fit snugly into the active sites of EGFR, and BRAF(V600E) kinases. Compound 23, 31 and 33 adopted similar binding orientations and interactions to those of erlotinib and vemurafenib.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2020.104260