BITS Faculty Publications

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    Calcium chloride linked camel milk derived casein nanoparticles for the delivery of sorafenib in hepatocarcinoma cells
    (Tech Science Press, 2021-09) Dubey, Uma S.
    Sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma, is limited by its low oral bioavailability. To overcome this drawback, we have developed novel camel milk casein-derived nanoparticles as a drug delivery system. Camel milk casein is not only biocompatible on oral administration but is actually a dietary protein of pharmaceutical relevance. Casein is used because of its amphiphilic nature, self-assembling property, ability to show sustained release, and capability of encapsulating both hydrophilic and hydrophobic drugs. In this study, camel milk casein nanoparticles loaded with sorafenib were developed and characterized. Characterization of casein nanoparticles was done by dynamic light scattering (DLS), zeta potential analysis, scanning light microscopy (SEM), and FTIR. The drug content in nanoparticle and drug-protein binding studies were conducted by UV spectroscopy. The cytotoxicity and cellular uptake efficiency studies were performed in HepG2 cell lines. It was observed that the cytotoxic effect of sorafenib loaded camel milk casein nanoparticles was more than free sorafenib in HepG2 cells. This work suggests camel milk casein as a suitable drug delivery molecule for sorafenib. In the future, it may also be used in enhancing the efficacy and specific distribution of other water-insoluble anticancer drugs.
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    Metal-free, visible-light-mediated synthesis of tetracyclic benzimidazole: regioselective c–h functionalization with in vitro and computational study of anti-breast cancer compounds
    (ACS, 2025-02) Murugesan, Sankaranarayanan; Mukherjee, Sudeshna
    Globally, breast cancer is the leading cause of mortality. Within the field of antibreast cancer drug design by several compound docking studies, eight new N-containing nonsteroid tetracyclic derivatives have been synthesized via regioselective intramolecular C–H functionalization by visible light. The adopted methodology is highly efficient, green, and sustainable to unload a new pathway with excellent yield. It offers a rapid, low-cost, catalyst-free method for creating physiologically active molecules from easily accessible substrates. The synthesized substances were described using spectroscopic methods like HRMS, 1HNMR, 13CNMR, and XRD analysis. This study explores the cytotoxic potential of novel compounds against human MCF-7 breast cancer cells. This study includes in vitro experiments to assess the effect of our compounds on cells. These experiments include cytotoxicity assessment by cell cycle, apoptosis, MTT test analysis by flow cytometry, reactive oxygen species (ROS) production assessment, etc. Among the novel compounds, compound 2e exhibited the most potent cytotoxic activity, with an inhibitory concentration (IC50) of 40 nM, surpassing the efficacy of established drugs such as exemestane (IC50 24.97 micromolar) and tamoxifen (IC50 5.45 μM). Compound 2e also significantly induced apoptosis and cell cycle arrest in the G1 phase, increasing the apoptotic cell population to 65.97%. Additionally, the compound led to a marked rise in the level of ROS generation, implicating oxidative stress in its mechanism of action. Molecular docking and dynamic simulation further supported the vigorous anticancer activity of compound 2e, demonstrating its promise as an effective breast cancer treatment.
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    Indolyl-α-keto-1,3,4-oxadiazoles: Synthesis, anti-cell proliferation activity, and inhibition of tubulin polymerization
    (Elsevier, 2021-04) Kumar, Anil; Kumar, Dalip
    A series of novel indolyl-α-keto-1,3,4-oxadiazole derivatives have been synthesized by employing molecular iodine-mediated oxidative cyclization of acylhydrazones. In vitro anti cell proliferation activity of these derivatives against various cancer cells lines such as human lymphoblast (U937), leukemia (Jurkat & SB) and human breast (BT474) was investigated. Among the synthesized indolyl-α-keto-1,3,4-oxadiazoles 19a-p, only one compound (19e) exhibited significant antiproliferative activity against a panel of cell lines. The compound 19e with 3,4,5-trimethoxyphenyl motif, endowed strong cytotoxicity against U937, Jurkat, BT474 and SB cancer cells with IC50 values of 7.1, 3.1, 4.1, and 0.8 µM, respectively. Molecular docking studies suggested a potential binding mode for 19e in the colchicine binding site of tubulin. When tested for in vitro tubulin polymerizaton, 19e inhibited tubulin polymezations (IC50 = 10.66 µM) and induced apoptosis through caspase 3/7 activation. Further, the derivative 19e did not cause necrosis when measured using lactate dehydrogenase assay.
