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  3. Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities

Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities

  • Eur J Med Chem. 2018 Apr 25:150:567-578. doi: 10.1016/j.ejmech.2018.03.001.
Shaimaa A Abdelatef 1,  Mohammed T El-Saadi 1,  Noha H Amin 1,  Ahmed H Abdelazeem 2,  Hany A Omar 3,  Khaled R A Abdellatif 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt. Electronic address: ahmed.abdelazeem@pharm.bsu.edu.eg.
  • 3 Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, 62514, Egypt.
  • 4 Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef, 62514, Egypt; Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Saudi Arabia. Electronic address: khaled.ahmed@pharm.bsu.edu.eg.
PMID: 29549841 DOI: 10.1016/j.ejmech.2018.03.001
Abstract

A novel series of spirobenzo[h]chromene and spirochromane derivatives was designed, synthesized and evaluated as potential Anticancer agents against MCF-7 (human breast carcinoma), HT-29 (human colorectal adenocarcinoma) and A549 (human lung carcinoma) cell lines using MTT assay. Eight compounds 7, 8e, 13a-e and 16 showed a better Anticancer activity than that of sorafenib, the multi-kinase inhibitor with IC50 values between 1.78 and 5.47 μM or erlotinib with IC50 values over 20 μM. Representative compounds 8e, 13c and 16 were selected for further mechanistic investigation via EGFR, B-RAF and tubulin polymerization assays. Compound 16 was the most potent EGFR inhibitor (IC50 = 1.2 μM), yet compounds 8e, 13c and 16 displayed moderate tubulin polymerization inhibition effects. Molecular docking studies of those compounds revealed their possible binding modes into the active sites of both EGFR and B-RAF kinases. The newly developed compounds represent a therapeutically promising approach for the treatment of different types of Cancer.

Keywords

Anticancer agents; B-RAF; Docking; EGFR; Spirobenzo[h]chromene; Spirochromane.

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