Browsing by Author "Alok Shukla"

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Anticancer evaluation of Co(III) complex derived from 1-isonicotinoyl-4-(4-nitrophenyl)-3-thiosemicarbazide: Structural characterization, photophysical, and Hirshfeld studies
(Elsevier B.V., 2025) Ram Nayan Gautam; Alok Shukla; Suryansh Chandra; Sundeep Kumar; Arbind Acharya; Mamata K. Singh; Ray Jay Butcher; Manoj Kumar Bharty
A new cationic complex, [Co((intph)(en)2]Cl, derived from the 1-isonicotinoyl-4-(4-nitrophenyl)-3-thiosemicarbazide (H2intph), is reported. The synthesized ligand and its corresponding Co(III) complex were successfully characterized by applying FT-IR and UV–visible spectroscopic techniques and single crystal ray diffraction data. Molecular geometries of the ligand and its Co(III) complex were accurately determined from their respective X-ray crystallographic analysis. The ligand and [Co((intph)(en)2]Cl crystallize in Triclinic and monoclinic systems with space groups P-1 and P 21/n, respectively. The crystal structures of H2intph and [Co((intph)(en)2]Cl are stabilized by weak C-H⋯O, N-H⋯O, and C-H⋯Cl hydrogen bonding interactions. Hirshfeld surface analysis was accomplished to investigate intermolecular hydrogen bonding interactions found in ligand H2intph and [Co((intph)(en)2]Cl. The cytotoxicity of the ligand and the complex [Co((intph)(en)2]Cl was assessed for their anticancer potential against human glioblastoma (U87) and Dalton lymphoma (DL) cell lines. The complex exhibited IC50 values of 100 μg/mL for U87 cells and 120 μg/mL for DL cells, indicating the concentration at which 50 % of cell viability was inhibited. In comparison, the ligand was less effective in the MTT assay against both U87 and DL cells. These results suggest that the complex [Co((intph)(en)2]Cl significantly reduces glioblastoma cell viability. Treatment with the complex induced cell death through both apoptotic and necrotic pathways, as evidenced by Hoechst/PI double staining. Additionally, there was an increase in intracellular reactive oxygen species (ROS), highlighting the role of oxidative stress in the anticancer activity of the [Co((intph)(en)2]Cl complex. Furthermore, fluorescence studies were carried out which revealed the order of fluorescence behaviors between the ligand and the Co(III) complex to be Co(III) complex > H2intph. © 2024 Elsevier B.V.
Antitumor potential of ivermectin against T-cell lymphoma-bearing hosts
(Springer, 2025) Alok Shukla; Arpit Sharma; Shivani Gupta; Abha Mishra; Amit Kumar Singh
Ivermectin, a broad-spectrum antiparasitic agent from the ivermectin family, has shown promising anticancer potential. Originally developed for veterinary and human use against parasitic infections, ivermectin demonstrated significant antitumor effects in our study against tumor cells (Dalton’s lymphoma cells). A dose-dependent decrease in tumor cell viability was observed following 24-h treatment with ivermectin, with an IC₅₀ value calculated at 10.55 µg/mL. In comparison, the standard anticancer drug cisplatin exhibited a slightly higher cytotoxic potency, with an IC₅₀ of 8.32 µg/mL under the same treatment duration. Flow cytometric analysis revealed that ivermectin induced cell cycle arrest in the G0–G1 phase. Apoptotic tumor cell death was confirmed via Annexin V/PI staining, further supported by nuclear condensation, a hallmark of apoptosis, visualized through both confocal microscopy and flow cytometry. The apoptosis was determined to be mitochondrial-dependent, as evidenced by a decline in mitochondrial membrane potential (ΔΨm) observed through JC-1 assay. The treatment increased DAPI-positive cells and exhibited severe chromatin condensation. Additionally, cell death was validated using Acridine Orange and Propidium Iodide staining, which highlighted increased cell membrane rupture and death through apoptosis and necrosis. Mitochondrial dependent apoptosis further supported by increased ROS production upon ivermectin treatment. Moreover, In vivo, ivermectin treatment led to a substantial reduction in tumor size in tumor-bearing mice, along with normalization of spleen size, body weight, and improvement histopathology of liver. These findings collectively support the therapeutic potential of ivermectin as a repurposed anticancer agent, acting through multiple mechanisms including cell cycle arrest, ROS generation, mitochondrial dysfunction, and apoptosis. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.
