Publications by authors named "Uttam Pal"

45 Publications

In-vitro and microbiological assay of functionalized nano-hybrids to validate their differential efficacy in nano-theranostics: A combined spectroscopic and computational study.

ChemMedChem 2021 Sep 22. Epub 2021 Sep 22.

SNBNCBS, CBMS, Block JD, Sector III, Salt Lake City, 700098, Kolkata, INDIA.

Functionalized nanoparticles (NPs) reveal new frontiers in simultaneous therapeutics and diagnostics, often termed as theranostics. Functionalization of an inorganic nanoparticle with an organic ligand typically predominates its interaction with various cellular components, which eventually leads to the therapeutic outcome diminishing the adverse side effects. Other physical properties of the organic-inorganic complex (nanohybrid) including fluorescence, x-ray or MRI contrast offer diagnosis of anomalous target cells. Here, we have functionalized Mn 3 O 4 nanoparticles with organic ligands citrate (C-Mn 3 O 4 ) and folic acid (FA-Mn 3 O 4 ) and investigated their differential antimicrobial activities using Staphylococcus hominis as a model bacteria. The results suggest that the FA-Mn 3 O 4 NPs were able to kill S. hominis more efficiently through membrane rupture. We have used high end density functional theory (DFT) calculation to rationalize the distinctive specificity of the drug actions of the functionalized-NPs. FRET studies confirmed the enhanced affinity of FA-Mn 3 O 4 towards the bacteria compared to C-Mn 3 O 4 , which leads to the enhanced anti-microbial activity for FA-Mn 3 O 4 . We have further shown that the functionalized NPs offer significant x-ray contrast in in-vitro studies. Cumulatively the results indicate that the FA-Mn 3 O 4 NPs could be a potential theranostic agent against bacterial infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.202100494DOI Listing
September 2021

Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.

PLoS One 2021 10;16(9):e0257206. Epub 2021 Sep 10.

Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India.

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432871PMC
September 2021

Are Clinicians Responsible for the Development of Antibiotic Resistance at a Tertiary Health Care Hospital? A Qualitative Study from Outlook of Doctors.

Indian J Community Med 2021 Apr-Jun;46(2):336-337. Epub 2021 May 29.

Department of Urology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijcm.IJCM_286_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281841PMC
May 2021

Thermo-optic measurements and their inter-dependencies for delineating cancerous breast biopsy tissue from adjacent normal.

J Biophotonics 2021 Aug 31;14(8):e202100041. Epub 2021 May 31.

Department of Electronic Systems Engineering, The Indian Institute of Science, Bengaluru, India.

The histopathological diagnosis of cancer is the current gold standard to differentiate normal from cancerous tissues. We propose a portable platform prototype to characterize the tissue's thermal and optical properties, and their inter-dependencies to potentially aid the pathologist in making an informed decision. The measurements were performed on 10 samples from five subjects, where the cancerous and adjacent normal were extracted from the same patient. It was observed that thermal conductivity (k) and reduced-scattering-coefficient (μ' ) for both the cancerous and normal tissues reduced with the rise in tissue temperature. Comparing cancerous and adjacent normal tissue, the difference in k and μ' (at 940 nm) were statistically significant (p = 7.94e-3), while combining k and μ' achieved the highest statistical significance (6.74e-4). These preliminary results promise and support testing on a large number of samples for rapidly differentiating cancerous from adjacent normal tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbio.202100041DOI Listing
August 2021

Hybrid Spectral-IRDx: Near-IR and Ultrasound Attenuation System for Differentiating Breast Cancer from Adjacent Normal Tissue.

IEEE Trans Biomed Eng 2021 May 4;PP. Epub 2021 May 4.

Objective: While performing surgical excision for breast cancer (lumpectomy), it is important to ensure a clear margin of normal tissue around the cancer to achieve complete resection. The current standard is histopathology; however, it is time-consuming and labour-intensive requiring skilled personnel.

Method: We describe a Hybrid Spectral-IRDx - a combination of the previously reported Spectral-IRDx tool with multimodal ultrasound and NIR spectroscopy techniques. We show how this portable, cost-effective, minimal-contact tool could provide rapid diagnosis of cancer using formalin-fixed (FF) and deparaffinized (DP) breast biopsy tissues.

Results: Using this new tool, measurements were performed on cancerous/fibroadenoma and its adjacent normal tissues from the same patients (N=14). The acoustic attenuation coefficient () and reduced scattering coefficient (s) (at 850, 940, and 1060 nm) for the cancerous/fibroadenoma tissues were reported to be higher compared to adjacent normal tissues, a basis of delineation. Comparing FF cancerous and adjacent normal tissue, the difference in s at 850 nm and 940 nm were statistically significant (p=3.17e-2 and 7.94e-3 respectively). The difference in between the cancerous and adjacent normal tissues for DP and FF tissues were also statistically significant (p=2.85e-2 and 7.94e-3 respectively). Combining multimodal parameters and s (at 940 nm) show highest statistical significance (p=6.72e-4) between FF cancerous/fibroadenoma and adjacent normal tissues.

Conclusion: We show that Hybrid Spectral-IRDx can accurately delineate between cancerous and adjacent normal breast biopsy tissue.

