Synthesis and characterization of N-substituted thiosemicarbazones: DNA/BSA binding, molecular docking, anticancer activity, ADME study and computational investigations

Manakkadan, Vipin; Haribabu, Jebiti; Palakkeezhillam, Vishnunarayanan Namboothiri Vadakkedathu; Rasin, Puthiyavalappil; Mandal, Manas K.; Kumar, Vaishnu Suresh; Bhuvanesh, Nattamai; Udayabhaskar, R.; Sreekanth, Anandaram

doi:10.1016/j.molstruc.2023.135494

Cited by 11 publications

(3 citation statements)

References 70 publications

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“…The fluorescence of BSA is influenced by its surrounding environment. To our interest, the polarity and/or conformations of the fluorophores of BSA changes when interacting with a ligand, which results in a changed fluorescence intensity . The binding affinity of the ligands can be assessed by the extent to which the fluorescence of BSA is quenched/enhanced.…”

Section: Resultsmentioning

confidence: 99%

Biomolecular Interactions and Anticancer Mechanisms of Ru(II)-Arene Complexes of Cinnamaldehyde-Derived Thiosemicarbazone Ligands: Analysis Combining In Silico and In Vitro Approaches

Vadakkedathu Palakkeezhillam,

Haribabu,

Kumar

et al. 2024

ACS Appl. Bio Mater.

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Our study focuses on synthesizing and exploring the potential of three N-(4) substituted thiosemicarbazones derived from cinnamic aldehyde, alongside their Ru(II)-(η 6 -p-cymene)/ (η 6 -benzene) complexes. The synthesized compounds were comprehensively characterized using a range of analytical techniques, including FT-IR, UV−visible spectroscopy, NMR ( 1 H, 13 C), and HRMS. We investigated their electronic and physicochemical properties via density functional theory (DFT). X-ray crystal structures validated structural differences identified by DFT. Molecular docking predicted promising bioactivities, supported by experimental observations. Notably, docking with EGFR suggested an inhibitory potential against this cancer-related protein. Spectroscopic titrations revealed significant DNA/BSA binding affinities, particularly with DNA intercalation and BSA hydrophobic interactions. RuPCAM displayed the strongest binding affinity with DNA (K b = 6.23 × 10 7 M −1 ) and BSA (K b = 9.75 × 10 5 M −1 ). Assessed the cytotoxicity of the complexes on cervical cancer cells (HeLa), and breast cancer cells (MCF-7 and MDA-MB 231), revealing remarkable potency. Additionally, selectivity was assessed by examining MCF-10a normal cell lines. The active complexes were found to trigger apoptosis, a vital cellular process crucial for evaluating their potential as anticancer agents utilizing staining assays and flow cytometry analysis. Intriguingly, complexation with Ru(II)-arene precursors significantly amplified the bioactivity of thiosemicarbazones, unveiling promising avenues toward the creation of powerful anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Biomolecular Interactions and Anticancer Mechanisms of Ru(II)-Arene Complexes of Cinnamaldehyde-Derived Thiosemicarbazone Ligands: Analysis Combining In Silico and In Vitro Approaches

Vadakkedathu Palakkeezhillam,

Haribabu,

Kumar

et al. 2024

ACS Appl. Bio Mater.

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“…The pyrene-1-carboxaldehyde TSC ligands (L1P-L3P) were synthesized from the pyrene-1-carboxaldehyde (230 mg, 1 mmol) with pyrrolidine-1-carbothiohydrazide, morpholine-4-carbothiohydrazide, and 4-cyclohexylthiosemicarbazide by following the previously reported procedures . As shown in earlier research, TSCs with a heterocyclic or aromatic N-terminal substituent (electron-donating character) are more effective against cancer cells. , L1P and L2P were two of the ligands used that we had previously reported …”

Section: Experimental Sectionmentioning

confidence: 99%

Unraveling the Anticancer Efficacy and Biomolecular Properties of Ru(II)-Arene Complexes of Pyrene-Based Thiosemicarbazone Ligands: A Comprehensive In Silico/In Vitro Exploration