Cobalt (III) complex exerts anti-cancer effects on T cell lymphoma through induction of cell cycle arrest and promotion of apoptosis
(Springer Science and Business Media Deutschland GmbH, 2022) Praveen Kumar Verma; Rishi Kant Singh; Sandeep Kumar; Alok Shukla; Sanjay Kumar; Mannu Kumar Gond; Manoj Kumar Bharty; Arbind Acharya
Purpose: Cobalt-based compounds are emerging as a non-platinum-based anti-cancer effective therapeutic agent. However, there is a limited study regarding the therapeutic efficacy of Cobalt-based drugs against Non-Hodgkin’s Lymphoma (NHLs) such as T cell lymphoma. Therefore, in the present study we investigated the anti-tumor role of cobalt(III) complex [Co(ptsm)NH3(o-phen)]·CH3OH on Dalton’s Lymphoma (DL) cells. Materials and methods: Cytotoxicity of the cobalt complex was estimated by MTT assay. Analysis of mitochondrial membrane potential, cell cycle and Reactive oxygen species (ROS) generation, and Annexin V/PI staining was done by Flow cytometry, while AO/EtBr staining by fluorescence microscopy in cobalt complex treated DL cell. Expression of cell cycle and apoptosis regulatory protein was analyzed by Western blotting. In addition, in vivo study of the cobalt complex was evaluated in well-established DL bearing mice by monitoring physiological parameters and mean survival time. Results: Our study showed that cobalt complex triggered apoptosis and induced cell cycle arrest in DL cells. Furthermore, this also decreased mitochondrial membrane potential and increased intracellular ROS generation in cancer cells. In addition, changed expression of cell cycle and apoptosis regulatory protein was found with enhanced activity of caspase-3 and 9 in the treated cells. Additionally, administration of cobalt complex showed a significant increase in the survivability of tumor-bearing host, which was accomplished by decreasing physiological parameters. Conclusion: Taken together, these data revealed anti-tumor potential of cobalt complex against DL cells through cell cycle arrest and mitochondrial-dependent apoptosis. Henceforth, cobalt-based drugs could be a new generation therapeutic drug to treat hematological malignancies. Graphical abstract: [Figure not available: see fulltext.]. © 2022, Springer Nature Switzerland AG.
DDX3X dynamics, glioblastoma's genetic landscape, therapeutic advances, and autophagic interplay
(Springer, 2024) Arpit Sharma; Shruti S. Raut; Alok Shukla; Shivani Gupta; Amit Singh; Abha Mishra
Glioblastoma is one of the most aggressive and deadly forms of cancer, posing significant challenges for the medical community. This review focuses on key aspects of Glioblastoma, including its genetic differences between primary and secondary types. Temozolomide is a major first-line treatment for Glioblastoma, and this article explores its development, how it works, and the issue of resistance that limits its effectiveness, prompting the need for new treatment strategies. Gene expression profiling has greatly advanced cancer research by revealing the molecular mechanisms of tumors, which is essential for creating targeted therapies for Glioblastoma. One important protein in this context is DDX3X, which plays various roles in cancer, sometimes promoting it or otherwise suppressing it. Additionally, autophagy, a process that maintains cellular balance, has complex implications in cancer treatment. Understanding autophagy helps to identify resistance mechanisms and potential treatments, with Chloroquine showing promise in treating Glioblastoma. This review covers the interplay between Glioblastoma, DDX3X, and autophagy, highlighting the challenges and potential strategies in treating this severe disease. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Depth exploration of gadolinium-modified bismuth iron titanate: A comprehensive investigation
(Elsevier B.V., 2025) Sushil Joshi; Alok Shukla; Nitin Suresh Kumar; Akanksha Maurya; Ram Naresh Prasad Choudhary
This study discusses the structural, dielectric, electrical, and magnetic response of gadolinium-doped bismuth iron titanate Bi0.85Gd0.15Fe0.5Ti0.5O3. It is synthesized by a high-temperature solid-state reaction method. XRD analysis shows the multiphase nature of the material consisting of three-phase symmetry, i.e., orthorhombic, cubic, and tetragonal. SEM (Scanning electron microscopy) analysis confirms a polycrystalline microstructure with a 5–6 µm average grain size, while EDX (Energy-dispersive X-ray spectroscopy) validates the stoichiometric presence of Bi, Gd, Fe, Ti, and O with appropriate atomic percentages. The dielectric studies demonstrate frequency-dependent behavior dominated by Maxwell-Wagner polarization and space charge effects, with the dielectric constant (εᵣ) decreasing with frequency and increasing with temperature. Impedance spectroscopy reveals non-Debye relaxation and contributions from grain and grain boundaries, supported by Nyquist plots and equivalent circuit modeling. AC conductivity follows Jonscher's power law and indicates that the material follows correlated barrier hopping (CBH) conduction mechanism. Magnetic measurement shows the small ferromagnetic behavior with Mr = 9.85 E-3 emu/g. Based on the compound electrical and magnetic properties; it can be used for various applications in multifunctional devices. © 2025 The Authors
