2. Academic Validation
  3. Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities

Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities

  • Daru. 2024 Jun;32(1):263-278. doi: 10.1007/s40199-024-00514-1.
Manasa Gangadhar Shetty 1,  Padmini Pai 1,  Bipasa Dey 1,  Kapaettu Satyamoorthy 2,  Suranjan Shil 3,  Usha Yogendra Nayak 4,  Ashwini T 4,  Babitha Kampa Sundara 5
Affiliations

Affiliations

  • 1 Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • 2 Shri Dharmasthala Manjunatheshwara (SDM) University, Manjushree Nagar, Sattur, Dharwad, 580009, Karnataka, India.
  • 3 Department of Chemistry, Manipal Centre for Natural Sciences (Centre of Excellence), Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • 4 Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
  • 5 Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India. babitha.ks@manipal.edu.
PMID: 38683491 DOI: 10.1007/s40199-024-00514-1
Abstract

Background: Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) Enzymes are commonly observed in various cancers. Researchers are focusing on these Enzymes in Cancer studies with the aim of developing effective chemotherapeutic drugs for Cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in Cancer treatment, making it a promising strategy.

Objectives: The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor.

Methods: The N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2.

Results: The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC50 of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC50 values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of Reactive Oxygen Species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC Inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7.

Conclusion: The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule.

Keywords

1,10-Phenanthroline; Anti-cancer; Dual targeting; HDAC; Hydroxamic acid; RR.

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