Significance: The results obtained establish the proof-of-principle and large-scale testing of this multimodal breast cancer diagnostic platform for core biopsy diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TBME.2021.3077582DOI Listing
May 2021

Host assisted molecular recognition by human serum albumin: Study of molecular recognition controlled protein/drug mimic binding in a microfluidic channel.

Int J Biol Macromol 2021 Apr 4;176:137-144. Epub 2021 Feb 4.

Department of Chemical, Biological & Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata 700106, India. Electronic address:

Human serum albumin (HSA) plays a pivotal role in drug release from its delivery vehicles such as cyclodextrins (CDs) by binding to the drugs. Here molecular recognition and binding of a drug mimic (CD1) to HSA have been explored in a microfluidic channel when CD1 is encapsulated in β-cyclodextrin (βCD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB), respectively, to investigate whether change of the host vehicle modulate the rate of drug binding to the serum protein. Molecular recognition of βCD encapsulated CD1 by HSA occurs by the conformational selection fit mechanism leading to rapid binding of CD1 to HSA (k ~ 700 s) when the βCD/CD1 complex interacts with HSA. In contrary, HSA recognizes CD1 encapsulated in TRIMEB by an induced fit mechanism leading to a significantly slower binding rate (k ~ 20.8 s) of the drug mimic to the protein. Thus molecular recognition controls the rate of HSA binding by CD1 which in turn modulates the rate of delivery of the drug mimic from its macrocyclic hosts. The remarkable change in the molecular recognition pathway of CD1 by HSA, upon change of the host from βCD to TRIMEB, originates from significantly different conformational flexibility of the host/drug mimic complexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2021.02.002DOI Listing
April 2021

Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model.

Adv Healthc Mater 2021 04 16;10(7):e2001736. Epub 2020 Dec 16.

Department of Chemical, Biological and Macromolecular Sciences, S. N. Bose National Centre for Basic Sciences, Block JD, Sector 3, Salt Lake, Kolkata, 700106, India.

The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, it is shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn O NP) efficiently mimics glutathione peroxidase (GPx) enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H O scavenging. A detailed computational study reveals the mechanism of the nanozyme action. The in vivo therapeutic efficacy of C-Mn O nanozyme is further established in a preclinical animal model of Huntington's disease (HD), a prevalent progressive neurodegenerative disorder, which has no effective medication to date. Management of HD in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202001736DOI Listing
April 2021

The Role of Imidazolium-Based Surface-Active Ionic Liquid to Restrain the Excited-State Intramolecular H-Atom Transfer Dynamics of Medicinal Pigment Curcumin: A Theoretical and Experimental Approach.

ACS Omega 2020 Oct 1;5(40):25582-25592. Epub 2020 Oct 1.

Department of Chemistry, University of Delhi, Delhi 110007, India.

The naturally occurring polyphenolic compound curcumin has shown various medicinal and therapeutic effects. However, there are various challenges associated with curcumin, which limits its biomedical applications, such as its high degradation rate and low aqueous solubility at neutral and alkaline pH. In the present study, efforts have been directed towards trying to resolve such issues by encapsulating curcumin inside the micelles formed by imidazolium-based surface-active ionic liquid (SAIL). The shape and size of the micelles formed by the SAIL have been characterized by using DLS analysis as well as TEM measurements. The photo-physics of curcumin in the presence of ionic liquid (IL) and also with the addition of salt (NaCl) has been explored by using different optical spectroscopic tools. The time-dependent absorption studies have shown that there is relatively higher suppression in the degradation rate of curcumin after encapsulation by the imidazolium-based SAIL in an aqueous medium. The TCSPC studies have revealed that there is deactivation in the nonradiative intramolecular hydrogen transfer process of curcumin in the presence of IL micelles as well as with the addition of salt. Furthermore, the time-dependent fluorescence anisotropy measurement has been carried out to figure out the location of curcumin inside the micellar system. In order to correlate all experimental findings, density functional theory (DFT) and classical molecular dynamics (MD) simulations at neutral pH media have been performed. It has been found that the van der Waals force of interactions plays a major role in the stabilization of curcumin in the micelles rather than the coulombic forces. It also has been observed that the van der Waals interactions remain unaffected in the presence of salt. However, as revealed by the MD simulation results, the micelles are found to be more compact in size after the addition of salt. The RMSD results show that the micelles formed by the SAIL achieve greater stability after a particular time constraint. Our results have divulged that the SAIL could act as a promising drug delivery system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.0c02438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557247PMC
October 2020

Unprecedented Regio- and Stereoselective Synthesis of Pyrene-Grafted Dispiro[indoline-3,2'-pyrrolidine-3',3″-indolines]: Expedient Experimental and Theoretical Insights into Polar [3 + 2] Cycloaddition.

ACS Omega 2020 Sep 14;5(37):24081-24094. Epub 2020 Sep 14.

Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, 21955 Makkah, Saudi Arabia.