Evidence that PKCα inhibition in Dalton's Lymphoma cells augments cell cycle arrest and mitochondrial-dependent apoptosis
(Elsevier Ltd, 2022) Rishi Kant Singh; Praveen Kumar Verma; Sandeep Kumar; Alok Shukla; Naveen Kumar; Sanjay Kumar; Arbind Acharya
Protein kinase Cα (PKCα), belonging to ser/thr protein kinase, perform various biological functions. Overexpression of PKCα has been observed in multiple human malignancies including lymphoma. However, the molecular pathogenesis and involvement of PKCα in Non-Hodgkin lymphoma (NHL) are not clearly understood. Hence, deciphering the role of PKCα in NHL management may provide a better therapeutic option. In the present study, we used selective pharmacological inhibitors Gö6976 and Ro320432 that potentially inhibit PKCα-mediated signaling in DL cells, resulting in the inhibition of cell growth and mitochondrial-dependent apoptosis. PKCα inhibition by these inhibitors also displays cell cycle arrest at the G1 phase and causes growth retardation of DL cells. Our results extended the mechanism of PKCα in NHL, and provided potential implications for its therapy. © 2022 Elsevier Ltd
Exploring the anticancer activity of 1-(2-methyl-3-furoyl)-4-phenyl-3-thiosemicarbazide and its Mn(II) complex: Synthesis, spectral, crystal structures, and Hirshfeld surface analysis
(Elsevier B.V., 2025) Rahul Chaurasia; Alok Shukla; Shivendra Kumar Pandey; Seema Gupta; Nishant Shekhar; Arbind Acharya; Ray Jay Butcher; Manoj Kumar Bharty
The chemistry of mixed ligand transition metal complexes has been of interest of researchers owing to its diverse application and bonding features. Herein, a new thiosemicarbazide derivative namely 1-(2-methyl-3-furoyl)-4-phenyl-3-thiosemicarbazide (HmfpTSC) has been synthesized along with its [Mn(mfpTSC)2(o-phen)] (C1) complex. The prepared ligand (HmfpTSC) and the complex have been confirmed via spectroscopic and single-crystal X-ray data. The HmfpTSC and complex crystallize in a monoclinic crystal system with space group P21/c and P21/n, respectively. HmfpTSC behaves as a uninegative bidentate ligand and its two-unit binds with metal ion along with one unit of o-phen. Using Hirshfeld surface analysis, the weak interactions seen in HmfpTSC and complex have been quantitatively investigated. The MTT assay was used to assess the cytotoxicity of HmfpTSC and [Mn(mfpTSC)2(o-phen)] complex against Dalton's lymphoma cells. Further, the mechanism of anticancer action of ligand and complex was investigated through DAPI, AO/EB staining, and flow cytometry. The both AO/EB and DAPI staining provided compelling evidence of complex-induced cellular and nuclear changes consistent with apoptosis and necrosis. © 2024
Exploring the synthesis, characterization, crystal structures, DFT calculation, hirshfeld surface analysis, and anticancer activity of Ni(II) complex of 1-(4-nitrobenzoyl)-4-phenyl-3-thiosemicarbazide
(Elsevier B.V., 2025) Shivendra Kumar Pandey; Rahul Chaurasia; Alok Shukla; Riya Kumari; Nishant Shekhar; Arti Srivastava; Arbind Acharya; Ray Jay Butcher; Manoj Kumar Bharty
The chemistry of biologically active thiosemicarbazide has been of interest to researchers owing to its diverse application and bonding features. In the present study, a new thiosemicarbazide derivative namely 1-(4-nitrobenzoyl)-4-phenyl-3-thiosemicarbazide (HnbphTSC) has been prepared and along with its [Ni(nbphTSC)2(en)]·CHCl3 (1) complex. The prepared ligand (HnbphTSC) and complex 1 have been characterized through spectroscopic and single-crystal X-ray data. The HnbphTSC and complex 1 crystallize in triclinic and monoclinic crystal systems with space groups P1¯ and P21/C, respectively. The weak interactions present in HnbphTSC and complex 1 have been quantitively studied through hirshfeld surface analysis. The physiochemical characteristics of HnbphTSC and complex 1 are also verified using DFT calculations, and the resultant results are in strong agreement with the experimental findings. The HOMO and LUMO energy gap have been calculated as 3.160 eV and 2.212 eV for HnbphTSC and complex 1, respectively. MTT assay was used to evaluate the cytotoxicity of HnbphTSC and complex 1 against Dalton's lymphoma (DL) cells. We further assessed the mode of tumor cell death and the drug's effect on nuclear condensation and plasma membrane integrity by employing DAPI/PI dual staining technique. © 2024 Elsevier B.V.
