Department of Chemistry

Indian Institute of Technology Palakkad&nbsp;(IIT Palakkad or IIT PKD) is a public autonomous&nbsp;engineering&nbsp;and&nbsp;research&nbsp;institute located in&nbsp;Palakkad,&nbsp;Kerala. It was&nbsp;one of the five new&nbsp;IITs&nbsp;proposed in the&nbsp;2014 Union budget of India. The campus was inaugurated on 3 August 2015. The institute has 94 faculty, 978 students, and 63 non-teaching staffs.

IT Palakkad currently offers four-year Bachelor of Technology (B.Tech) and two years MS programmes in 8 different engineering disciplines including&nbsp;Computer Science, Electrical, Mechanical, Civil among others.

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IIT Palakkad

Epidermal growth factor receptor (EGFR)-targeted therapy has been proven vital in the last two decades for the treatment of multiple cancer types, including nonsmall cell lung cancer, glioblastoma, breast cancer and head and neck squamous cell carcinoma. Unfortunately, the majority of approved EGFR inhibitors fall into the drug resistance category because of continuous mutations and acquired resistance. Recently, autophagy has surfaced as one of the emerging underlying mechanisms behind resistance to EGFR-tyrosine kinase inhibitors (TKIs). Previously, we developed a series of 4″-alkyl EGCG (4″-Cn EGCG, n = 6, 8, 10, 12, 14, 16 and 18) derivatives with enhanced anticancer effects and stability. Therefore, the current study hypothesized that 4″-alkyl EGCG might induce cytoprotective autophagy upon EGFR inhibition and inhibition of autophagy may lead to improved cytotoxicity. In this study, we have observed growth inhibition and caspase-3-dependent apoptosis in 4″-alkyl EGCG derivativetreated glioblastoma cells (U87-MG). We also confirmed that 4″-alkyl EGCG could inhibit EGFR in the cells, as well as mutant L858R/T790M EGFR, through an in vitro kinase assay. Furthermore, we have found that EGFR inhibition with 4″-alkyl EGCG induces cytoprotective autophagic responses, accompanied by the blockage of the AKT/mTOR signaling pathway. In addition, cytotoxicity caused by 4″-C10 EGCG, 4″-C12 EGCG and 4″-C14 EGCG was significantly increased after the inhibition of autophagy by the pharmacological inhibitor chloroquine. These findings enhance our understanding of the autophagic response toward EGFR inhibitors in glioblastoma cells and suggest a potent combinatorial strategy to increase the therapeutic effectiveness of EGFR-TKIs. © 2023 American Chemical Society.

World University root node

ACS Omega

4″-Alkyl EGCG Derivatives Induce Cytoprotective Autophagy Response by Inhibiting EGFR in Glioblastoma Cells

The two-electron reduction of 2,3-dimethylbuta-1,3-diene (DMB) with β-diketiminate and guanidinate substituted dimagnesium(I) compounds has given complexes in which two bidentate amido-magnesium fragments are bridged through the π-system of the DMB dianion, viz. [(LMg)2(μ-DMB)] (L=XylNacnac, [HC(MeCNXyl)2]−, Xyl=2,6-xylyl; or Priso=[(DipN)2CNPri2]−, Dip=2,6-diisopropylphenyl). Similar double reductions of [4]dendralene (4dend) have afforded the complexes, [(LMg)2(μ-4dend)] (L=ArNacnac, Ar=Xyl or mesityl (Mes); or Priso) in which the 4dend dianion is π-coordinated to the bidentate amido-magnesium fragments. Treatment of several such complexes with THF leads to Z- to E-isomerization of the dendralene fragment and formation of purely σ-bonded Mg−C interactions in the THF coordinated products [{(ArNacnac)(THF)Mg}2(μ-4dend)] (Ar=Xyl, Mes or Dip). Reaction of myrcene (Myr) with [{(XylNacnac)Mg}2] proceeds via reductive coupling of Myr to give a previously unknown acyclic, branched C20 tetra-olefin dianion complex [{(XylNacnac)(THF)Mg}2(μ-Myr)2]. Preliminary reactions of [(LMg)2(μ-DMB)] with H2 and/or CO yielded a series of products, including novel magnesium hydride compounds, products derived from couplings of CO with the reduced DMB fragment (viz. magnesium dimethylcyclohexadienediolates) and one magnesium cyclopropanetriolate complex from the magnesium(I) induced coupling of DMB with H2 and CO. © 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