A series of dispiro[indoline-3,2'-pyrrolidine-3',3″-indolines] was synthesized via a multicomponent polar [3 + 2] cycloaddition (32CA) reaction of isatin derivatives, sarcosine and ()-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives. The regio- and stereochemistries of the cycloadducts were established on the basis of one-dimensional (1D) (H-, C-, C-CRAPT NMR) and two-dimensional (2D) homonuclear and heteronuclear correlation NMR spectrometry experiments (H-H gDQFCOSY, C-H-HSQCAD, C-H-HMBCAD, H-H-ROESYAD). The molecular mechanism and regio- and stereoselectivities of the cycloaddition (CA) reaction have been investigated utilizing a density functional theory (DFT) method and were thoroughly explained based on the transition-state stabilities and global/local electrophilicity/nucleophilicity reactivity indices of the reactants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.0c03510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513337PMC
September 2020

Biophysical and theoretical studies of the interaction between a bioactive compound 3,5-dimethoxy-4-hydroxycinnamic acid with calf thymus DNA.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Jan 11;245:118936. Epub 2020 Sep 11.

Department of Chemistry, Presidency University, 86/1 College Street, Kolkata, West Bengal, India. Electronic address:

3,5-Dimethoxy-4-hydroxycinnamic acid commonly known as Sinapic acid is a well-known derivative of hydroxycinnamic acids, is commonly present in human diet. Due to its wide variety of pharmacological activities like antioxidant, antimicrobial, anti-inflammatory, anticancer, and anti-anxiety, it has attracted much attention for the researchers. In our previous published work we have already analyzed the interaction between sinapic acid (SA) with a model transport protein. In this work our aim is to demonstrate a detailed investigation of the binding interaction between sinapic acid with another carrier of genetic information in a living cell, the DNA. Here we have used calf thymus DNA (ct-DNA) as a model. The binding characteristic of SA with ct-DNA was investigated by different spectroscopic and theoretical tools. The spectroscopic investigation revealed that quenching of intrinsic fluorescence of SA by ct-DNA occurs through dynamic quenching mechanism. The thermodynamic parameters established the involvement of hydrogen bonding and weak van der Waals forces in the interaction. Further, the circular dichroism, competitive binding experiment with ethidium bromide and potassium iodide quenching experiment suggested that SA possibly binds to the groove position of the ct-DNA. Finally, molecular docking analysis established the SA binds to minor groove position of ct-DNA in G-C rich region through hydrogen bonding interaction. Additionally, gel electrophoresis analysis has been performed to determine the protective efficacy of SA against UVB induced DNA damage and 50 μM of SA was found to protect the DNA from UVB induced damage. We hope that our study could provide the validation of SA on behalf of therapeutics and development of next generation therapeutic drug as well as designing new efficient drug molecule and methodology for the interaction study of the drug with DNA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.saa.2020.118936DOI Listing
January 2021

Towards a Portable Platform Integrated With Multispectral Noncontact Probes for Delineating Normal and Breast Cancer Tissue Based on Near-Infrared Spectroscopy.

IEEE Trans Biomed Circuits Syst 2020 08 30;14(4):879-888. Epub 2020 Jun 30.

Currently, the confirmation of diagnosis of breast cancer is made by microscopic examination of an ultra-thin slice of a needle biopsy specimen. This slice is conventionally formalin-fixed and stained with hematoxylin-eosin and visually examined under a light microscope. This process is labor-intensive and requires highly skilled doctors (pathologists). In this paper, we report a novel tool based on near-infrared spectroscopy (Spectral-IRDx) which is a portable, non-contact, and cost-effective system and could provide a rapid and accurate diagnosis of cancer. The Spectral-IRDx tool performs absorption spectroscopy at near-infrared (NIR) wavelengths of 850, 935, and 1060 nm. We measure normalized detected voltage (V) with the tool in 10 deparaffinized breast biopsy tissue samples, 5 of which were cancer (C) and 5 were normal (N) tissues. The difference in V at 935 nm and 1060 nm between cancer and normal tissues is statistically significant with p-values of 0.0038 and 0.0022 respectively. Absorption contrast factor (N/C) of 1.303, 1.551, and 1.45 are observed for 850, 935, and 1060 nm respectively. The volume fraction contrast (N/C) of lipids and collagens are reported as 1.28 and 1.10 respectively. Higher absorption contrast factor (N/C) and volume fraction contrast (N/C) signifies higher concentration of lipids in normal tissues as compared to cancerous tissues, a basis for delineation. These preliminary results support the envisioned concept for noninvasive and noncarcinogenic NIR-based breast cancer diagnostic platform, which will be tested using a larger number of samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TBCAS.2020.3005971DOI Listing
August 2020

Flexibility modulates the catalytic activity of a thermostable enzyme: key information from optical spectroscopy and molecular dynamics simulation.

Soft Matter 2020 Mar 5;16(12):3050-3062. Epub 2020 Mar 5.

Department of Microbiology, St. Xavier's College, 30, Mother Teresa Sarani, Kolkata 700016, India.

Enzymes are dynamical macromolecules and their conformation can be altered via local fluctuations of side chains, large scale loop and even domain motions which are intimately linked to their function. Herein, we have addressed the role of dynamic flexibility in the catalytic activity of a thermostable enzyme almond beta-glucosidase (BGL). Optical spectroscopy and classical molecular dynamics (MD) simulation were employed to study the thermal stability, catalytic activity and dynamical flexibility of the enzyme. An enzyme assay reveals high thermal stability and optimum catalytic activity at 333 K. Polarization-gated fluorescence anisotropy measurements employing 8-anilino-1-napthelenesulfonic acid (ANS) have indicated increasing flexibility of the enzyme with an increase in temperature. A study of the atomic 3D structure of the enzyme shows the presence of four loop regions (LRs) strategically placed over the catalytic barrel as a lid. MD simulations have indicated that the flexibility of BGL increases concurrently with temperature through different fluctuating characteristics of the enzyme's LRs. Principal Component Analysis (PCA) and the Steered Molecular Dynamics (SMD) simulation manifest the gatekeeper role of the four LRs through their dynamic fluctuations surrounding the active site which controls the catalytic activity of BGL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9sm02479dDOI Listing
March 2020

Probing the Hydrogen Bond Involving Acridone Trapped in a Hydrophobic Biological Nanocavity: Integrated Spectroscopic and Docking Analyses.

