2. Academic Validation
  3. Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors

Design and synthesis of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as antiproliferative EGFR and BRAFV600E dual inhibitors

  • Bioorg Chem. 2020 Nov;104:104260. doi: 10.1016/j.bioorg.2020.104260.
Lamya H Al-Wahaibi 1,  Ahmed M Gouda 2,  Ola F Abou-Ghadir 3,  Ola I A Salem 3,  Asmaa T Ali 4,  Hatem S Farghaly 4,  Mostafa H Abdelrahman 5,  Laurent Trembleau 6,  Hajjaj H M Abdu-Allah 7,  Bahaa G M Youssif 8
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 3 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
  • 4 Biochemistry Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.
  • 5 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
  • 6 School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB243UE, United Kingdom.
  • 7 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: hajjaj@aun.edu.eg.
  • 8 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: bgyoussif@ju.edu.sa.
PMID: 32920363 DOI: 10.1016/j.bioorg.2020.104260
Abstract

Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRafV600E 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 BRafV600E, a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their antiproliferative 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 BRafV600E 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 µM, respectively) and BRafV600E (IC50 = 0.1 and 0.29 µM, 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 BRafV600E kinases. Compound 23, 31 and 33 adopted similar binding orientations and interactions to those of erlotinib and vemurafenib.

Keywords

Antiproliferative; Apoptosis; BRAF(V600E); EGFR; Pyrazino-indole.

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