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Tajindra Singh Saluja,1 Vijay Kumar,2 Monika Agrawal,3 Abhilasha Tripathi,4 Rajesh Kumar Meher,5 Kamini Srivastava,1 Anurag Gupta,1 Anjana Singh,6 Arun Chaturvedi,2 Satyendra Kumar Singh1 1Stem Cell/Cell Culture Unit, Center for Advance Research, King George’s Medical University, Lucknow, Uttar Pradesh, India; 2Department of Surgical Oncology, King George’s Medical University, Lucknow, Uttar Pradesh, India; 3Department of Obstetrics & Gynecology, King George’s Medical University, Lucknow, Uttar Pradesh, India; 4Department of Pharmacology, King George’s Medical University, Lucknow, Uttar Pradesh, India; 5Department of Biotechnology and Bioinformatics, Sambalpur University, Sambalpur, Odisha, India; 6Department of Biochemistry, AIIMS, Rishikesh, Uttarakhand, IndiaCorrespondence: Satyendra Kumar SinghStem Cell/Cell Culture Unit,Center for Advance Research, King George’s Medical University, Lucknow, Uttar Pradesh 226003, IndiaTel +91 9415-204-356Email satyendraks@kgmcindia.eduIntroduction: Despite improved therapeutics in oral squamous cell carcinoma (OSCC), tumor cells that are either quiescent and/or endowed with stem cell–like attributes usually survive treatment and recreate tumor load at relapse. Through this study, we aimed strategically to eliminate these stem cell–like cancer cells using a combination drug approach.Methods: Primary cultures from 15 well–moderately differentiated OSCC were established, and the existence of cancer cells with stem cell–like characteristics using five cancer stem cell (CSC) specific markers — CD44, CD133, CD147, C166, SOX2 and spheroid assay was ascertained. Next, we assessed quiescence in CSCs under normal and growth factor–deprived conditions using Ki67. Among several gene signatures regulating quiescent cellular state, we evaluated the effect of inhibiting Dyrk1b in combination with topoisomerase II and histone deacetylase inhibitors in targeting quiescent CSCs. Multiple drug-effect analysis was carried out with CompuSyn software to determine combination-index values.Results: We observed that CD44+CD133+ showed the highest level of SOX2 expression. CSCs showed varying degrees of quiescence, and inhibition of Dyrk1b decreased quiescence and sensitized CSCs to apoptosis. In the drug-combination study, Dyrk1b inhibitor was combined with topoisomerase II and histone deacetylase inhibitors to target quiescent CSCs. In combination, a synergistic effect was seen even at a 16-fold lower dose than IC50. Furthermore, combined treatment decreased glutathione levels and increased ROS and mitochondrial stress, leading to increased DNA damage and cytochrome c in CSCs.Conclusion: We report marker-based identification of CSC subpopulations and synergy of Dyrk1b inhibitor with topoisomerase II and HDAC inhibitors in primary OSCC. The results provide a new therapeutic strategy to minimize quiescence and target oral CSCs simultaneously.Keywords: oral cancer, cancer stem cells, drug combination, synergy, apoptosis

Oral squamous cell carcinoma (OSCC) is a disease of significant concern with higher mortality rates. Conventional treatment approaches have several drawbacks, leading to the opening of new research avenues in the field of nanoparticle-based cancer therapeutics. The study aimed at the synthesis of gold nanoparticles (Pm-AuNPs) from the aqueous bark extract of Pterocarpus marsupium , followed by its characterization and in vitro anticancer evaluation against OSCC. The synthesized Pm-AuNPs were characterized using UV-visible spectroscopy, particle size analyser, zeta potential, FTIR and SEM techniques. The anticancer potential of the Pm-AuNPs was evaluated against OSCC cell lines (SCC29b, SSC154 and OECM-1) through in vitro assays. The IC 50 value was found to be 25 ± 1.2, 45 ± 1.5 and 75 ± 2.1 µg/mL for the three OSCC cell lines, elucidating Pm-AuNPs cytotoxic effects and mechanism of action. Intracellular ROS and SOX detection, mitochondrial transmembrane potential analysis and apoptosis detection were used to confirm the activity of Pm-AuNPs against OSCC. Acute toxicity studies on Wistar rats confirmed the non-toxic nature of the Pm-AuNPs at a higher dose concentration up to 2000 mg/kg body weight. The findings underscore Pm-AuNPs as promising candidates for future anticancer therapeutics, providing insights into their mechanism of action and therapeutic efficacy against OSCC.