FNC (4′-azido-2′-deoxy-2′-fluoro(arbino)cytidine) as an Effective Therapeutic Agent for NHL: ROS Generation, Cell Cycle Arrest, and Mitochondrial-Mediated Apoptosis
(Springer, 2024) Naveen Kumar; Alok Shukla; Sanjay Kumar; Ilya Ulasov; Rishi Kant Singh; Sandeep Kumar; Anand Patel; Lokesh Yadav; Ruchi Tiwari; Rachana Paswan; Shivashish Priyadarshi Mohanta; Kaushalendra; Jyeoti Antil; Arbind Acharya
Cytotoxic nucleoside analogs (NAs) hold great promise in cancer therapeutics by mimicking endogenous nucleosides and interfering with crucial cellular processes. Here, we investigate the potential of the novel cytidine analog, 4′-azido-2′-deoxy-2′-fluoro(arbino)cytidine (FNC), as a therapeutic agent for Non-Hodgkin lymphoma (NHL) using Dalton’s lymphoma (DL) as a T-cell lymphoma model. FNC demonstrated dose- and time-dependent inhibition of DL cell growth and proliferation. IC-50 values of FNC were measured at 1 µM, 0.5 µM, and 0.1 µM after 24, 48, and 72 h, respectively. Further elucidation of FNC’s mechanism of action uncovers its role in inducing apoptosis in DL cells. Notable DNA fragmentation and nuclear condensation point to activated apoptotic pathways. FNC-induced apoptosis was concomitant with changes in cellular membranes, characterized by membrane rupture and altered morphology. The robust anticancer effects of FNC are linked to its capacity to induce reactive oxygen species (ROS) production, prompting oxidative stress-mediated apoptosis. Additionally, FNC disrupted mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction, further promoting apoptosis. Dysregulation of apoptotic genes, with upregulation of Bax and downregulation of Bcl-2 and Bcl-xl, implicates the mitochondrial-mediated apoptosis pathway. Furthermore, FNC-induced G2/M phase cell cycle arrest was mediated through modulation of the cell cycle inhibitor p21. Overall, this study highlights the potential of FNC as a promising therapeutic agent for NHL. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
From development to clinical success: the journey of established and next-generation BTK inhibitors
(Springer, 2025) Shivani Gupta; Arpit Sharma; Alok Shukla; Abha Mishra; Amit Kumar Singh
Over the past decade, Bruton’s tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström’s macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.
Mitochondrial-mediated apoptosis as a therapeutic target for FNC (2′-deoxy-2′-b-fluoro-4′-azidocytidine)-induced inhibition of Dalton’s lymphoma growth and proliferation
(Springer Science and Business Media B.V., 2024) Naveen Kumar; Sanjeev Kumar; Alok Shukla; Sanjay Kumar; Rishi Kant Singh; Ilya Ulasov; Sandeep Kumar; Anand Kumar Patel; Lokesh Yadav; Ruchi Tiwari; Rachana; Shivashish Priyadarshi Mohanta; Kaushalendra; Vikram Delu; Arbind Acharya
Purpose: T-cell lymphomas, refer to a diverse set of lymphomas that originate from T-cells, a type of white blood cell, with limited treatment options. This investigation aimed to assess the efficacy and mechanism of a novel fluorinated nucleoside analogue (FNA), 2′-deoxy-2′-β-fluoro-4′-azidocytidine (FNC), against T-cell lymphoma using Dalton’s lymphoma (DL)-bearing mice as a model. Methods: Balb/c mice transplanted with the DL tumor model received FNC treatment to study therapeutic efficacy against T-cell lymphoma. Behavioral monitoring, physiological measurements, and various analyses were conducted to evaluate treatment effects for mechanistic investigations. Results: The results of study indicated that FNC prevented DL-altered behavior parameters, weight gain and alteration in organ structure, hematological parameters, and liver enzyme levels. Moreover, FNC treatment restored organ structures, attenuated angiogenesis, reduced DL cell viability and proliferation through apoptosis. The mechanism investigation revealed FNC diminished MMP levels, induced apoptosis through ROS induction, and activated mitochondrial-mediated pathways leading to increase in mean survival time of DL mice. These findings suggest that FNC has potential therapeutic effects in mitigating DL-induced adverse effects. Conclusion: FNC represents an efficient and targeted treatment strategy against T-cell lymphoma. FNC’s proficient ability to induce apoptosis through ROS generation and MMP reduction makes it a promising candidate for developing newer and more effective anticancer therapies. Continued research could unveil FNC’s potential role in designing a better therapeutic approach against NHL. © 2023, The Author(s).
