2. Academic Validation
  3. Synthesis of 5-hydroxyisatin thiosemicarbazones, spectroscopic investigation, protein-ligand docking, and in vitro anticancer activity

Synthesis of 5-hydroxyisatin thiosemicarbazones, spectroscopic investigation, protein-ligand docking, and in vitro anticancer activity

  • Bioorg Chem. 2024 Dec:153:107872. doi: 10.1016/j.bioorg.2024.107872.
Upendra Chaudhary 1,  Piyush Kumar 2,  Pratibha Sharma 2,  Anshul Chikara 2,  Ayanti Barua 2,  Kuldeep Mahiya 3,  Jhashanath Adhikari Subin 4,  Paras Nath Yadav 5,  Yuba Raj Pokharel 6
Affiliations

Affiliations

  • 1 Central Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal.
  • 2 Faculty of Life Science and Biotechnology, South Asian University, Rajpur Rd, Maidan Garhi, New Delhi 110068, India.
  • 3 Department of Chemistry, F G M Government College, Adampur, Mandi Adampur, Hisar 125052, Haryana, India.
  • 4 Scientific Research and Training Nepal P. Ltd., Bioinformatics and Cheminformatics Division, Kaushaltar, Bhaktapur, Nepal.
  • 5 Central Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal. Electronic address: paras.yadav@tu.edu.np.
  • 6 Faculty of Life Science and Biotechnology, South Asian University, Rajpur Rd, Maidan Garhi, New Delhi 110068, India. Electronic address: yrp@sau.ac.in.
PMID: 39442462 DOI: 10.1016/j.bioorg.2024.107872
Abstract

A series of novel modifications were performed at the N(4) position of 5-hydroxyisatin thiosemicarbazone (TSC). The structure-activity approach is applied to design and synthesize derivatives by condensing thiosemicarbazides with 5-hydroxy isatin. The TSCs were characterized by various spectroscopic techniques viz. FTIR, 1H NMR, 13C NMR, UV-Vis, HRMS data, CHN elemental analysis, and single crystal X-ray diffraction. Biological evaluation of the synthesized compounds revealed the Anticancer potency of the TSC analogues against breast Cancer (MD-AMD-231, MCF-7), lung Cancer (A549, NCI-H460), prostate Cancer (PC3), and skin Cancer (A431). The molecules, L2, L3, and L6 showed activity in the micromolar range (IC50; 0.19-2.19 μM). L6 exhibited the highest potency against skin Cancer A431 cell line, with an IC50 of 0.19 μM compared to 1.8 μM with triapine and showed low toxicity against PNT-2 cells with an SI index of >100 μM. The mechanistic study revealed that L6 inhibited Cancer cell proliferation, colony formation, and 3-dimensional spheroid formation by targeting the Ras/MAPK axis. It induced DNA damage and impaired DNA damage repair machinery, which led to the accumulation of DSB. Also, it lowered the ERK1/2 expression, which affected the Caspase 3 activity and showed higher binding affinity compared to the FDA-approved drug Lenalidomide in molecular docking studies. Our findings demonstrated the possible future Anticancer drug potency of L6 in the skin Cancer A431 cells.

Keywords

5-Hydroxyisatin; Anticancer potency; DNA Damage Repair; DSB; Molecular docking; Skin cancer; Thiosemicarbazone.

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