Cancer is a challenging and second most deadly disease. The epidermal growth factor receptors (EGFRs) dimerize upon ligand bindings to the extracellular domain that intiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphrylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. In this study, we unravel the binding mechanism of newly synthesized thiazolo-[2,3-b] quinazolin-6-one and evaluate their anti-cancer activity against ovary and prostate carcinoma cell lines (OVCAR-3 and PC-3). Synthesized molecules exhibited promising anti-cancer activity against OVCAR-3 and PC-3 carcinoma cell lines with inhibitory concentrations ranging from 13.4 ± 0.43 to 23.6 ± 1.22 μM and 7.5 ± 0.62 to 67.5 ± 1.24 μM, respectively. These compounds induced apoptosis and resulted in cell cycle arrest at G1 and G2/M transition phases. Next, the nude mice models were taken to investigate the toxicity of the 4bi compound, and in vivo investigations revealed no effects upon examined organs (liver and kidney) treated at different concentrations. Moreover, the combined in silico approaches, molecular docking, molecular dynamics simulations, and MM/PBSA methods were performed to assess the binding affinity and stability of bioinspired synthesized congeners with the epidermal growth factor receptor tyrosine kinase (EGFR-TK). The free binding energy (ΔG bind ) of the 4bi molecule was found comparable to Erlotinib drug. The test molecule could be competent for further usage to determine its efficicacy in cancer therapeutics., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

This study emphasizes the explorations of binding of Prima-1 MET with two targets, p53 a tumor suppressor protein, and tyrosine kinase of epidermal growth factor receptor. In silico investigations reveal that Prima-1 MET showed robust binding with both targets. Molecular docking simulations demonstrated the binding affinity of Prima-1 MET with p53 and tyrosine kinase was found to be -38.601 kJ/mol and -38.976 kJ/mol. In addition, the stability of Prima-1 MET was explored by molecular dynamics simulation. Prima-1 MET attains stability in the binding site of the respective protein till the simulation period is over. Moreover, the free binding energy Δ G bind was calculated by the molecular mechanics Poisson Boltzmann surface area method. The Δ G bind of Prima-1 MET with tyrosine kinase was found to be -58.585 ± 0.327 kJ/mol and with p53 it was -35.910 ± 0.335 kJ/mol. Next, cytotoxicity of the Prima-1 MET was evaluated using multiple cancer cell lines and the IC 50 value were ranging between 4.5 and 30 μM. The cell death was identified by apoptosis assay. Further, the p53 and tyrosine kinase expression was monitored using immunofluorescence techniques, it was found Prima-1 MET induces the expression of p53 protein and mimics the level of tyrosine kinase oncogenic target. Also, reactive oxygen species (ROS) and membrane potential activity of Prima-1 MET was evaluated by using a lung cancer cell line. A significant decrease in intracellular ROS was observed and resulted in disruption of mitochondrial transmembrane potential. This study uncovers the underlying mechanism of Prima-1 MET and could be helpful to design further leads against lung cancers.Communicated by Ramaswamy H. Sarma.

We report a competent and selective hydrosilylation of nitriles and tertiary amides catalyzed by the readily available zinc bis(hexamethyldisilazide) under solvent-free and mild conditions, making it a sustainable and desirable alternative to existing methods. Both protocols afforded high conversion, superior selectivity, and a broad substrate scope, from electron-withdrawing to electron-donating and heterocyclic substitutions.