Langmuir 2020 02 3;36(5):1241-1251. Epub 2020 Feb 3.

Chemical Sciences Division , Saha Institute of Nuclear Physics , 1/AF Bidhannagar , Kolkata 700064 , India.

Spectroscopic analyses reveal that acridone (AD) penetrates through the structure and enters the hydrophobic cavity of the protein β-lactoglobulin (βLG). Although the protein contains two tryptophan (Trp) residues, AD interacts with only one (Trp-19), which is authenticated by the appearance of a single isoemissive point in TRANES. Alteration in the secondary structure of the protein while AD pierces through βLG is evident from the circular dichroism spectroscopic study. The ground-state interaction between AD and βLG is proven from the UV-vis spectroscopic study and the static nature of quenching of intrinsic fluorescence of the protein by the ligand. The steady-state fluorescence study in varied temperatures indicates the involvement of hydrogen bonding in the ligand-protein interaction. Further, the time-resolved fluorescence anisotropy study gives a hint of the presence of a hydrogen bond in AD-βLG interaction, which possibly involves the rotamers of Trp-19. In fact, the idea of involvement of rotamers of Trp-19 is obtained from the increase in fluorescence lifetime of βLG in the presence of AD. The docking study agrees to the involvement of hydrogen bonding in AD-βLG interaction. The direct evidence of hydrogen bonding between Trp and AD is obtained from the laser flash photolysis studies where the signature of formation of ADH and Trp through hydrogen abstraction between Trp and AD, loosely bound through hydrogen bonding, gets prominence. Thus, binding of AD to βLG involves hydrogen bonding in a hydrophobic pocket of the protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.9b03506DOI Listing
February 2020

Order, Disorder, and Reorder State of Lysozyme: Aggregation Mechanism by Raman Spectroscopy.

J Phys Chem B 2020 01 27;124(1):50-60. Epub 2019 Dec 27.

Structural Biology and Bioinformatics Division , Indian Institute of Chemical Biology, Council of Scientific and Industrial Research , 4, Raja S.C. Mullick Road , Kolkata 700032 , India.

Lysozyme, like many other well-folded globular proteins, under stressful conditions produces nanoscale oligomer assembly and amyloid-like fibrillar aggregates. With engaging Raman microscopy, we made a critical structural analysis of oligomer and other assembly structures of lysozyme obtained from hen egg white and provided a quantitative estimation of a protein secondary structure in different states of its fibrillation. A strong amide I Raman band at 1660 cm and a N-Cα-C stretching band at ∼930 cm clearly indicated the presence of a substantial amount of α-helical folds of the protein in its oligomeric assembly state. In addition, analysis of the amide III region and Raman difference spectra suggested an ample presence of a PPII-like secondary structure in these oligomers without causing major loss of α-helical folds, which is found in the case of monomeric samples. Circular dichroism study also revealed the presence of typical α-helical folds in the oligomeric state. Nonetheless, most of the Raman bands associated with aromatic residues and disulfide (-S-S-) linkages broadened in the oligomeric state and indicated a collapse in the tertiary structure. In the fibrillar state of assembly, the amide I band became much sharper and enriched with the β-sheet secondary structure. Also, the disulfide bond vibration in matured fibrils became much weaker compared to monomer and oligomers and thus confirmed certain loss/cleavage of this bond during fibrillation. The Raman band of tryptophan and tyrosine residues indicated that some of these residues experienced a greater hydrophobic microenvironment in the fibrillar state than the protein in the oligomeric state of the assembly structure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpcb.9b09139DOI Listing
January 2020

Multi-spectroscopic and computational evaluation on the binding of sinapic acid and its Cu(II) complex with bovine serum albumin.

Food Chem 2019 Dec 30;301:125254. Epub 2019 Jul 30.

Department of Chemistry, Presidency University, 86/1 College Street, Kolkata 700073, India. Electronic address:

Researches based on metal complexes of plant-derived phenolic acids have attracted much attention due to their beneficial applications in the development of functional food products, dietary supplements and pharmacology. Binding of phenolic acids with serum proteins greatly influences their pharmacological properties. In this context, interactions of a naturally occurring phenolic acid, sinapic acid (SA) and its Cu complex with a model transport protein, bovine serum albumin (BSA), have been explored by means of different spectroscopic and theoretical tools. Spectroscopic studies revealed that the interaction of SA and its Cu complex with BSA occurred through quenching of intrinsic fluorescence of BSA. Site-specific experimental and docking studies were performed to predict the binding site. The geometies of bound Cu and interacting residues of protein were predicted from a solution dynamics study. Interestingly, the complexation of SA with Cu enhanced the antioxidant activity of SA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.foodchem.2019.125254DOI Listing
December 2019

Preferential photochemical interaction of Ru (III) doped carbon nano dots with bovine serum albumin over human serum albumin.