Mn(II) catalyzed synthesis of 5(4-hydroxyphenyl)-2-(N-phenylamino)-1,3,4-oxadiazole: Crystal structure, DFT, molecular docking, Hirshfeld surface analysis, and in vitro anticancer activity on DL cells
(Elsevier B.V., 2022) M.K. Gond; Alok Shukla; Shivendra Kumar Pandey; M.K. Bharty; B. Maiti; A. Acharya; N. Tiwari; D. Katiyar; R.J. Butcher
The syntheses and screening of novel synthetic molecules have gained attention as a potential therapeutic agent in the treatment of cancer. In the present study, a new compound 5(4-hydroxyphenyl)-2-(N-phenylamino)-1,3,4-oxadiazole (Hppo) has been synthesized and its anticancer activity is investigated against Dalton's lymphoma (DL) tumor cells derived from murine T-cell lymphoma. The Hppo has been characterized through IR, NMR, and single-crystal X-ray data. The structure of Hppo is stabilized via hydrogen bonding interactions and crystallizes in an orthorhombic system with space group P b c n. The fingerprint plots associated with Hirshfeld surface analysis indicate that there are different types of weak interactions viz. C-H···N, O-H···N and C-H···O. The DFT calculations are also performed to verify physiochemical properties of Hppo and the results obtained are in good agreement with the experimental results. The HOMO and LUMO energy gap of 7.344 eV for Hppo indicates good NLO properties. The cytotoxicity activity of Hppo is tested against Dalton's lymphoma cells using MTT assay which reveals that the compound showed admirable anticancer activity (IC50= 50 µg/mL), which is better than many previously reported compounds. The mechanism of action of Hppo is investigated by performing different biological studies and the results obtained reveal that Hppo acts through down-regulating mitochondrial membrane potential and up-regulating reactive oxygen species production. Molecular docking studies are also performed to obtain more insights on biological activities of Hppo and its mode of action against CYP-19 (PDB: 3EQM), JAK2 (PDB: 5AEP), BCL-2 (PDB: 2O2F), and caspase3 (PDB: 1RE1), and result displayed favorable binding interactions with binding energy -7.43, -7.96, -6.61, and -6.88 Kcal/mol. © 2021 Elsevier B.V.
Moringa oleifera L. leaf extract induces cell cycle arrest and mitochondrial apoptosis in Dalton's Lymphoma: An in vitro and in vivo study
(Elsevier Ireland Ltd, 2023) Sandeep Kumar; Praveen Kumar Verma; Alok Shukla; Rishi Kant Singh; Anand Kumar Patel; Lokesh Yadav; Sanjay Kumar; Naveen Kumar; Kaushalendra; Arbind Acharya
Ethnopharmacological relevance: The present work is based on a wide spectrum of evidences available from scientific literature which reflects nutritional and medicinal values of natural products such as plants and their extracts. Moringa oleifera is one such popular plant species amidst indigenous tribal communities which is frequently used to treat ailments such as piles, sore throat, eye and ear infections and even poisonous bites of tropical fauna such as insects or snakes. Furthermore decoction of leaf and bark was used to cure fever and cough. Evidences further reveal that Moringa oleifera L. (Family Moringaceae), is widely distributed not only over the Indian sub-continent, but also over Philippines, Central America, Saudi Arabia and the Caribbean Islands and have been traditionally used to treat cancers since ancient times. However, therapeutic effects of Moringa oleifera on Non-Hodgkin Lymphoma (NHL) are yet to be established. Aim of the study: The study aims to investigate the anti-cancer effects of Moringa oleifera leaf extract against murine NHL Non-Hodgkin cells in vitro and in vivo. Material and methods: The pharmacologically active compounds of Moringa oleifera leaf extract were identified by GC-HRMS analysis. Tests of Moringa oleifera leaf extract's cytotoxicity against DL cells were carried out using the MTT assay. Chromatin condensation along with other morphological alterations were visualized through Fluorescence microscopy. Changes in the mitochondrial membrane potential (ΔΨm), the cell cycle, and apoptosis were analysed through flow cytometer. We tried to identify proteins involved in apoptosis and cell cycle through Western blotting using BALB/c mice as a model organism. Results: GC-HRMS study revealed that a methanol based leaf extract of Moringa oleifera (MOML) comprises of a variety of bioactive chemicals. Our results indicate that MOML successfully reduced the proliferation of DL cells by lowering ΔΨm, changing overall cell morphology. DL cells treated with MOML showed arrested cell cycle at the G2/M phase and substantially up-regulated the expression of p53 and p21. Elevated levels of Bax, Cyt-c, and Caspase-3 and lowered expression levels of Bcl-2 protein suggested induction of apoptosis. Mechanistically, the anticancer efficacy of MOML is attributed to MEK/ERK-mediated pathway inactivation in DL cells. It is also interesting to note that MOML-mediated inhibition of DL growth was accompanied by apoptosis induction and improvement in hematological parameters in DL-bearing mice. Conclusion: Our finding suggested that MOML induces apoptosis and abrogates the growth of Dalton's lymphoma both in vitro and in vivo. © 2022 Elsevier B.V.