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    Indole Derivatives as Anticancer Agents for Breast Cancer Therapy: A Review
    (Bentham Science, 2016) Sidhu, Jagpreet Singh
    Breast cancer (BC) is the second most common cause of cancer-related deaths in women throughout the world. Multiple drugs have been approved by US-FDA for breast related malignancies. Frequent emergence of resistances creates the severe need of newer moieties that are free from such problems. Drugs targeting breast cancer have been observed to be based on the multiple mechanisms of action, and various indole based anticancer agents have also been explored. Moreover, indoles have promising anti-cancer potential; there has been the emphasis on the synthesis of indole derivatives to overcome problems faced by existing therapeutic agents. Taking into consideration the above-mentioned facts we have analyzed in detail the possible role of indole based anticancer agents typically for breast related malignancies. This is the first exhaustive review that jointly covers various synthetic anticancer indole derivatives and related signaling pathways by which these derivatives have shown promising anti-breast cancer potential.
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    Apoptosis inducing activity of steroidal constituents from Solanum xanthocarpum and Asparagus racemosus
    (Elsevier, 2010-08) Paul, Atish Tulshiram
    A series of Sarsapogenin and Diosgenin derived steroidal constituents (1-12), isolated from Solanum xanthocarpum and Asparagus racemosus were screened for their ability to induce cell death and apoptosis of colon carcinoma cells. The carbohydrate moieties linked to the steroid backbones were found to strongly influence cytotoxic activity and cell death mode (apoptosis or necrosis). Compound 10, from A. racemosus was found to be a potent inducer of apoptosis.
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    ER stress modulated Klotho restoration: A prophylactic therapeutic strategy against acute kidney injury-diabetes comorbidity
    (Elsevier, 2024-01) Gaikwad, Anil Bhanudas
    Klotho is a renoprotective factor that is at the forefront of research as a potential therapeutic agent and biomarker of acute kidney injury (AKI). Endoplasmic reticulum (ER) stress and Klotho downregulation are the critical hallmarks of AKI progression. Importantly, the crosstalk between ER and Klotho is still elusive in AKI under diabetic condition. Therefore, this study aimed to elucidate the affiliation between ER stress and Klotho regulation by using the ischemia-reperfusion renal injury (IRI) model based on male Wistar rats and the hypoxia-reperfusion injury (HRI) using NRK52E cells. Study outcomes demonstrated that the expression of AKI biomarkers: plasma creatinine, neutrophil gelatinase-associated lipocalin, kidney-injury molecule 1, and ER stress markers such as binding immunoglobulin binding protein (BiP), R/PKR-like ER kinase (PERK), and eukaryotic initiation factor-2 (eIF2α), were observed during AKI. Increased ER stress was associated with apoptosis induction as depicted by increased levels of Poly (ADP-ribose) polymerase (PARP) and caspase-7 and decreased tubular Klotho expression. Under diabetic settings, ER stress and apoptosis were exacerbated by additional Klotho downregulation. Treatment with Tauroursodeoxycholic acid (TUDCA) inhibited the ER stress, apoptosis, restored endogenous Klotho levels and ameliorated AKI under diabetic and non-diabetic conditions. ER stress and Klotho appear to be shared factors involved in the pathogenesis of AKI-diabetes comorbidity and targeting them could prove a novel therapeutic approach.
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    Design, synthesis and structure–activity relationship studies of novel spirochromanone hydrochloride analogs as anticancer agents
    (Future Science Group, 2022-01) Murugesan, Sankaranarayanan
    Literature reports suggest spirochromanone derivatives exhibit anticancer activity. Methodology: The authors designed and synthesized 18 spirochromanone derivatives (Csp 1–18). The compounds were characterized and evaluated for anticancer activity against human breast cancer (MCF-7) and murine melanoma (B16F10) cell lines. Results: The anticancer activity ranged from 4.34 to 29.31 μm. The most potent compounds, Csp 12 and Csp 18, were less toxic against the human embryonic kidney (HEK-293) cell line and ∼ two/∼fourfold selective toward MCF-7 than B16F10 in comparison to the reference, BG-45. Csp 12 caused 28.6% total apoptosis, leading to significant cytotoxicity, and arrested the G2 phase of the cell cycle in B16F10 cells. A molecular docking study of Csp 12 exhibited effective binding at the active site of the epidermal growth factor receptor kinase domain. Conclusion: This study highlights the importance of spirochromanones as anticancer agents.