Int J Biol Macromol 2019 Sep 29;137:483-494. Epub 2019 Jun 29.

Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India. Electronic address:

The excitation wavelength dependent emission of carbon nano dots (CNDs) restricts their use in photophysical studies. However, instead of bare CNDs, the amine coated Ru (III) doped CNDs (Ru:CNDEDAs) are quite eligible to generate excitation wavelength independent fluorescence with high quantum yield. Herein, we report a detailed study on the photochemical interaction between two different serum albumins, bovine serum albumin (BSA) and human serum albumin (HSA), with Ru:CNDEDAs synthesized in our laboratory, using steady-state and time-resolved spectroscopic techniques. Absorption study reveals the formation of ground state complex between Ru:CNDEDAs and BSA/HSA while the circular dichroism study implies that Ru:CNDEDAs perturbs the secondary structure of the albumin proteins. Steady-state fluorescence study helps in understanding energy transfer from tryptophan, the fluorophore moiety of BSA and HSA, to Ru:CNDEDAs. Time-resolved studies within nanosecond time domain clarify the phenomenon of energy transfer from BSA/HSA to Ru:CNDEDAs with varied efficiency. Molecular dynamic simulation ascertains that the efficiency of energy transfer is highly dependent on the stability of protein-nanoparticle complex. This study provides a qualitative description regarding the structural rigidity of transport protein, BSA compared to HSA, which determines the transport ability of CNDs to deliver the desired drug molecule to the targeted cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2019.06.126DOI Listing
September 2019

Encapsulation of Thymol in cyclodextrin nano-cavities: A multi spectroscopic and theoretical study.

Spectrochim Acta A Mol Biomol Spectrosc 2019 Feb 12;208:339-348. Epub 2018 Oct 12.

Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700 009, India.

Cyclodextrins have a wide range of applications in different areas of drug delivery and pharmaceutical industry due to their complexation ability and other versatile characteristics. Here we have studied the binding interactions of a small biologically important phenolic molecule, Thymol (Th), with both α and β cyclodextrins (CDs), which are well known drug delivery vehicles. Extent of encapsulation has been determined using several spectroscopic techniques. In fluorescence experiments, significant increase in fluorescence intensities have been discerned for both the CDs but there had been a much early saturation for αCD. Anisotropy experiments have been performed too and very surprisingly no appreciable increase in anisotropy value was observed in either case. Isothermal titration calorimetry (ITC) data, however, show signature of binding of Th with the βCD. These intriguing results were explained with the help of molecular docking and dynamics simulation studies. The docking calculations have shown that Th goes inside both α and βCD. In keeping with the final NMR data and molecular dynamics we have ultimately concluded that solvated Th molecules are the main participants in the interaction with CDs which is responsible for these intriguing behaviors. Finally we have also performed an antioxidant assay to reveal the practical application of such encapsulation. It has been found that on encapsulation there is an enhancement of the antioxidant behavior of Th. Then we have also performed an antibacterial assay to show the unchanged antibacterial properties of Th on encapsulation. Hence it can be deduced that Th can be safely delivered through CDs in living system without hampering its beneficial properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.saa.2018.10.011DOI Listing
February 2019

Structural Insight of Amyloidogenic Intermediates of Human Insulin.

ACS Omega 2018 Feb;3(2):2452-2462

Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4, Raja S.C. Mullick Road, Kolkata 700032, India.

Engaging Raman spectroscopy as a primary tool, we investigated the early events of insulin fibrilization and determined the structural content present in oligomer and protofibrils that are formed as intermediates in the fibril formation pathway. Insulin oligomer, as obtained upon incubation of zinc-free insulin at 60 °C, was mostly spherical in shape, with a diameter of 3-5 nm. Longer incubation produced "necklace"-like beaded protofibrillar assembly species. These intermediates eventually transformed into 5-8 nm thick fibers with smooth surface texture. A broad amide I band in the Raman spectrum of insulin monomer appeared at 1659 cm, with a shoulder band at 1676 cm. This signature suggested the presence of major helical and extended secondary structure of the protein backbone. In the oligomeric state, the protein maintained its helical imprint (∼50%) and no substantial increment of the compact cross-β-sheet structure was observed. A nonamide helix signature band at 940 cm was present in the oligomeric state, and it was weakened in the fibrillar structure. The 1-anilino-8-naphthalene-sulfonate binding study strongly suggested that a collapse in the tertiary structure, not the major secondary structural realignment, was the dominant factor in the formation of oligomers. In the fibrillar state, the contents of helical and disordered secondary structures decreased significantly and the β-sheet amount increased to ∼62%. The narrow amide I Raman band at 1674 cm in the fibrillar state connoted the formation of vibrationally restricted highly organized β-sheet structure with quaternary realignment into steric-zipped species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.7b01776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045404PMC
February 2018

Correction: Crystal-defect-induced facet-dependent electrocatalytic activity of 3D gold nanoflowers for the selective nanomolar detection of ascorbic acid.

Nanoscale 2018 Jul;10(28):13792

Chemical Sciences Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhannagar, Kolkata 700064, India.