A series of chalcone-based 4-Nitroacetophenone derivatives were designed and synthesized by the single-step condensation method. These compounds were identified by 1 H NMR, 13 C NMR, MS, and FTIR analysis. Further, the derivatives were evaluated against four cancer cell lines H1299, MCF-7, HepG2, and K526. The IC 50 value of potent compounds NCH-2, NCH-4, NCH-5, NCH-6, NCH-8, and NCH-10 was 4.5-11.4 μM in H1299, 4.3-15.7 μM in MCF-7, 2.7-4.1 μM in HepG2 and 4.9-19.7 μM in K562. To assess the toxicity against healthy cells all potent molecules were evaluated against the HEK-293T cell line, and IC 50 values exhibited by NCH-2, and NCH-3 were 77.8, 74.3, and other molecules showed IC 50 values > 100 μM. The EGFR expression was determined by using rabbit anti-EGFR monoclonal antibody and significant EGFR expression was knocked down observed in H1299 treated with NCH-10 as well as erlotinib. The underlying mechanism behind cell death was investigated through bioinformatics. First, the molecules were optimized and docked to the binding site of the EGFR kinase domain. The best complexes were simulated for 100-ns and compounds NCH-2, NCH-4, and NCH-10 achieved stability similar to the erlotinib bound kinase domain. The free energy binding (Δ G bind ) of NCH-10 was found to be more negative -226.616 ± 2.148 kJ/mol calculated by Molecular Mechanics Poisson Boltzmann's Surface Area (MM-PBSA) method. Both in vitro and in silico results conclude that the present class of chalcone-based 4-Nitroacetophenone derivatives are potent anti-cancer agents targeting EGFR-TKD and are 39 folds more effective against H1299, MCF-7, HepG2, and K562 carcinoma cell lines than healthy HEK-293T cell lines.Communicated by Ramaswamy H. Sarma.

Hydrilla verticillata (L.f.) Royle is a perennial aquatic plant, which exhibits nutritional as well as therapeutic properties. The present study has been carried out to evaluate anti-inflammatory and immunomodulatory activities along with in silico evaluation of potential selective COX-2 and TNF-α inhibitors from methanolic extract of H. verticillata (L.f.) Royle. The potential therapeutic compounds have been identified by high-resolution GC-MS analysis. Its capacity to inhibit inflammatory responses using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells has been explored. The anti-inflammatory properties of the plant extract were investigated by inhibiting inducible nitric oxide (NO) synthase and reduced NO generation driven by LPS on stimulated RAW 264.7 macrophage cells. Further investigation for the underlying molecular mechanism of the anti-inflammatory activity of plant extract has been carried out by molecular docking and molecular dynamics simulation approaches with COX-2 and TNF-α inhibitors ability against the most potent phytocompound phytol from the plant extract. To evaluate whether the extract causes any toxicity, the cytotoxicity test has been carried out with the Human embryonic kidney cell line (Hek-293), Mouse fibroblast (L929), human mesenchyme stem cells (hMSCs) and human breast epithelial cell line (MCF-10a). Ultimately, our findings suggest that the plant extract have great potential to reduce inflammation without causing any toxicity to normal cell.Communicated by Ramaswamy H. Sarma.

We report here the hydroboration of nitriles, alkynes, and carboxylic acids using amidophosphine boranes {(BH 3 )(PPh 2 )-NC(CH 3 ) 3 }, {(BH 3 ) 2 (PPh) 2 N(CH 2 )C 6 H 5 }, and {(BH 3 ) 2 (PPh 2 ) 2 N-(BH 3 )CH 2 C 6 H 4 N} as reducing agents. These compounds were synthesized to replace more commonly used borane reagents. Solid amidophosphine boranes, which were synthesized with ease, demonstrated excellent reactivity and functional group tolerance toward a wide variety of nitriles, alkynes, and carboxylic acids, affording the corresponding ammonium salts, alkenes, and alcohols in good yield.

