2. Academic Validation
  3. Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity

Novel 2-indolinone thiazole hybrids as sunitinib analogues: Design, synthesis, and potent VEGFR-2 inhibition with potential anti-renal cancer activity

  • Eur J Med Chem. 2020 Dec 15:208:112752. doi: 10.1016/j.ejmech.2020.112752.
Huda K Mahmoud 1,  Thoraya A Farghaly 2,  Hanan G Abdulwahab 3,  Nadia T Al-Qurashi 4,  Mohamed R Shaaban 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt.
  • 2 Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt; Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia. Electronic address: thoraya-f@hotmail.com.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
  • 4 Department of Basic Science, University College in Adam, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia.
  • 5 Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt; Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia.
PMID: 32947227 DOI: 10.1016/j.ejmech.2020.112752
Abstract

Novel 2-indolinone thiazole hybrids were designed and synthesized as VEGFR-2 inhibitors based on sunitinib, an FDA-approved Anticancer drug. The proposed structures of the prepared 2-indolinone thiazole hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-VEGFR-2 activity. All tested compounds exhibited a potent submicromolar inhibition of VEGFR-2 kinase with IC50 values ranging from 0.067 to 0.422 μM, relative to sunitinib reference drug (IC50 = 0.075 ± 0.002 μM). Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity, comparable or nearly equipotent to sunitinib. Compound 13b stood out as the most potent against VEGFR-2 showing IC50 value of 0.067 ± 0.002 μM, lower than that of sunitinib. In addition, the most potent derivatives were assessed for their Anticancer activity against two renal Cancer cell lines. Compound 13b (IC50 = 3.9 ± 0.13 μM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 μM) against CAKI-1 cell line. Moreover, thiazole 15b displayed excellent Anticancer activity against CAKI-1 cell line (IC50 = 3.31 ± 0.11 μM), superior to that of sunitinib (IC50 = 4.93 ± 0.16 μM). Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 μM) against A498 cell line. Besides, compound 15b revealed a safety profile much better than that of sunitinib against normal human renal cells. Furthermore, a docking study revealed a proper fitting of the most active compounds into the ATP binding site of VEGFR-2, rationalizing their potent anti-VEGFR-2 activity.

Keywords

Anti-renal cancer activity; Docking study; Indolinone; Sunitinib; Thiazoles.

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