Oxadiazole-2-thione based Co(II) complexes as antiproliferative agents: Synthesis and structural characterization
(Elsevier B.V., 2025) Ajay Vishwakarma; Alok Shukla; Sankatha P. Sonkar; Swati Singh; Diptee Mitra; Ram Chandra; Shailendra Yadav; Arbind Acharya; Manoj Kumar Bharty
The study of mixed-ligand complexes of transition metal ions has attracted significant interest due to their diverse applications and unique bonding properties. In this work, we report the synthesis of two potassium salts, [5-(4-pyridyl)-1,3,4]-oxadiazole-2-thione (Kpot) and 5-phenyl-1,3,4-oxadiazole-2-thione (Kphot), and their corresponding Co(II) complexes, [Co(pot)2(en)2] (1) and [Co(phot)2(en)2] (2). These ligands and complexes were characterized through spectroscopic techniques. In addition, complexes 1 and 2 were characterized by single-crystal X-ray diffraction (XRD) data. Both complexes crystallize in the monoclinic system with the space group P21/n. The ligands act as uninegative monodentate donors, coordinating with Co(II) ions along with two ethylenediamine (en) molecules as co-ligands. Emission spectra revealed that the complexes exhibit higher fluorescence intensity than the free ligands. Intermolecular interactions in complexes 1 and 2 were further analyzed using Hirshfeld surface analysis. The anticancer potential of the ligands and their Co(II) complexes was evaluated using the MTT assay, where both complexes exhibited significant suppression of tumor cell viability. Notably, complex 2 demonstrated superior activity compared to both the ligands and complex 1. Additionally, the anticancer effects were confirmed using DAPI and AO/EB staining techniques under confocal microscopy, as well as Annexin V/PI staining analyzed via flow cytometry. DAPI and AO/EB staining revealed compromised plasma membranes and chromatin condensation, indicative of apoptosis. Flow cytometry analysis further demonstrated that treatment with complex 2 induced both apoptosis and necrosis in tumor cells. © 2025 Elsevier B.V.
Pharmacological Insights: Mitochondrial ROS Generation by FNC (Azvudine) in Dalton’s Lymphoma Cells Revealed by Super Resolution Imaging
(Springer, 2024) Naveen Kumar; Vikram Delu; Ilya Ulasov; Sanjay Kumar; Rishi Kant Singh; Sandeep Kumar; Alok Shukla; Anand Kumar Patel; Lokesh Yadav; Ruchi Tiwari; Kumari Rachana; Shivashish Priyadarshi Mohanta; Varsha Singh; Anuradha Yadav; Kaushalendra Kaushalendra; Arbind Acharya
Nucleoside analogs are a common form of chemotherapy that disrupts DNA replication and repair, leading to cell cycle arrest and apoptosis. Reactive oxygen species (ROS) production is a significant mechanism through which these drugs exert their anticancer effects. This study investigated a new nucleoside analog called FNC or Azvudine, and its impact on ROS production and cell viability in Dalton’s lymphoma (DL) cells. The study found that FNC treatment resulted in a time- and dose-dependent increase in ROS levels in DL cells. After 15 and 30 min of treatment with 2 and 1 mg/ml of FNC, mitochondrial ROS production was observed in DL cells. Furthermore, prolonged exposure to FNC caused structural alterations and DNA damage in DL cells. The results suggest that FNC’s ability to impair DL cell viability may be due to its induction of ROS production and indicate a need for further investigation. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Piperazine-Based Co(III), Ni(II), Cu(II), and Zn(II) Carbodithioate Complexes as Potential Anticancer Agent
(American Chemical Society, 2025) Seema Gupta; Alok Shukla; Shivendra Kumar Pandey; Shalini Jha; Berhanu W. Zewde; Arbind Acharya; Raymond John Butcher; Manoj Kumar Bharty
The development of facile and cost-effective anticancer metallodrugs possessing minimal side effects is urgently needed. Piperazine-containing anticancer drugs are already available on the market. A piperazine-based potassium 4-(ethoxycarbonyl)piperazine-1-carbodithioate [pecpcdt] (L) ligand and its metal complexes [Co(ecpcdt)3] (1), [Ni(ecpcdt)2] (2), [Cu(ecpcdt)2] (3), and [Zn(ecpcdt)2] (4) were synthesized. These compounds were characterized by different spectroscopic methods and single-crystal X-ray crystallography data. Ni(II) and Cu(II) complexes have distorted square planar geometry, whereas the Co(III) complex has distorted octahedral geometry around the metal ions. Complexes are weakly fluorescent in the solution compared to the free ligand. The complexes were further examined for their in vitro anticancer activities against the primary Dalton’s lymphoma (DL) cells along with standard drug cisplatin. The anticancer studies of metal complexes have been performed through various biochemical assays, and the findings thus obtained suggest that they demonstrate an effective anticancer