2. Academic Validation
  3. Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2- a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity

Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2',3':4,5]thiazolo[3,2- a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2205043. doi: 10.1080/14756366.2023.2205043.
Mai A E Mourad 1,  Ayman Abo Elmaaty 1,  Islam Zaki 2,  Ahmed A E Mourad 3,  Amal Hofni 4,  Ahmed E Khodir 5,  Esam M Aboubakr 4,  Ahmed Elkamhawy 6 7,  Eun Joo Roh 8 9,  Ahmed A Al-Karmalawy 10
Affiliations

Affiliations

  • 1 Medicinal Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt.
  • 3 Pharmacology and Toxicology Department, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt.
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, Egypt.
  • 5 Department of Pharmacology, Faculty of Pharmacy, Horus University, New Damietta, Egypt.
  • 6 BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.
  • 7 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
  • 8 Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul, Korea.
  • 9 Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon, Korea.
  • 10 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, Egypt.
PMID: 37165800 DOI: 10.1080/14756366.2023.2205043
Abstract

Topoisomerases II are ubiquitous enzymes with significant genotoxic effects in many critical DNA processes. Additionally, epidermal growth factor receptor (EGFR) plays pivotal role in tumour growth and angiogenesis. A novel series of naphtho[2',3':4,5]thiazolo[3,2-a]pyrimidine hybrids have been designed, synthesised and evaluated for their topo IIα/EGFR inhibitory and apoptotic inducer activities. Cytotoxicity of the synthesised hybrids was evaluated against MCF-7, A549 and HCT-116 cell lines. Of the synthesised hybrids, 6i, 6a and 6c experienced superior cytotoxic activity compared to doxorubicin and erlotinib against the tested Cancer cells. The molecular mechanism of these hybrids revealed their ability to successfully inhibit topo IIα and EGFR activities in micromolar concentration and may serve as Topo II catalytic inhibitor. Moreover, these hybrids significantly arrested cell cycle at G2/M phase together with increased p53, caspae-7, caspase-9 levels and Bax/Bcl-2 ratio. The synthesised hybrids showed efficient binding pattern in molecular docking study and have acceptable drug likeness characters.

Keywords

EGFR; Thiazolopyrimidine; apoptosis; naphthoquinone; topoisomerase IIα.

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