Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme

Khaled El-Adl; Abdel-Ghany A El-Helby; Helmy Sakr; Ibrahim H Eissa; Sanadelaslam S A El-Hddad; Fatma M I A Shoman

doi:10.1016/j.bioorg.2020.104059

Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme

Bioorg Chem. 2020 Sep:102:104059. doi: 10.1016/j.bioorg.2020.104059. Epub 2020 Jun 30.

Authors

Khaled El-Adl¹, Abdel-Ghany A El-Helby², Helmy Sakr², Ibrahim H Eissa², Sanadelaslam S A El-Hddad², Fatma M I A Shoman³

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt. Electronic address: eladlkhaled74@azhar.edu.eg.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
³ MD in Clinical Pathology, Blood Bank Specialist, Blood Bank Directorate Manager, Ministry of Health, Cairo, Egypt.

PMID: 32653608
DOI: 10.1016/j.bioorg.2020.104059

Abstract

Novel series of 5-benzylidenethiazolidine-2,4-dione derivatives 4_a-c-8_a-f were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 8_f was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC₅₀ = 11.19 ± 0.8, 8.99 ± 0.7 and 7.10 ± 0.4 µM respectively. Compound 8_f exhibited lower activity than sorafenib, (IC₅₀ = 9.18 ± 0.6, 8.37 ± 0.7 and 5.10 ± 0.4 µM respectively), against HepG2 and HCT116 but exhibited nearly the same activity against MCF-7 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC₅₀ = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and HCT116 but nearly the same activity against MCF-7cell lines respectively. The most active derivatives 6_c,d,f,g and 8_a-f were evaluated for their inhibitory activities against VEGFR-2. The elongation of the structures to have distal moieties enhanced anticancer and VEGFR-2 inhibitory activities as in compounds 8_a-f. Among them, compounds 8_f was found to be the most potent derivative that inhibited VEGFR-2 at IC₅₀ value of 0.22 ± 0.02 µM, which is nearly the half as that of sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular design was performed to investigate their binding mode and affinities towards VEGFR-2 receptor. The data obtained from docking studies were highly correlated with that obtained from the biological screening.

Keywords: Anticancer agents; Molecular docking; Thiazolidine-2,4-dione; VEGFR-2 inhibitors.

MeSH terms

Drug Design
Humans
Molecular Docking Simulation / methods*
Molecular Structure
Structure-Activity Relationship
Thiazolidinediones / chemical synthesis*
Thiazolidinediones / pharmacology
Thiazolidinediones / therapeutic use*
Vascular Endothelial Growth Factor Receptor-2 / drug effects*

Substances

Thiazolidinediones
Vascular Endothelial Growth Factor Receptor-2