activity. [Co(ecpcdt)3] (1) shows superior cytotoxicity against DL cells than complexes [Cu(ecpcdt)2] (3), [Zn(ecpcdt)2] (4), and cisplatin. The superiority preferences of these complexes follows [Co(ecpcdt)3] (1) > [pecpcdt] > [Cu(ecpcdt)2] (3) > [Ni(ecpcdt)2] (2) > [Zn(ecpcdt)2] (4). Further assays were performed on a cobalt(III) complex having the highest efficacy to gain insights into the mechanism of cell death and showed that reduced mitochondrial membrane potential and increased mitochondrial ROS production, highlighting mitochondrial-dependent apoptosis as the major mechanism for tumor cell death. On the other hand, the viability of normal splenocytes was minimally affected by the [Co(ecpcdt)3] (1) treatment. © 2025 The Authors. Published by American Chemical Society.
Potential implications of protein kinase Cα in pathophysiological conditions and therapeutic interventions
(Elsevier Inc., 2023) Rishi Kant Singh; Sanjay Kumar; Sandeep Kumar; Alok Shukla; Naveen Kumar; Anand Kumar Patel; Lokesh Kumar Yadav; Kaushalendra; Meera Antiwal; Arbind Acharya
PKCα is a molecule with many functions that play an important role in cell survival and death to maintain cellular homeostasis. Alteration in the normal functioning of PKCα is responsible for the complicated etiology of many pathologies, including cancer, cardiovascular diseases, kidney complications, neurodegenerative diseases, diabetics, and many others. Several studies have been carried out over the years on this kinase's function, and regulation in normal physiology and pathological conditions. A lot of data with antithetical results have therefore accumulated over time to create a complex framework of physiological implications connected to the PKCα function that needs comprehensive elucidation. In light of this information, we critically analyze the multiple roles played by PKCα in basic cellular processes and their molecular mechanism during various pathological conditions. This review further discusses the current approaches to manipulating PKCα signaling amplitude in the patient's favour and proposed PKCα as a therapeutic target to reverse pathological states. © 2023 Elsevier Inc.
Safety Assessment of a Nucleoside Analogue FNC (2’-deoxy-2’-β-fluoro-4’-azidocytidine ) in Balb/c Mice: Acute Toxicity Study
(Asian Pacific Organization for Cancer Prevention, 2023) Naveen Kumar; Vikram Delu; Alok Shukla; Rishi Kant Singh; Ilya Ulasov; Daria Fayzullina; Sandeep Kumar; Anand Kumar Patel; Lokesh Yadav; Ruchi Tiwari; Kumari Rachana; Shivashish Priyadarshi Mohanta; Sanjay Kumar; Kaushalendra Kaushalendra; Arbind Acharya
Objectives: The present study aimed to provide an insight into the acute toxicity of a novel fluorinated nucleoside analogue (FNA), FNC (Azvudine or2’-deoxy-2’-β-fluoro-4’-azidocytidine). FNC showed potent anti-viral and anticancer activities and approved drug for high-load HIV patients, despite, its acute toxicity study being lacking. Materials and Methods: OECD-423 guidelines were followed during this study and the parameters were divided into four categories - behavioral parameters, physiological parameters, histopathological parameters, and supplementary tests. The behavioral parameters included feeding, body weight, belly size, organ weight and size, and mice behavior. The physiological parameters consisted of blood, liver, and kidney indicators. In histopathological parameters hematoxylin and eosin staining was performed to analyse the histological changes in the mice organs after FNC exposure. In addition, supplementary tests were conducted to assess cellular viability, DNA fragmentation and cytokine levels (IL-6 and TNF-α) in response to FNC. Results: In the behavioral parameters FNC induced changes in the mice-to-mice interaction and activities. Mice’s body weight, belly size, organ weight, and size remained unchanged. Physiological parameters of blood showed that FNC increased the level of WBC, RBC, Hb, and neutrophils and decreased the % count of lymphocytes. Liver enzymes SGOT (AST), and ALP was increased. In the renal function test (RFT) cholesterol level was significantly decreased. Histopathological analysis of the liver, kidney, brain, heart, lungs, and spleen showed no sign of tissue damage at the highest FNC dose of 25 mg/kg b.wt. Supplementary tests for cell viability showed no change in viability footprint, through our recently developed dilution cum-trypan (DCT) assay, and Annexin/PI. No DNA damage or apoptosis was observed in DAPI or AO/EtBr studies. Pro-inflammatory cytokines IL-6 and TNF-α increased in a dose-dependent manner. Conclusion: This study concluded that FNC is safe to use though higher concentration shows slight toxicity. © This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License.