Correction for 'Crystal-defect-induced facet-dependent electrocatalytic activity of 3D gold nanoflowers for the selective nanomolar detection of ascorbic acid' by Sandip Kumar De, et al., Nanoscale, 2018, 10, 11091-11102.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8nr90141dDOI Listing
July 2018

Crystal-defect-induced facet-dependent electrocatalytic activity of 3D gold nanoflowers for the selective nanomolar detection of ascorbic acid.

Nanoscale 2018 Jun;10(23):11091-11102

Chemical Science Division, Saha Institute of Nuclear Physics, Kolkata, West Bengal, India.

Understanding and exploring the decisive factors responsible for superlative catalytic efficiency is necessary to formulate active electrode materials for improved electrocatalysis and high-throughput sensing. This research demonstrates the ability of bud-shaped gold nanoflowers (AuNFs), intermediates in the bud-to-blossom gold nanoflower synthesis, to offer remarkable electrocatalytic efficiency in the oxidation of ascorbic acid (AA) at nanomolar concentrations. Multicomponent sensing in a single potential sweep is measured using differential pulse voltammetry while the kinetic parameters are estimated using electrochemical impedance spectroscopy. The outstanding catalytic activity of bud-structured AuNF [iAuNFp(Bud)/iGCp ≅ 100] compared with other bud-to-blossom intermediate nanostructures is explained by studying their structural transitions, charge distributions, crystalline patterns, and intrinsic irregularities/defects. Detailed microscopic analysis shows that density of crystal defects, such as edges, terraces, steps, ledges, kinks, and dislocation, plays a major role in producing the high catalytic efficiency. An associated ab initio simulation provides necessary support for the projected role of different crystal facets as selective catalytic sites. Density functional theory corroborates the appearance of inter- and intra-molecular hydrogen bonding within AA molecules to control the resultant fingerprint peak potentials at variable concentrations. Bud-structured AuNF facilitates AA detection at nanomolar levels in a multicomponent pathological sample.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8nr03087aDOI Listing
June 2018

DNA Damage and Apoptosis Induction in Cancer Cells by Chemically Engineered Thiolated Riboflavin Gold Nanoassembly.

ACS Appl Mater Interfaces 2018 Feb 27;10(5):4582-4589. Epub 2018 Jan 27.

Department of Chemistry, Government General Degree College, Singur, Hooghly, West Bengal 712409, India.

Herein we have engineered a smart nuclear targeting thiol-modified riboflavin-gold nano assembly, [email protected], which accumulates selectively in the nucleus without any nuclear-targeting peptides (NLS/RGD) and shows photophysically in vitro DNA intercalation. A theoretical model using Molecular Dynamics has been developed to probe the mechanism of formation and stability as well as dynamics of the [email protected] in aqueous solution and within the DNA microenvironment. The [email protected] facilitate the binucleated cell formation that is reflected in the significant increase of DNA damage marker, γ-H2AX as well as the arrest of most of the HeLa cells at the pre-G1 phase indicating cell death. Moreover, a significant upregulation of apoptotic markers confirms that the cell death occurs through the apoptotic pathway. Analyses of the microarray gene expression of [email protected] treated HeLa cells show significant alterations in vital biological processes necessary for cell survival. Taken together, our study reports a unique nuclear targeting mechanism through targeting the riboflavin receptors, which are upregulated in cancer cells and induce apoptosis in the targeted cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.7b18837DOI Listing
February 2018

Curcumin stably interacts with DNA hairpin through minor groove binding and demonstrates enhanced cytotoxicity in combination with FdU nucleotides.

Biochim Biophys Acta Gen Subj 2018 Mar 28;1862(3):485-494. Epub 2017 Oct 28.

Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

We report, based on biophysical studies and molecular mechanical calculations that curcumin binds DNA hairpin in the minor groove adjacent to the loop region forming a stable complex. UV-Vis and fluorescence spectroscopy indicated interaction of curcumin with DNA hairpin. In this novel binding motif, two ɣ H of curcumin heptadiene chain are closely positioned to the A-H8 and A-H8, while G-H8 is located in the close proximity of curcumin α H. Molecular dynamics (MD) simulations suggest, the complex is stabilized by noncovalent forces including; π-π stacking, H-bonding and hydrophobic interactions. Nuclear magnetic resonance (NMR) spectroscopy in combination with molecular dynamics simulations indicated curcumin is bound in the minor groove, while circular dichroism (CD) spectra suggested minute enhancement in base stacking and a little change in DNA helicity, without significant conformational change of DNA hairpin structure. The DNA:curcumin complex formed with FdU nucleotides rather than Thymidine, demonstrated enhanced cytotoxicity towards oral cancer cells relative to the only FdU substituted hairpin. Fluorescence co-localization demonstrated stability of the complex in biologically relevant conditions, including its cellular uptake. Acridine orange/EtBr staining further confirmed the enhanced cytotoxic effects of the complex, suggesting apoptosis as mode of cell death. Thus, curcumin can be noncovalently complexed to small DNA hairpin for cellular delivery and the complex showed increased cytotoxicity in combination with FdU nucleotides, demonstrating its potential for advanced cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2017.10.018DOI Listing
March 2018

Mesoporous silica for drug delivery: Interactions with model fluorescent lipid vesicles and live cells.

J Photochem Photobiol B 2018 Jan 1;178:19-26. Epub 2017 Nov 1.

Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India.

