2. Academic Validation
  3. Discovery of 4-[2.2]paracyclophanylthiazole derivatives as topoisomerase ll/malic enzyme 1 inhibitors modulating autophagy/apoptosis pathways in breast cancer therapy

Discovery of 4-[2.2]paracyclophanylthiazole derivatives as topoisomerase ll/malic enzyme 1 inhibitors modulating autophagy/apoptosis pathways in breast cancer therapy

  • Bioorg Chem. 2026 Jun 15:174:109695. doi: 10.1016/j.bioorg.2026.109695.
Lamiaa E Abd El-Haleem 1,  Ashraf A Aly 2,  Asmaa H Mohamed 3,  Mariam T Fahmi 4,  Alan B Brown 5,  Olaf Fuhr 6,  Tarek M Okda 7,  Marwa E Abdelaziz 8,  Eman J El-Agroudy 9
Affiliations

Affiliations

  • 1 Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt; Interdisciplinary Research Center for Hydrogen Technologies and Carbon Management (IRC- HTCM), King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia. Electronic address: [email protected].
  • 2 Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt. Electronic address: [email protected].
  • 3 Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt. Electronic address: [email protected].
  • 4 Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt. Electronic address: [email protected].
  • 5 Department of Chemistry and Chemical Engineering, Florida Institute of Technology, Melbourne, FL 32901, USA. Electronic address: [email protected].
  • 6 Institute of Nanotechnology (INT) and Karlsruhe Nano Micro Facility (KNMFi), Karlsruhe, Institute of Technology (KIT), Kaiserstraße 12, 76131 Karlsruhe, Germany. Electronic address: [email protected].
  • 7 Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. Electronic address: [email protected].
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. Electronic address: [email protected].
PMID: 41812428 DOI: 10.1016/j.bioorg.2026.109695
Abstract

Two series of [2.2]paracyclophanylthiazoles 5a-h and 7a-e were rationally designed, synthesized, and screened for Anticancer activity against breast Cancer cell lines representing both luminal (MCF-7) and aggressive (MDA-MB-231) subtypes, as well as safety profiling by a normal epithelial breast cell line MCF-10A. Of these, thiazolidinone derivatives 7a, 7d, and 7e possessed outstanding dual antiproliferative potency against MCF-7 (IC₅₀ = 3.1 ± 0.17, 3.76 ± 0.08, 1.19 ± 0.07 μM) and MDA-MB-231 (IC₅₀ = 1.04 ± 0.07, 1.08 ± 0.05, 2.50 ± 0.12 μM), significantly better than doxorubicin (IC₅₀ = 6.87 ± 0.18 μM and 4.16 ± 0.13 μM, respectively). Thiosemicarbazide derivative 3d also showed impressive cytotoxic potency against MCF-7 cells (IC₅₀ = 4.74 ± 0.14 μM). All four compounds were also safe for normal MCF-10A cells. Mechanistic studies revealed that most active derivatives engaged both Autophagy and Apoptosis pathways by modulating Beclin-1, Bax, Bcl-2, and caspase-9 with compound 7a validated by LC3-II and cleaved PARP assays. In addition, compounds 7a and 7e exhibited robust Topo II inhibitory activity, whereas 7a and 7d efficiently disabled ME-1 function, both of which exhibited better IC₅₀ values than doxorubicin. Such biological results were also reinforced by molecular docking studies, which confirmed desirable binding of active candidates by Topo II and ME-1 active sites, along with reasonable scoring energies and accepted physiochemical properties. Overall, these studies recognize paracyclophanyl-thiazolidinone hybrid 7a as a potential dual Topo II/ME-1 inhibitor of clinical interest for treating triple-negative breast Cancer (TNBC).

Keywords

Apoptosis; Autophagy; Bax; Bcl-2; Beclin-1; Caspase-9; Cleaved PARP; Hydrazonothiazolidin-4-ones; LC3-II; Malic enzyme-1; Scaffold hopping; Topoisomerase II; [2.2]Paracyclophanyl-hydrazinecarbothioamides.

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