Vadakkedathu Palakkeezhillam,

Haribabu,

Kumar

et al. 2024

Organometallics

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We report the successful synthesis and comprehensive characterization of novel Ru(II)-arene complexes incorporating pyrene-based thiosemicarbazone (TSC) ligands. Utilizing a suite of advanced spectroscopic techniques including ultraviolet–visible (UV–visible), Fourier transform infrared (FT-IR), 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS), the intricate structural and electronic nuances of these complexes were elucidated. X-ray crystallographic data unequivocally affirmed the ligands’ preferential coordination through the thionyl sulfur and imine nitrogen moieties with the Ru(II) ion. Rigorous density functional theory (DFT) computations reveal these complexes as exemplary electron donors, concomitantly hinting at their significant bioactive potential. Notably, molecular docking and molecular dynamic simulation studies suggest that they are potential SND1 protein inhibitors, which are essential proteins in the functioning of cancer cells. Furthermore, they have a strong affinity for binding to CT-DNA and bovine serum albumin (BSA), indicating DNA intercalation and a strong protein-binding ability. Intriguingly, the Ru-arene TSC complexes unveiled potent cytotoxic activity against an array of cancerous cell linesmost notably MDA-MB-231 (IC50 = 10.2 ± 0.02 μM), A549 (IC50 = 25.7 ± 0.07 μM), and HeLa (IC50 = 20.7 ± 0.05 μM) for RuP2P emerging as a standout agent.

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“…Thiosemicarbazones are a class of ligands known for a long time to present many biological properties in their free form or coordinated with different metal ions. Many studies have reported that these ligands exhibit significant antibacterial and antitumor activity in vitro and in vivo, and are of great interest in developing therapeutic compounds, especially in cancer treatment, that act directly in the brain and other tissues [16][17][18][19]. Thiosemicarbazones also have the great advantage of their high versatility, as they possess both soft sulfur and hard nitrogen donor atoms that allow complexation with various metal ions in different geometries, including gold and palladium [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Crystal Design, Antitumor Activity and Molecular Docking of Novel Palladium(II) and Gold(III) Complexes with a Thiosemicarbazone Ligand

Gatto

Almeida

Nascimento

et al. 2023

IJMS

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The current research describes the synthesis and characterization of 2-acetylpyridine N(4)-cyclohexyl-thiosemicarbazone ligand (HL) and their two metal complexes, [Au(L)Cl][AuCl2] (1) and [Pd(L)Cl]·DMF (2). The molecular structures of the compounds were determined by physicochemical and spectroscopic methods. Single crystal X-ray diffraction was employed in the structural elucidation of the new complexes. The complexes showed a square planar geometry to the metal center Au(III) and Pd(II), coordinated with a thiosemicarbazone molecule by the NNS-donor system and a chloride ion. Complex (1) also shows the [AuCl2]− counter-ion in the asymmetric unit, and complex (2) has one DMF solvent molecule. These molecules play a key role in the formation of supramolecular structures due to different interactions. Noncovalent interactions were investigated through the 3D Hirshfeld surface by the dnorm function and the 2D fingerprint plots. The biological activity of the compounds was evaluated in vitro against the human glioma U251 cells. The cytotoxicity results revealed great antitumor activity in complex (1) compared with complex (2) and the free ligand. Molecular docking simulations were used to predict interactions and properties with selected proteins and DNA of the synthesized compounds.

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Synthesis and characterization of N-substituted thiosemicarbazones: DNA/BSA binding, molecular docking, anticancer activity, ADME study and computational investigations

Cited by 11 publications

References 70 publications

Biomolecular Interactions and Anticancer Mechanisms of Ru(II)-Arene Complexes of Cinnamaldehyde-Derived Thiosemicarbazone Ligands: Analysis Combining In Silico and In Vitro Approaches

Biomolecular Interactions and Anticancer Mechanisms of Ru(II)-Arene Complexes of Cinnamaldehyde-Derived Thiosemicarbazone Ligands: Analysis Combining In Silico and In Vitro Approaches

Unraveling the Anticancer Efficacy and Biomolecular Properties of Ru(II)-Arene Complexes of Pyrene-Based Thiosemicarbazone Ligands: A Comprehensive In Silico/In Vitro Exploration

Crystal Design, Antitumor Activity and Molecular Docking of Novel Palladium(II) and Gold(III) Complexes with a Thiosemicarbazone Ligand

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