NQO1 induction and radiation-based biodistribution study of a new quinoline derivative identified in a screen of 6,8-diiodoquinazolinone sulfonamide conjugates

TY - JOUR

T1 - NQO1 induction and radiation-based biodistribution study of a new quinoline derivative identified in a screen of 6,8-diiodoquinazolinone sulfonamide conjugates

AU - Soliman, Aiten M.

AU - Ghorab, Mostafa M.

AU - Higgins, Maureen

AU - Dinkova-Kostova, Albena T.

AU - Korany, Mohamed

AU - Amin, Mohamed A.

AU - Khedr, Mohammed A.

AU - Sakr, Tamer M.

N1 - Publisher Copyright: © 2025 Elsevier Masson SAS

PY - 2025/10/15

Y1 - 2025/10/15

N2 - A series of quinazoline derivatives 10–23 incorporating benzenesulfonamide and various aliphatic, aromatic and heterocyclic acetamide tails were designed, synthesized, and in vitro evaluated for their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. Compounds 13 and 20 exhibited the highest potency among this series, with CD values 14 and 3 μM, respectively. The quinoline derivative 20 was subjected to radiolabeling. The radio-synthesized derivative was assessed for its biodistribution in normal and tumor-bearing animal models, where it displayed high in vivo stability and selectivity toward tumor cells. Molecular docking of 20 within the Nrf2-binding site of Kelch-like ECH-associated protein 1 (Keap1) predicted the highest binding affinity –8.76 kcal/mol with the least RMSD value 1.01 Å. It showed a stable binding confirmed by RMSF compared to the co-crystallized ligand. This study identifies compound 20 as a promising antioxidant for continued optimization in redox-modulating research.

AB - A series of quinazoline derivatives 10–23 incorporating benzenesulfonamide and various aliphatic, aromatic and heterocyclic acetamide tails were designed, synthesized, and in vitro evaluated for their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. Compounds 13 and 20 exhibited the highest potency among this series, with CD values 14 and 3 μM, respectively. The quinoline derivative 20 was subjected to radiolabeling. The radio-synthesized derivative was assessed for its biodistribution in normal and tumor-bearing animal models, where it displayed high in vivo stability and selectivity toward tumor cells. Molecular docking of 20 within the Nrf2-binding site of Kelch-like ECH-associated protein 1 (Keap1) predicted the highest binding affinity –8.76 kcal/mol with the least RMSD value 1.01 Å. It showed a stable binding confirmed by RMSF compared to the co-crystallized ligand. This study identifies compound 20 as a promising antioxidant for continued optimization in redox-modulating research.

KW - Biodistribution

KW - Docking

KW - NQO1

KW - Nrf2

KW - Quinazoline

KW - Sulfonamide

UR - https://www.scopus.com/pages/publications/105008242783

U2 - 10.1016/j.ejmech.2025.117855

DO - 10.1016/j.ejmech.2025.117855

M3 - Article

C2 - 40554306

AN - SCOPUS:105008242783

SN - 0223-5234

VL - 296

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 117855

ER -