We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔG binding of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔG binding -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC 50 concentration) ranges between 4.04 and 33.93 μM against breast cancer cells without affecting normal cells (IC 50 value > 952 μM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The cyanobacteria are the promising candidate for synthesizing gold nanoparticles (AuNPs), due to their ability to accumulate heavy metals from the cellular environment and additionally contain varied bioactive compounds as reducing and stabilizing agents. This study describes the N 2 -fixing cyanobacterium Nostoc calcicola-mediated bioreduction of AuNPs and the inherent antimicrobial, antioxidant, and antiproliferative activities in vitro. Biosynthesized Nc-AuNPs were characterized by spectral characterization techniques. The formation of AuNPs was physically confirmed by the colour change from pale green to dark violet. The UV-Vis analysis, further, proved the reduction in Nc-AuNPs with the cyanobacterium and showed a spectral peak at 527 nm. FESEM-EDX images suggested the surface morphology of the NPs as spherical, cuboidal, and size between 20 and 140 nm. The antimicrobial studies of Nc-AuNPs were carried out by agar-well diffusion method and MIC values against five pathogenic bacterial and two fungal strains were noted. The AuNPs exhibited potential antimicrobial activity against h-pathogenic bacteria with inhibitory zones ranging at 11-18 mm; against fungi ranging at 13-17 mm. Significant antioxidant potentialities were explored by a DPPH assay with an IC 50 value of 55.97 μg/ mL. Furthermore, in the anticancer efficacy assay, the Nc-AuNPs inhibited cellular proliferation in human breast adenocarcinoma and cervical cancer cell lines at IC 50 concentration, 37.3 μg/ml, and 44.5 μg/ml, respectively. Conclusively, N. calcicola would be an excellent source for synthesizing stable colloidal AuNPs that had significant credibility as phycological (algal) nanomedicines as novel prodrugs with multiple bioactivities., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: SARS-CoV-2 is a deadly viral disease and uncounted deaths occurs since its first appearance in the year 2019. The antiviral drugs, benzylisoquinoline alkaloids, and coumarin molecules were searched using different online engines for drug repurposing with SARS-CoV-2 and to investigate the effects on main viral protease (Mpro) upon their bindings., Methods: A database composed of antiviral drugs, benzylisoquinoline alkaloids, and Coumarin molecules was screened through a molecular docking strategy to uncover the interactions of collected molecules with SARS-CoV-2 Mpro. Further, molecular dynamics simulations (MDS) were implemented for 100 ns to calculate the stability of the best complexed molecular scaffold with Mpro. The conformations of the simulated complexes were investigated by using principal component analysis (PCA) and Gibbs energy landscape (FEL) and DSSP together. Next, free binding energy (ΔG bind ) was calculated using the mmpbsa method., Results: Molecular docking simulations demonstrate 17 molecules exhibited better binding affinity out of 99 molecules present in the database with the viral protease Mpro, followed ADMET properties and were documented. The Coumarin-EM04 molecular scaffold exhibited interactions with catalytical dyad HIS41, CYS145, and neighboring amino acids SER165 and GLN189 in the catalytical site. The crucial factor RMSD was calculated to determine the orientations of Coumarin-EM04. The Coumarin-EM04 complexed with Mpro was found stable in the binding site during MDS. Furthermore, the free energy binding ΔG bind of Coumarin-EM04 was found to be -187.471 ± 2.230 kJ/mol, and for Remdesivir ΔG bind was -171.926 ± 2.237 kJ/mol with SARS-CoV-2 Mpro ., Conclusion: In this study, we identify potent molecules that exhibit interactions with catalytical dyad HIS41 and CYS145 amino acids and unravel Coumarin-EM04 exhibited ΔG bind higher than Remdesivir against Mpro and thus may serve better antiviral agent against SARS-CoV-2., Competing Interests: All authors declare no conflict of interest., (© 2023 The Authors. Published by Elsevier B.V.)

Epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) plays a pivotal role in cellular signaling, growth, and metabolism. The EGFR-TKD is highly expressed in cancer cells and was endorsed as a therapeutic target for cancer management to overcome metastasis, cell proliferation, and angiogenesis. The novel thiazolo-[2,3-b]quinazolinones series were strategically developed by microwave-assisted organic synthesis and multi dominos reactions aimed to identify the potent thiazolo-[2,3-b]quinazolinone inhibitor against EGFR-TKD. This study explores the binding stability and binding strength of newly developed series via molecular docking, molecular dynamics simulation, and MM/PBSA and MM/GBSA calculations. The binding interaction was observed to be through the functional groups on aryl substituents at positions 3 and 5 of the thiazolo-[2, 3-b]quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions corroborating their bindings similar to the reference FDA-approved drug erlotinib in the active site. ADMET predictions reveal that derivatives 5ab, 5aq, and 5bq are drug-like and may be effective in in vitro study. Molecular dynamics simulation for 100 ns of docked complexes revealed their stability at the atomistic level. The ΔGbinding of thiazolo-[2,3-b]quinazolinone was found to be 5ab - 22.45, 5aq - 22.23, and 5bq - 20.76 similar to standard drug, and erlotinib - 24.11 kcal/mol was determined by MM/GBSA method. Furthermore, the anti-proliferative activity of leads of thiazolo-[2,3-b]quinazolinones (n = 3) was studied against breast cancer cell line (MCF-7) and non-small lung carcinoma cell line (H-1299). The highest inhibitions in cell proliferation were shown by 5bq derivatives, and the IC 50 was found to be 6.5 ± 0.67 µM against MCF-7 and 14.8 µM against H-1299. The noscapine was also taken as a positive control and showed IC 50 at higher concentrations 37 ± 1 against MCF-7 and 46.5 ± 1.2 against H-1299., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We present a series of 9-arylimino derivatives of noscapine (an antitussive plant alkaloid) that binds to tubulin and displaying anticancer activity against a panel of breast cancer cells. These compounds were rationally designed by coupling of Schiff base containing imine groups at position-9 of the isoquinoline ring of noscapine. Based on a combination of Glide docking and free energy of binding (FEB) calculation, we have screened a panel of three 9-compounds, 12-14 with improved binding affinity with tubulin compared to noscapine. The predicted FEB is -6.166 kcal/mol for 12 , -6.411 kcal/mol for 13 and -7.512 kcal/mol for 14 . In contrast, the predicted FRB of noscapine is -5.135 kcal/mol. These novel derivatives were strategically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast tumor cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.6 and 26.4 µM, which is 11.02-2.03 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrest cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrest the cell cycle in the G2/M-phase and induced apoptosis. Thus, we conclude that 9-arylimino derivatives of noscapine have great potential to be a novel therapeutic agent for breast cancers.Communicated by Ramaswamy H. Sarma.