Chemistry - A European Journal

Reductive Metallation of Dendralenes and Myrcene Using Dimagnesium(I) Compounds: A Facile Route to Unsaturated Organomagnesium Compounds

A novel class of Pd(II) pyrene aroylhydrazone complexes (Pd1–Pd4) of general formula [Pd(L)(PPh3)Cl] (L = pyrene aroylhydrazones) was synthesized and their solid-state structures were determined by single-crystal XRD study. In vitro cytotoxicity of Pd1–Pd4 were examined against two cancer cell lines, HeLa and MCF-7 and two non-cancerous cell line, HEK 293T and 3T3-L1 to assess their selectivity. Among these, Pd2 and Pd3 had the most significant cytotoxic effects in comparison to cisplatin, a traditional anticancer medication featuring undesirable side effects, in tested cancer cell lines. Moreover, they showed noticeably less toxicity towards non-cancerous cell lines. Their interactions with serum albumin were confirmed experimentally as well as with molecular docking. Pd3 was also found to effectively interact with DNA as revealed by DNA interactions studies. Pd3-treated HeLa cells exhibited nuclear apoptotic features such as chromatin condensation and nuclear fragmentation and was also found to induce ROS which further led to decrease in mitochondrial membrane potential in cancer cells. Further, Pd3 was efficiently internalized by HeLa cells as evident from cellular imaging using confocal microscopy. Taken together, we report a novel class of Pd(II) pyrene aroylhydrazone complexes displaying strong protein/DNA binding and anti-cancer activity via ROS generation under in vitro circumstances. © 2023

Journal of Molecular Structure

Pyrene aroylhydrazone-based Pd(II) complexes for DNA/protein binding, cellular imaging and in vitro anticancer activity via ROS production

Sequence-defined oligomers (SDOs) with their unique monomeric sequence and customizable nature are attracting the attention of researchers globally. The structural and functional diversity attainable in SDOs makes this platform promising, albeit with challenges in the synthesis. Herein, we report the design and synthesis of a novel class of SDO by incorporating tertiary amines into the backbone from commercially available inexpensive materials. Tertiary amines were selected due to their various material and biomedical applications. Even though the synthesis and purification of amine compounds are challenging, their various significant applications, such as pharmaceuticals, catalysts, surfactants, corrosion inhibitors, dye intermediates, polymer additives, rubber accelerators, gas treating agents, agriculture and analytical chemistry, make them fascinating. The synthetic strategy that is designed here is extremely efficient and economical for the scalable synthesis of the SDO and is support-free, protection-deprotection chemistry-free and catalyst/template-free. Most importantly, no extra design and synthesis of the monomer is required here. The key reactions employed for the SDO synthesis are (i) transformation of the hydroxy group to a halide and (ii) substitution of the halide by the secondary amine units. Including the purifying processes, the multigram synthesis of 4-mer was completed in 12-14 h. The synthetic strategy was established by synthesizing two different sequences of SDOs. The SDOs are characterized by 1H NMR and LC-MS. The tandem MS (MS/MS) experiment was conducted in order to validate the sequences over the SDO chain. Furthermore, the SDO platform was advanced in two ways: (i) by increasing the chain length via attaching a linker, which provides a rapid method for increasing the tertiary amine over the SDO chain and (ii) postsynthetic modification of SDO with other functional groups, including guanidine for biological importance and a well-known fluorophore dansyl group for material significance. © 2024 American Chemical Society.

