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  3. Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells

Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells

  • Eur J Med Chem. 2021 Jan 15:210:113081. doi: 10.1016/j.ejmech.2020.113081.
Rawan M Sbenati 1,  Seyed-Omar Zaraei 2,  Mohammed I El-Gamal 3,  Hanan S Anbar 4,  Hamadeh Tarazi 5,  Malaka M Zoghbor 1,  Najma A Mohamood 1,  Mahta M Khakpour 1,  Dana M Zaher 1,  Hany A Omar 6,  Nour N Alach 1,  Mahmoud K Shehata 1,  Randa El-Gamal 7
Affiliations

Affiliations

  • 1 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 2 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
  • 3 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt. Electronic address: malgamal@sharjah.ac.ae.
  • 4 Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates.
  • 5 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 6 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
  • 7 Department of Medical Biochemistry, Faculty of Medicine, University of Mansoura, Mansoura, 35516, Egypt.
PMID: 33310290 DOI: 10.1016/j.ejmech.2020.113081
Abstract

Sorafenib is one of the clinically used Anticancer agents that inhibits several kinases. In this study, novel indole-based rigid analogues of sorafenib were designed and synthesized in order to enhance kinase selectivity and hence minimize the side effects associated with its use. The target compounds possess different linkers; urea, amide, sulfonamide, or thiourea, in addition to different terminal aryl moieties attached to the linker in order to investigate their impact on biological activity. They were tested against Hep3B, Huh7, and Hep-G2 hepatocellular carcinoma (HCC) cell lines to study their potency. Among all the tested target derivatives, compound 1h exerted superior antiproliferative potency against all the three tested HCC cell lines compared to sorafenib. Based on these preliminary results, compound 1h was selected for further biological and in silico investigations. Up to 30 μM, compound 1h did not inhibit 50% of the proliferation of WI-38 normal cells, which indicated promising selectivity against HCC cells than normal cells. In addition, compound 1h exerted superior kinase selectivity than sorafenib. It is selective for VEGFR2/KDR/Flk-1 and VEGFR3/Flt-4 angiogenesis-related kinases, while sorafenib is a multikinase inhibitor. Superior kinase selectivity of compound 1h to sorafenib can be attributed to its conformationally-restricted indole nucleus and the bulky N-methylpiperazinyl moiety. Western blotting was carried out and confirmed the ability of compound 1h to inhibit VEGFR2/KDR/Flk-1 kinase inside Hep-G2 HCC cells in a dose-dependent pattern. Compound 1h induces Apoptosis and necrosis in Hep-G2 cell line, as shown by Caspase-3/7 and Lactate Dehydrogenase (LDH) release assays, respectively. Moreover, compound 1h is rather safe against hERG. Thus, we could achieve a more selective kinase inhibitor than sorafenib with retained or even better antiproliferative potency against HCC cell lines. Furthermore, molecular docking and dynamic simulation studies were carried out to investigate its binding mode with VEGFR2/KDR/Flk-1 kinase. The molecule has a unique orientation upon binding with the kinase.

Keywords

Antiproliferative activity; In silico; Indole; Kinase selectivity; Rigidified analogues; Sorafenib.

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