Neurological complications following aortic surgery are most often cerebrovascular accidents due to embolism, or spinal infarcts resulting in hemiparesis or hemiplegia. Guillain-Barre syndrome is a rare cause of quadriparesis. Here, we report a 49-year old male who presented with acute aortic dissection and underwent the Bentall procedure following which he developed quadriparesis, subsequently diagnosed to be a case of Guillain-Barre syndrome. He was successfully treated with intravenous immunoglobulin., Competing Interests: The authors declare no conflict of interest related to this article., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

We developed 1,3-diynyl derivatives of noscapine (an opium alkaloid) through in silico combinatorial approach and screened out a panel of promising derivatives that bind tubulin and display anticancer activity. The selected derivatives such as 9-4- t Bu-Ph-Diyne (20p) , 9-3,4-Di-Cl-Diyne (20k) and 9-3,4-Di-F-Diyne (22s) noscapinoids revealed improved predicted binding energy of -6.676 kcal/mol for 20p , -7.294 kcal/mol for 20k and -7.750 kcal/mol for 20s respectively in comparison to noscapine (-5.246 kcal/mol). These 1,3-diynyl derivatives (20p, 29k and 20s) were strategically synthesized in high yields by regioselective modification of noscapine scaffold and HPLC purified (purity is >96%). The decrease in intrinsic fluorescence of purified tubulin to 8.39%, 17.39% and 25.47% by 20p, 20k and 20s respectively, compared to control suggests their binding capability to tubulin. Their cytotoxicity activity was validated based on cellular studies using two human breast adenocarcinoma (MCF-7 and MDA-MB-231), a panel of primary breast tumor cells and one normal human embryonic kidney cell (293 T). The 1,3-diynyl noscapinoids, 20p, 20k and 20s inhibited cellular proliferation in all the cancer cells that ranged between 6.2 and 38.9 µM, without affecting the normal healthy cells (cytotoxicity is <5% at 100 µM). Further, these novel derivatives arrest cell cycle in the G2/M-phase, followed by induction of apoptosis to cancer cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.Communicated by Ramaswamy H. Sarma.

The scaffold structure of noscapine (an antitussive plant alkaloid) was modified by inducting N-aryl methyl pharmacophore at C-9 position of the isoquinoline ring to rationally design and screened three novel 9-(N-arylmethylamino) noscapinoids, 15-17 with robust binding affinity with tubulin. The selected 9-(N-arylmethylamino) noscapinoids revealed improved predicted binding energy of -6.694 kcal/mol for 15, -7.118 kcal/mol for 16 and -7.732 kcal/mol for 17, respectively in comparison to the lead molecule (-5.135 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDA-MB-231, as well as with a panel of primary breast tumor cells. These derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.2 and 32.2 μM, which is 11.9 to 1.8 fold lower than that of noscapine. These novel derivatives effectively arrest the cell cycle in the G2/M phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 9-(N-arylmethyl amino) noscapinoids, 15-17 have a high probability to be a novel therapeutic agent for breast cancers., (© 2021 John Wiley & Sons A/S.)