ACS Macro Letters

Sequence-Defined Tertiary Amine-Based Oligomer Employing a Scalable, Support-Free and Protection/Deprotection-Free Iterative Strategy

This study presents an innovative approach for the detection of 5-nitroimidazole antibiotics, namely ornidazole, secnidazole, metronidazole and tinidazole. These antibiotics are widely used to treat microbial infections in both humans and livestock industries. Their unregulated use poses environmental and health risks due to their persistence in water bodies and potential to contribute to drug resistance. In response, this research proposes the utilisation of the self-aggregation property of a single unmodified non-aromatic amino acid, ʟ-lysine, for the detection of these antibiotics. Lysine exhibits strong fluorescence in water in a concentration-dependent manner and the interaction of lysine with 5-nitroimidazole antibiotics resulted in the quenching of its fluorescence. With this technique, we obtained a detection limit of 2.5 μM for metronidazole (MDZ), 2.65 μM for ornidazole (ODZ), 3.13 μM for secnidazole (SDZ) and 2.98 μM for tinidazole (TDZ). This cost-effective approach also offers practicality through visual detection on paper strips as well as successful application in detecting those antibiotics in milk samples and animal products. Taking advantage of the unique properties of lysine and its interaction with antibiotics, this method provides a robust, simplified yet efficient means of detecting 5-nitroimidazole antibiotics, which holds significant potential for real-world implementation. © 2023 Elsevier B.V.

Microchemical Journal

Selective luminescent detection of 5-nitroimidazole antibiotics through self-aggregates of a single non-aromatic amino acid, ʟ-lysine

Protein S-palmitoylation mediated by DHHCs is recognized as a distinct and reversible form of lipid modification connected with several health perturbations, including neurodegenerative disorders, cancer and autoimmune conditions. However, the pharmacological characteristics of current pan-DHHC inhibitors, particularly their toxicity and off-target effects, have hindered their in-depth cellular investigations. The therapeutic properties of the natural compounds, with minimal side effects, allowed us to evaluate them as DHHC-targeting inhibitors. Here, we performed an insilico screening of 115 phytochemicals to assess their interactions with the DHHC20 binding site. Among these compounds, lutein, 5-hydroxyflavone and 6-hydroxyflavone exhibited higher binding energy (−9.2, −8.5 and −8.5 kcal/mol) in the DHHC20 groove compared to pan-DHHC inhibitor 2-BP (−7.0 kcal/mol). Furthermore, we conducted a 100 ns MD simulation to evaluate the stability of these complexes under physiological conditions. The MDsimulation results indicated that DHHC20 formed a more stable conformation with lutein compared to 5-hydroxyflavone and 6-hyroxyflavone via hydrophobic and H-bond interactions. Conclusively, these results could serve as a promising starting point for exploring the use of these natural molecules as DHHC20 inhibitors. Communicated by Ramaswamy H. Sarma. © 2024 Informa UK Limited, trading as Taylor & Francis Group.

Journal of Biomolecular Structure and Dynamics

Identification of selective plant-derived natural carotenoid and flavonoids as the potential inhibitors of DHHC-mediated protein S-palmitoylation: an in silico study

S-palmitoylation is a dynamic lipid-based protein post-translational modification facilitated by a family of protein acyltransferases (PATs) commonly known as DHHC-PATs or DHHCs. It is the only lipid modification that is reversible and this very fact uniquely qualifies it for therapeutic interventions through the development of DHHC inhibitors. Herein, we report that 4″-alkyl ether lipophilic derivatives of EGCG can effectively inhibit protein S-palmitoylation in vitro. With the help of metabolic labeling followed by copper(I)-catalyzed azide-alkyne cycloaddition Click reaction, we demonstrate that 4″-C14 EGCG and 4″-C16 EGCG markedly inhibited S-palmitoylation in various mammalian cells including HEK 293T, HeLa and MCF-7 using both in gel fluorescence as well as confocal microscopy. Further, these EGCG derivatives were able to attenuate the S-palmitoylation to the basal level in DHHC3-overexpressed cells, suggesting that they are plausibly targeting DHHCs. Confocal microscopy data qualitatively reflected spatial and temporal distribution of S-palmitoylated proteins in different sub-cellular compartments and the inhibitory effects of 4″-C14 EGCG and 4″-C16 EGCG were clearly observed in the native cellular environment. Our findings were further substantiated by in silico analysis which revealed promising binding affinity and interactions of 4″-C14 EGCG and 4″-C16 EGCG with key amino acid residues present in the hydrophobic cleft of the DHHC20 enzyme. We also demonstrated the successful inhibition of S-palmitoylation of GAPDH by 4″-C16 EGCG. Taken together, our in vitro and in silico data strongly suggest that 4″-C14 EGCG and 4″-C16 EGCG can act as potent inhibitors for S-palmitoylation and can be employed as a complementary tool to investigate S-palmitoylation. © 2023 Elsevier B.V.