Formulated mesoporous silica nanoparticle (MSN) systems offer the best possible drug delivery system through the release of drug molecules from the accessible pores. In the present investigation, steady state and time resolved fluorescence techniques along with the fluorescence imaging were applied to investigate the interactions of dye loaded MSN with fluorescent unilamellar vesicles and live cells. Here 1,2-dimyristoyl-sn-glycero-3-phospocholine (DMPC) was used to prepare Small Unilamellar Vesicles (SUVs) as the model membrane with fluorescent 1,6-diphenyl-1,3,5-hexatriene (DPH) molecule incorporated inside the lipid bilayer. The interaction of DPH incorporated DMPC membrane with Fluorescein loaded MSN lead to the release of Fluorescein (Fl) dye from the interior pores of MSN systems. The extent of release of Fl and spatial distribution of the DPH molecule has been explored by monitoring steady-state fluorescence intensity and fluorescence lifetime at physiological condition. To investigate the fate of drug molecule released from MSN, fluorescence anisotropy has been used. The drug delivery efficiency of the MSN as a carrier for doxorubicin (DOX), a fluorescent chemotherapeutic drug, has also been investigated at physiological conditions. The study gives a definite confirmation for high uptake and steady release of DOX in primary oral mucosal non-keratinized squamous cells in comparison to naked DOX treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphotobiol.2017.10.023DOI Listing
January 2018

Formation of Annular Protofibrillar Assembly by Cysteine Tripeptide: Unraveling the Interactions with NMR, FTIR, and Molecular Dynamics.

J Phys Chem B 2017 07 23;121(26):6367-6379. Epub 2017 Jun 23.

Organic and Medicinal Chemistry and ‡Structural Biology and Bio-Informatics Division, CSIR-Indian Institute of Chemical Biology , 4, Raja S.C. Mullick Road, Kolkata, West Bengal 700032, India.

Both hydrogen-bonding and hydrophobic interactions play a significant role in molecular assembly, including self-assembly of proteins and peptides. In this study, we report the formation of annular protofibrillar structure (diameter ∼500 nm) made of a newly synthesized s-benzyl-protected cysteine tripeptide, which was primarily stabilized by hydrogen-bonding and hydrophobic interactions. Atomic force microscopy and field emission scanning electron microscopy analyses found small oligomers (diameter ∼60 nm) to bigger annular (outer diameter ∼300 nm; inner diameter, 100 nm) and protofibrillar structures after 1-2 days of incubation. Rotating-frame Overhauser spectroscopic (ROESY) analysis revealed the presence of several nonbonded proton-proton interactions among the residues, such as amide protons with methylene group, aromatic protons with tertiary butyl group, and methylene protons with tertiary butyl group. These added significant stability to bring the peptides closer to form a well-ordered assembled structure. Hydrogen-deuterium exchange NMR measurement further suggested that two individual amide protons among the three amide groups were strongly engaged with the adjacent tripeptide via H-bond interaction. However, the remaining amide proton was found to be exposed to solvent and remained noninteracting with other tripeptide molecules. In addition to chemical shift values, a significant change in amide bond vibrations of the tripeptide was found due to the formation of the self-assembled structure. The amide I mode of vibrations involving two amide linkages appeared at 1641 and 1695 cm in the solid state. However, in the assembled state, the stretching band at 1695 cm became broad and slightly shifted to ∼1689 cm. On the contrary, the band at 1641 cm shifted to 1659 cm and indicated that the -C═O bond associated with this vibration became stronger in the assembled state. These changes in Fourier transform infrared spectroscopy frequency clearly indicated changes in the amide backbone conformation and the associated hydrogen-bonding pattern due to the formation of the assembled structure. In addition to hydrogen bonding, molecular dynamics simulation indicated that the number of π-π interactions also increased with increasing number of tripeptides participated in the self-assembly process. Combined results envisaged a cross β-sheet assembly unit consisting of four intermolecular hydrogen bonds. Such noncovalent peptide assemblies glued by hydrogen-bonding and other weak forces may be useful in developing nanocapsule and related materials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpcb.7b04373DOI Listing
July 2017

Tamarixetin 3-O-β-d-Glucopyranoside from Azadirachta indica Leaves: Gastroprotective Role through Inhibition of Matrix Metalloproteinase-9 Activity in Mice.

J Nat Prod 2017 05 11;80(5):1347-1353. Epub 2017 May 11.

Department of Natural Products, National Institute of Pharmaceutical Education and Research , Kolkata 700032, WB, India.

Neem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-β-d-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC value of ca. 50 μM. Molecular docking and dynamics showed the binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.6b00957DOI Listing
May 2017

Constrained Photophysics of 5,7-dimethoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one in the Bioenvironment of Serum Albumins: A Spectroscopic Endeavour Supported by Molecular Docking Analysis.

J Fluoresc 2017 Jul 22;27(4):1547-1558. Epub 2017 Apr 22.

Chemical Sciences Division, Saha Institute of Nuclear Physics, Kolkata, 700064, India.

This paper vividly indicates that steady state as well as time-resolved fluorescence techniques can serve as highly sensitive monitors to explore the interactions of 5,7-dimethoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one with model transport proteins, bovine serum albumin (BSA) and human serum albumin (HSA). Besides these, we have used fluorescence anisotropy study to assess the degree of restrictions imparted by the micro-environments of serum albumins. Again, to speculate the triplet excited state interaction between such fluorophore and albumin proteins (BSA& HSA), laser flash-photolysis experiments have been carried out. Molecular docking experiments have also been performed to support the conclusions obtained from steady state experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10895-017-2094-2DOI Listing
July 2017

Envisaging Structural Insight of a Terminally Protected Proline Dipeptide by Raman Spectroscopy and Density Functional Theory Analyses.