Silibinin: a natural flavonoid with multifaceted anticancer potential and therapeutic challenges
(Springer, 2025) Snigdha Singh; Arpit Sharma; Tanu Pandey; Shivani Gupta; Alok Shukla; Santosh Kumar Singh; Amit Kumar Singh
Silibinin, the principal bioactive flavonolignan of Silybum marianum (milk thistle), has emerged as a promising natural agent with multifaceted anticancer potential. Extensive preclinical studies demonstrate its diverse pharmacological properties, including antioxidant, anti-inflammatory, and chemopreventive activities, which collectively contribute to its antitumor effects. At the molecular level, silibinin exerts cytotoxicity through the induction of apoptosis, involving both extrinsic (death receptor-mediated) and intrinsic (mitochondria-dependent) pathways. It modulates key signaling cascades such as EGFR, STAT3, and PI3K/AKT/mTOR, leading to suppression of proliferation, angiogenesis, invasion, and modulation of autophagy, stemness and Senescence. Importantly, silibinin acts as a modulator of apoptosis by restoring the balance between pro- and anti-apoptotic proteins, thereby sensitizing cancer cells to programmed cell death. Evidence across multiple malignancies, including hepatocellular carcinoma, breast, lung, and colorectal cancers etc, highlights its broad-spectrum therapeutic relevance. Clinical studies, though limited, suggest that silibinin may enhance the efficacy of standard chemotherapeutic, radiotherapeutic, and targeted regimens while reducing associated toxicities, underscoring its role as a synergistic adjuvant. However, challenges such as poor bioavailability, variable pharmacokinetics, and limited large-scale clinical validation constrain its translational application. To address these limitations, novel strategies such as nanocarrier-based delivery, structural modifications, and combination therapies are being actively investigated. Overall, silibinin represents a compelling natural flavonoid with dual preventive and therapeutic roles in oncology, though future research must overcome pharmacological barriers to fully harness its clinical potential. (Figure presented.) © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.
Solvent-dependent crystallization and anti-cancer activities based on Ni(II) and Co(II) complexes of 1-picolinoyl-4-phenyl-3-thiosemicarbazide: Synthesis, crystal structure, and photoluminescence study
(Elsevier B.V., 2023) Suryansh Chandra; Shubham Jaiswal; Alok Shukla; Ankit Kumar Singh; Somenath Garai; A. Bharti; A. Acharya; M.K. Bharty
In search of alternative of platinum-based drugs for the treatment of cancer, lead to the development of other potential metallodrug of transition metal complexes. The efficacious and novel experimental content of this paper reports the synthesis of [Ni(Hppts)2].CHCl3 (1a), [Ni(Hppts)2].(CH3)2SO (1b) and [Co(Hppts)2] (2) complexes of 1-picolinoyl-4-phenyl-3-thiosemicarbazide (H2ppts). The synthesized complexes have been characterized by UV-vis., Infrared, and NMR spectrometry. Furthermore, complexes 1a and 1b were characterized by single-crystal X-ray diffraction data. Emission spectra show that, complex 1a exhibits higher fluorescence intensity as compared to that of ligand H2ppts and complex 2. The order of fluorescence intensity was found as complex 1a > complex 2 > H2ppts. Moreover, Complexes 1a and 1b are stabilized via various types of intermolecular interactions. The cytotoxicity of complexes 1a, 2, and ligand was evaluated against Dalton's Lymphoma cells using standard MTT Assay. The anticancer activity results showed that complex 1a significantly reduced cell viability in a dose-dependent manner, whereas H2ppts and complex 2 did not show significant reduction in cell viability of DL cells when compared with the control. The complex 1a IC50 value was determined to be around 40 µg/mL. The anti-tumor activity concludes that the complex 1a has high anti-neoplastic activity on DL cells at low doses. © 2023 Elsevier B.V.