2. Academic Validation
  3. Innovative design and synthesis of dual-acting hCA IX/CDK-2 inhibitors through hetero ring fused pyrimidine utilization for cutting-edge anticancer therapy: Zein nanoparticles for in vivo lung cancer treatment

Innovative design and synthesis of dual-acting hCA IX/CDK-2 inhibitors through hetero ring fused pyrimidine utilization for cutting-edge anticancer therapy: Zein nanoparticles for in vivo lung cancer treatment

  • Bioorg Chem. 2025 Nov:166:109057. doi: 10.1016/j.bioorg.2025.109057.
Heba M Abosalim 1,  Tarek F El-Moselhy 1,  Nabaweya Sharafeldin 1,  Simone Giovannuzzi 2,  Paloma Begines 2,  Mohamed S Nafie 3,  Sherif Ashraf Fahmy 4,  Mohamed K Diab 5,  Asaad Babker 6,  Claudiu T Supuran 7,  Mervat H El-Hamamsy 1,  Haytham O Tawfik 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 2 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy.
  • 3 Department of Chemistry, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Bioinformatics and Functional Genomics Research Group, Research Institute of Sciences and Engineering (RISE), University of Sharjah, Sharjah 27272, United Arab Emirates; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
  • 4 Department of Pharmacy, Institute of Pharmaceutics and Biopharmaceutics, Marburg University, Robert-Koch-Str. 4, 35037 Marburg, Germany.
  • 5 Pest Physiology Department, Plant Protection Research Institute, Agricultural Research Center, Giza, 12311, Egypt.
  • 6 Department of Medical Laboratory Sciences, College of Health Sciences, Gulf Medical University, Ajman, United Arab Emirates.
  • 7 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
PMID: 41075615 DOI: 10.1016/j.bioorg.2025.109057
Abstract

A dual-targeting strategy is anticipated to enhance Cancer therapy efficacy. Accordingly, a series of fused pyrimidine analogues (5a-h and 8a-f) was rationally designed and synthesized as potential inhibitors towards Carbonic Anhydrase IX (hCA IX) and cyclin-dependent kinase-2 (CDK-2). The enzyme inhibition results revealed that compounds 5c and 5d exhibited potent inhibitory activity, with IC50 values of 0.29 μM and 0.32 μM and KI values of 39 nM and 42.2 nM, respectively. Unfortunately, compounds 5c and 5d revealed non-promising cell growth inhibition (GI%) against A549 Cancer cells (3 % and 9 %, respectively). Impressively, their Zein-nanoparticles (NPs) significantly promoted the GI% to 94.8 % and 96.5 % respectively. The nanoformulations of 5c and 5d significantly induced apoptotic lung Cancer cell death, leading to total Apoptosis that was 62.35 % and62.7 % of the control, 17.2 %, respectively. Gene expressions revealed significant upregulation of apoptosis-associated genes P53,Bax, and caspases 3, 8, 9; however, the anti-apoptotic gene Bcl-2 was downregulated in the A549 Cancer cells. In addition, the average particle sizes, polydispersity index (PDI), zeta potential, and encapsulation efficiency (EE%) of 5c@Zein NPs and 5d@Zein NPs were investigated. Both formulations showed monodispersed nanosized particles of 151.6 ± 9.2 and 162.4 ± 10.7 nm, with zeta potential values of -30.9 ± 1.8 and - 24.6 ± 2.1 mV, respectively. Moreover, 5c and 5d were highly encapsulated within the Zein NPs and showed a pH-triggered in vitro release manner. Validating the in vivo Cancer model, 5c-Zein NPs significantly ameliorated the induced changes by decreasing the lung index and inhibiting the CDK-2 and hCA IX proteins. Furthermore, molecular docking studies revealed specific and favorable interactions of compounds 5c and 5d within the binding pockets of hCA IX and CDK-2, which support their potential as dual-target inhibitors.

Keywords

Apoptosis; Dual hCA IX/CDK-2 inhibitors; Fused pyrimidines; Nanocarriers; Zein nanoparticles.

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