1. Academic Validation
  2. Design, synthesis and pharmacological evaluation of 1,4-naphthoquinone- 1,2,3-triazole hybrids as new anticancer agents with multi-kinase inhibitory activity

Design, synthesis and pharmacological evaluation of 1,4-naphthoquinone- 1,2,3-triazole hybrids as new anticancer agents with multi-kinase inhibitory activity

  • Sci Rep. 2025 Feb 24;15(1):6639. doi: 10.1038/s41598-025-87483-w.
Pegah Mardaneh 1 2 3 Somayeh Pirhadi 2 Maryam Mohabbati 2 Mehdi Khoshneviszadeh 2 Zahra Rezaei 1 Luciano Saso 4 Najmeh Edraki 5 Omidreza Firuzi 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 2 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 3 Student Research Committee, Shiraz University of medical Sciences, Shiraz, Iran.
  • 4 Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, P. le Aldo Moro 5, Rome, 00185, Italy.
  • 5 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. edrakin@sums.ac.ir.
  • 6 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. firuzio@sums.ac.ir.
Abstract

Targeting important oncogenic kinases that contribute to hallmarks of Cancer has revolutionized Cancer therapy. Ten 1,4-naphthoquinone derivatives linked to 1,2,3-triazole (4a-4j) were designed and synthesized as kinase inhibitors especially aimed at blocking CDK2, a validated and important Cancer target. Assessment of the antiproliferative activity of the synthesized compounds against lung (EBC-1), pancreatic ductal adenocarcinoma (PDAC, AsPC-1 and Mia-Paca-2), colorectal (HT-29), and breast Cancer (MCF-7) cells revealed that most of the derivatives possess considerable antiproliferative potential, with IC50 values as low as 0.3 µM. In contrast, the compounds relatively spared NIH3T3 non-cancer cell line. The kinase inhibitory effect of the best compounds was examined against a panel of 30 important oncogenic kinases. Derivatives 4a (bearing a benzyl ring) and 4i (bearing a p-methyl benzyl ring) inhibited CDK2, FLT4 (VEGFR3) and PDGFRA kinases with IC50 values in the range of 0.55-1.67 and 0.22-11.32 µM, respectively. These compounds also caused S phase arrest and induced characteristic features of Apoptosis in PDAC cells. Molecular modeling simulation validated the binding interactions between the synthesized derivatives and the active sites of the 3 target kinases. Finally, the compounds also possessed drug-like features as examined by in silico studies. The results of this study indicate that 1,4-naphthoquinone derivatives could have promising Anticancer potential as multi-kinase inhibitors.

Keywords

1,4-Naphthoquinone derivatives; Antitumoral agents; CDK2 inhibitor; Drug design; Targeted therapy.

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