Utility of sulfachloropyridazine in the synthesis of novel anticancer agents as antiangiogenic and apoptotic inducers

Sally S Zahran; Fatma A Ragab; Aiten M Soliman; Marwa G El-Gazzar; Walaa R Mahmoud; Mostafa M Ghorab

doi:10.1016/j.bioorg.2024.107411

Utility of sulfachloropyridazine in the synthesis of novel anticancer agents as antiangiogenic and apoptotic inducers

Bioorg Chem. 2024 Apr 30:148:107411. doi: 10.1016/j.bioorg.2024.107411. Online ahead of print.

Authors

Sally S Zahran¹, Fatma A Ragab², Aiten M Soliman³, Marwa G El-Gazzar¹, Walaa R Mahmoud², Mostafa M Ghorab⁴

Affiliations

¹ Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Egypt.
³ Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt. Electronic address: Aiten_mahmoud@yahoo.com.
⁴ Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt. Electronic address: mmsghorab@yahoo.com.

PMID: 38733747
DOI: 10.1016/j.bioorg.2024.107411

Abstract

In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC₅₀ of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site.

Keywords: Angiogenesis; Apoptosis; Sulfachloropyridazine; Thiocarbamates; Thiourea; VEGFR-2.