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    Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats
    (MDPI, 2021-09-17) Sakhuja, Rajeev; Mazumdar, Samrat; Chitkara, Deepak
    A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents
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    NMK-TD-100, a Novel Microtubule Modulating Agent, Blocks Mitosis and Induces Apoptosis in HeLa Cells by Binding to Tubuli
    (Plos One, 2013-10-07) Kumar, Dalip
    Thiadiazoles are one of the most widely utilized agents in medicinal chemistry, having a wide range of pharmacologic activity. Microtubules (MTs) have always remained a sought-after target in rapidly proliferating cancer cells. We screened for the growth inhibitory effect of synthetic 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles on cancer cells and identified NMK-TD-100, as the most potent agent. Cell viability experiments using human cervical carcinoma cell line (HeLa cells) indicated that the IC50 value was 1.42±0.11 µM for NMK-TD-100 for 48 h treatment. In further study, we examined the mode of interaction of NMK-TD-100 with tubulin and unraveled the cellular mechanism responsible for its anti-tumor activity. NMK-TD-100 induced arrest in mitotic phase of cell cycle, caused decline in mitochondrial membrane potential and induced apoptosis in HeLa cells. Immunofluorescence studies using an anti-α-tubulin antibody showed a significant depolymerization of the interphase microtubule network and spindle microtubule in HeLa cells in a concentration-dependent manner. However, the cytotoxicity of NMK-TD-100 towards human peripheral blood mononuclear cells (PBMC) was lower compared to that in cancer cells. Polymerization of tissue purified tubulin into microtubules was inhibited by NMK-TD-100 with an IC50 value of 17.5±0.35 µM. The binding of NMK-TD-100 with tubulin was studied using NMK-TD-100 fluorescence enhancement and intrinsic tryptophan fluorescence of tubulin. The stoichiometry of NMK-TD-100 binding to tubulin is 1:1 (molar ratio) with a dissociation constant of ~1 µM. Fluorescence spectroscopic and molecular modeling data showed that NMK-TD-100 binds to tubulin at a site which is very near to the colchicine binding site. The binding of NMK-TD-100 to tubulin was estimated to be ~10 times faster than that of colchicine. The results indicated that NMK-TD-100 exerted anti-proliferative activity by disrupting microtubule functions through tubulin binding and provided insights into its potential of being a chemotherapeutic agent.
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    Development of Novel Bis(indolyl)-hydrazide–Hydrazone Derivatives as Potent Microtubule-Targeting Cytotoxic Agents against A549 Lung Cancer Cells
    (ACS, 2016-04-25) Kumar, Dalip
    The biological significance of microtubules makes them a validated target of cancer therapy. In this study, we have utilized indole, an important pharmacological scaffold, to synthesize novel bis(indolyl)-hydrazide–hydrazone derivatives (NMK-BH compounds) and recognized NMK-BH3 as the most effective one in inhibiting A549 cell proliferation and assembly of tissue-purified tubulin. Cell viability experiments showed that NMK-BH3 inhibited proliferation of human lung adenocarcinoma (A549) cells, normal human lung fibroblasts (WI38) and peripheral blood mononuclear cells (PBMC) with IC50 values of ∼2, 48.5, and 62 μM, respectively. Thus, the relatively high cytotoxicity of NMK-BH3 toward lung carcinoma (A549) cells over normal lung fibroblasts (WI38) and PBMC confers a therapeutic advantage of reduced host toxicity. Flow cytometry, Western blot, and immunofluorescence studies in the A549 cell line revealed that NMK-BH3 induced G2/M arrest, mitochondrial depolarization, and apoptosis by depolymerizing the cellular interphase and spindle microtubules. Consistent with these observations, study in cell free system revealed that NMK-BH3 inhibited the microtubule assembly with an IC50 value of ∼7.5 μM. The tubulin–ligand interaction study using fluorescence spectroscopy indicated that NMK-BH3 exhibited strong and specific tubulin binding with a dissociation constant of ∼1.4 μM at a single site, very close to colchicine site, on β-tubulin. Collectively, these findings explore the cytotoxic potential of NMK-BH3 by targeting the microtubules and inspire its development as a potential candidate for lung cancer chemotherapy.