We present a new class of derivatives of noscapine, 1,3-diynyl-noscapinoids of an antitussive plant alkaloid, noscapine based on our in silico efforts that binds tubulin and displays anticancer activity against a panel of breast cancer cells. Structure-activity analyses pointed the C-9 position of the isoquinoline ring which was modified by coupling of 1,3-diynyl structural motifs to rationally design and screened a series of novel 1,3-diynyl-noscapinoids (20-22) with robust binding affinity with tubulin. The selected 1,3-diynyl-noscapinoids, 20-22 revealed improved predicted binding energy of -6.568 kcal/mol for 20, -7.367 kcal/mol for 21 and -7.922 kcal/mol for 22, respectively in comparison to the lead molecule (-5.246 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast cancer cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 6.2 to 38.9 μM, which is 6.7 to 1.5 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrests cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrests cell cycle in the G2/M-phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A library of 9-arylimino derivatives of noscapine was developed by coupling of Schiff base containing imine groups. Virtual screening using molecular docking with tubulin revealed three molecules, 12-14 that bind with high affinity. An improved predicted free energy of binding (FEB) of -5.390, -6.506 and -6.679 kcal/mol for the molecules 12-14 was found compared to noscapine (-5.135 kcal/mol). Furthermore, molecular dynamics simulation in combination with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) revealed robust binding free energy of -166.03, -169.75 and -170.63 kcal/mol for the molecules 12, 13 and 14, respectively. These derivatives were strategically synthesized and experimentally validated for their anticancer activity. Tubulin binding assay revealed substantial binding of molecules 12-14 with purified tubulin. Further, their anticancer activity was demonstrated using two cancer cell lines (MCF-7 and MDAMB-231) and a panel of primary breast tumour cells. All these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 30.1 and 5.8 µM, which is 1.7 to 7.52 fold lower than that of noscapine. Further, these novel derivatives arrest cell cycle in the G2/M-phase followed by induction of apoptosis. Thus, 9-arylimino noscapinoids 12-14 have a great potential to be a novel therapeutic agent for breast cancers.

Adrenoleukodystrophy classically presents in childhood with bronze skin, spastic tetraparesis, dysphagia, behavioural abnormalities and adrenal insufficiency. However, atypical presentations are known. Here we report an adolescent with adrenoleukodystrophy who first sought medical attention for glue sniffing., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumor progression. Synthetic derivatives of anti-cancer compound, noscapine (an opium alkaloid) such as Cl-noscapine, Br-noscapine and Folate-noscapine along with two of the reference compounds, TNP-470 and paclitaxel were examined for anti-angiogenic activities by using human umbilical vein endothelial cells (HUVECs). The noscapine derivatives showed anti-angiogenic activity albeit at high concentration compared to the reference compounds. All the tested compounds inhibited angiogenesis in a dose-dependent manner; the drug concentration causing 50% inhibition of cell survival was 11.87 μM for Cl-noscapine, 6.9 μM for Br-noscapine and 6.79 μM for folate-noscapine. Besides, all the noscapine derivatives significantly inhibited cord formation (IC50 for Cl-noscapine is 50.76 μM, for Br-noscapine is 90.08 μM and for folate-noscapine is 18.44 μM) as well as migration and invasion (IC50 value of Cl-noscapine is 28.01 μM, for Br-noscapine is 19.78 μM and for folate-noscapine is 10.76 μM) of endothelial cells. Based on these results, we speculated that the inhibitory effects on human endothelial cell proliferation of noscapine derivatives might be important for anti-angiogenesis.

Introduction: Follicular carcinoma of thyroid usually behaves in an indolent manner with low metastatic potential. Distant metastases as initial presentation is rare in follicular carcinoma; especially in young patients., Presentation of Case: We report the clinical, pathological features and the management of three different cases of follicular carcinoma of the thyroid with unusual presentations at the time of diagnosis. First case presented as thyroid abscess, second case with a large skull swelling in a pre-exiting goiter and the third case with a swelling in the sternum., Discussion: Follicular carcinoma of thyroid is the second category of well-differentiated thyroid cancer that constitutes about 10% of all thyroid malignancies. Blood borne metastasis is common with spread to lung, bone and other solid organs. In less than 10% cases of follicular carcinoma, there is evidence of lymphatic involvement. The patients' presentations above are highly unusual., Conclusion: Recognizing these cases has a significant impact on clinical decision-making and prognosis of the patients. Treatment in these patients should be individualized and an alternative therapeutic approach should be considered., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)