2. Academic Validation
  3. Design, Synthesis, and Anticancer Evaluation of Novel MGBs with Alkyne-Linked Thiazole Moieties

Design, Synthesis, and Anticancer Evaluation of Novel MGBs with Alkyne-Linked Thiazole Moieties

  • J Med Chem. 2025 Jul 24;68(14):15065-15084. doi: 10.1021/acs.jmedchem.5c01216.
Yousef A Msallam 1 2,  Wafaa S Ramadan 2,  Hadeel Al-Jubeh 2,  Anil Ravi 2,  Reem Sami Alhamidi 2,  Burcu Yener Ilce 2,  Varsha Menon 2,  Fatema Hersi 2,  Alaa Altaie 2 3,  Praveen Kumar 4 5,  Sanjay V Malhotra 4 5,  Hany A Omar 1 2,  Raafat El-Awady 1 2,  Rifat Hamoudi 2 3 6 7,  Hasan Y Alniss 1 2
Affiliations

Affiliations

  • 1 College of Pharmacy, Department of Medicinal Chemistry, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 2 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 3 Center of Excellence for Precision Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 4 Department of Cell Development & Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239, United States.
  • 5 Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, United States.
  • 6 College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
  • 7 Division of Surgery and Interventional Science, University College London, London NW3 2PF, United Kingdom.
PMID: 40637060 DOI: 10.1021/acs.jmedchem.5c01216
Abstract

Minor groove Binders (MGBs) are promising DNA-targeting agents for Cancer therapy. Using a structure-based drug design approach, we developed a novel class of MGBs featuring alkyne-linked thiazole moieties to enhance DNA-binding affinity, lipophilicity, and cytotoxic efficacy. The synthesized compounds were evaluated using the NCI-60 panel and SRB assay, identifying MGB1Y, MGB2Y, and MGB6Y as potent inhibitors of Cancer cell proliferation. Isothermal titration calorimetry, molecular docking, and molecular dynamics simulations confirmed their strong and reversible binding to the DNA minor groove, particularly at the 5'-ACTAGT-3' and 5'-AGTACT-3' binding sites. Transcriptomic analysis revealed downregulation of genes involved in cell cycle progression and chromatin organization alongside upregulation of lipid metabolism genes, suggesting the disruption of lipid homeostasis. Additionally, these compounds inhibit Topoisomerase I, further supporting their DNA-targeting mechanism. Their strong Anticancer activity, reversible noncovalent DNA interaction, and favorable binding properties highlight their potential for further development as Anticancer therapeutics.

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