2. Academic Validation
  3. Rationally designed febuxostat-based hydroxamic acid and its pH-Responsive nanoformulation elicits anti-tumor activity

Rationally designed febuxostat-based hydroxamic acid and its pH-Responsive nanoformulation elicits anti-tumor activity

  • Eur J Med Chem. 2024 Sep 10:279:116866. doi: 10.1016/j.ejmech.2024.116866.
Ritika 1,  Zi-Yi Liao 2,  Pin-Yu Chen 2,  N Vijayakamasewara Rao 3,  Jacob Mathew 4,  Ram Sharma 2,  Ajmer Singh Grewal 5,  Gurpreet Singh 6,  Sidharth Mehan 7,  Jing Ping Liou 8,  Chun Hsu Pan 9,  Kunal Nepali 10
Affiliations

Affiliations

  • 1 International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taiwan.
  • 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 3 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 4 Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106335, Taiwan.
  • 5 Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Near Guru Nanak Khalsa College, Yamuna Nagar, 135001, Haryana, India.
  • 6 Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.
  • 7 Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India; Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 9 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: panch@tmu.edu.tw.
  • 10 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: nepali@tmu.edu.tw.
PMID: 39293244 DOI: 10.1016/j.ejmech.2024.116866
Abstract

Attempts to furnish antitumor structural templates that can prevent the occurrence of drug-induced hyperuricemia spurred us to generate Xanthine Oxidase inhibitor-based hydroxamic acids and anilides. Specifically, the design strategy involved the insertion of febuxostat (Xanthine Oxidase Inhibitor) as a surface recognition part of the HDAC Inhibitor pharmacophore model. Investigation outcomes revealed that hydroxamic acid 4 elicited remarkable antileukemic effects mediated via HDAC isoform inhibition. Delightfully, the adduct retained Xanthine Oxidase inhibitory activity, though Xanthine Oxidase inhibition was not the underlying mechanism of its cell growth inhibitory effects. Also, compound 4 demonstrated significant in-vivo anti-hyperuricemic (PO-induced hyperuricemia model) and antitumor activity in an HL-60 xenograft mice model. Compound 4 was conjugated with poly (ethylene glycol) poly(aspartic acid) block copolymer to furnish pH-responsive nanoparticles (NPs) in pursuit of circumventing its cytotoxicity towards the normal cell lines. SEM analysis revealed that NPs had uniform size distributions, while TEM analysis ascertained the spherical shape of NPs, indicating their ability to undergo self-assembly. HDAC Inhibitor 4 was liberated from the matrix due to the polymeric nanoformulation's pH-responsiveness, and the NPs demonstrated selective Cancer cell targeting ability.

Keywords

Anilides; Febuxostat; HDAC inhibitor; Hematological malignancies; Hydroxamic acid; Tumor; Xanthine oxidase.

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