Biochimica et Biophysica Acta - Biomembranes

Protein S-palmitoylation is markedly inhibited by 4″-alkyl ether lipophilic derivatives of EGCG, the major green tea polyphenol: In vitro and in silico studies

Cancer is one of the major public health issues in the world. It has become the second leading cause of death, with approximately 75% of cancer deaths transpiring in low- or middle-income countries. It causes a heavy global economic cost estimated at more than a trillion dollars per year. The most common cancers are breast, colon, rectum, prostate and lung cancers. Many of these cancers can be treated effectively and cured if detected at the primary stage. Nowadays, around 50% of cancers are detected at late stages, leading to serious health complications and death. Early diagnosis of cancer diseases substantially increases the efficient treatment and high chances of survival. Biosensors are one of the potential screening methodologies useful in the early screening of cancer biomarkers. This review summarizes the recent findings about novel cancer biomarkers and their advantages over traditional biomarkers and novel biosensing and diagnostic methods for them; thus, this review may be helpful in the early recognition and monitoring of treatment response of various human cancers. © 2023 by the authors.

Fulltext

Biosensors

Recent Trends in Biosensing and Diagnostic Methods for Novel Cancer Biomarkers

This work presents a fluorescent sequence-defined oligo dithiocarbamate platform with a dansyl appendage for interaction studies with a range of proteins including BSA, HSA, proteinase, trypsin, lysozyme, hemoglobin and amylase. The platform involves six distinct sequence-defined oligomers (SDOs), each offering varied functionalities - dithiocarbamate (DTC), ester and amide - within the backbone and side chains; different architectures (linear and branched); and introduction of polar or non-polar groups. Fluorescence titration experiments and molecular docking were used to explore the interaction between the synthesized SDOs and the listed proteins. This analysis identified two promising candidates, particularly SDOs 1 and 2, based on higher FRET efficiency, indicating a stronger interaction with serum albumins. SDO 1, demonstrating the highest FRET, was utilized for specific and sensitive staining of serum albumin in native-polyacrylamide gel electrophoresis (Native-PAGE), providing selective fluorescent staining with a 25 times lower concentration of staining agent compared to conventional Coomassie blue staining. This innovative approach serves as an alternative tool for gel staining, especially for selective fluorescent staining of BSA and HSA. © 2023 The Royal Society of Chemistry.

RSC Advances

Selective and sensitive fluorescent staining of serum albumin in protein gel electrophoresis via sequence-defined oligo-dithiocarbamate

The design of reliable sensor systems for quick sensing and monitoring the trace concentrations of volatile organic compounds (VOCs) has been a topical area of research in recent years due to their serious menace to living systems and environmental hazardousness. In this article, we report two unique ‘cleft-shaped’ N-aryl-4-amino-1,8-naphthalimide derived Tröger's bases (TBNap-Ph and TBNap-Es) as efficient, fast fluorescence sensors for discriminative sensing of volatile organic amines (VOAs). The fluorescence titration studies using TBNap-Ph and TBNap-Es demonstrated discriminative fluorescence sensing responses for VOAs with high selectivity for benzylamine detection. The initial emission intensity of TBNap-Ph and TBNap-Es was enhanced drastically upon the addition of benzylamine. However, similar titration studies using other VOAs such as n-propylamine, n-butylamine, diethylamine, isopropylamine, 3-dimethylamino-1-propylamine, triethylamine, and ethanolamine elicited poor to negligible changes in the fluorescence emission intensity. The selective ‘turn-on’ fluorescence sensing of benzylamine was also reflected by sharp color changes and these sensors can be used to detect benzylamine at the parts-per-millions (ppm) level of sensitivity. Furthermore, the experimentally observed discriminative fluorescence sensing property of TBNap-Ph and TBNap-Es towards VOAs was supported by computational calculations. © 2023 Elsevier B.V.