J Phys Chem A 2016 Dec 6;120(49):9829-9840. Epub 2016 Dec 6.

Structural Biology & Bio-informatics Division and ‡Organic & Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology ; 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India.

The proline residue in a protein sequence generates constraints to its secondary structure as the associated torsion angles become a part of the heterocyclic ring. It becomes more significant when two consecutive proline residues link via amide linkage and produce additional configurational constraint to a protein's folding and stability. In the current manuscript we have illustrated conformation preference of a novel dipeptide, (R)-tert-butyl 2-((S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate. The dipeptide crystallized in the orthorhombic crystalline state and produced rod-shaped macroscopic material. The analysis of the crystal coordinates showed dihedral angles (φ, ψ) of the interlinked amide groups as (+72°, -147°) and the dihedral angles (φ, ψ) produced with the next carbonyl were (-68°, +151°), indicating polyglycine II (PGII) and polyproline II (PPII)-like helix states at the N- and C-terminals, respectively. These two states, PGII and PPII, are mirror image configurations and are expected to produce similar vibration bands from the associated carbonyl groups. However, the unique atomic arrangement in the molecule produces three carbonyl groups and one of them was very specific, being part of the main peptide linkage that connects both the pyrrolidine rings. The carbonyl group in the peptide bond exhibited a Raman vibration frequency at ∼1642 cm and is considered a signatory Raman marker band for the peptide bond linking two heterochiral proline residues. The carbonyl group (t-Boc) at the N-terminal of the peptide showed a characteristic vibration at ∼1685 cm and the C-terminal carbonyl group as a part of the ester showed a vibration signature at a significantly high frequency (1746 cm). Conformation analyses performed with density functional theory (DFT) calculations depicted that the dipeptide was stabilized in vacuum with dihedral angles (+72°, -154°) and (-72°, +151°) at the N- and C-terminals, respectively. Molecular dynamics (MD) simulation also showed that the peptide conformation having dihedral angles around (+75°, -150°) and (-75°, +150°) at the N- and C-terminals, respectively, was reasonably stable in water. Due to unique absence of the amide N-H, the peptide was ineffective in forming any intramolecular hydrogen bonding. MD investigation, however, revealed an intermolecular hydrogen bonding interaction with the water molecules, leading to its stability in aqueous solution. Metadynamics simulation analysis of the dipeptide in water also supported the PGII-PPII-like conformation at the N- and C-terminals, respectively, as the energetically stable conformation among the other possible combinations of conformations. The possible electronic transitions along with the HOMO-LUMO analysis further depicted the stability of the dipeptide in water and their possible absorption pattern. Time-dependent density functional theory (TDDFT) analysis showed strong negative rotatory strength of the dipeptide around 210 nm in water and acetonitrile, and it could be the source of experimentally observed high-amplitude negative absorption in the circular dichroism (CD) spectra around 200-203 nm. The very weak positive band (signature) in the region at ∼228 nm in CD spectra could also be correlated to the positive rotatory strength at 228 nm observed in ECD. To test the effect of such a dipeptide on a living cell, an MTT assay was performed and the result indicated no cytotoxic effect toward human hepatocellular carcinoma Hep G2 cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpca.6b10017DOI Listing
December 2016

Orientation of tyrosine side chain in neurotoxic Aβ differs in two different secondary structures of the peptide.

R Soc Open Sci 2016 Oct 5;3(10):160112. Epub 2016 Oct 5.

Structural Biology and Bioinformatics Division , Indian Institute of Chemical Biology, Council of Scientific and Industrial Research , 4, Raja S.c. Mullick Road, Kolkata 700032 , India.

Amyloid β (Aβ) peptide is present as a major component in amyloid plaque that is one of the hallmarks of Alzheimer's disease. The peptide contains a single tyrosine residue and Aβ has a major implication in the pathology of the disease progression. Current investigation revealed that the tyrosine side chain attained two different critical stereo orientations in two dissimilar conformational states of the peptide. The extended α-helical structure of the peptide observed in an apolar solvent or methanol/water mixture became disordered in aqueous medium and the radius of gyration decreased. In aqueous medium, the torsional angle around C-C of tyrosine group became -60°. However, in its α-helical conformation in an apolar system, the measured angle was 180° and this rotameric state may be reasoned behind stronger tyrosine fluorescence compared with the disordered state of the peptide. Molecular dynamics simulation analyses and spectroscopic studies have helped us to understand the major structural changes in the secondary structure of the peptide in the two conformational states. A conformational clustering indicated that the compact state is more stable with tyrosine residue attaining the torsion angle value of -60°, whereas the native state (in HFIP/water mixture) is prevalent at a torsion angle value of -180°. High solvent accessibility has possibly stabilized the particular rotameric state (-60°) of the tyrosine residue and could be the reason behind decrease in fluorescence of the sole tyrosine residue in an aqueous buffer solution (pH 7.4) compared with its fluorescence in the α-helical structure in the micellar environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsos.160112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098961PMC
October 2016

Silver-catalysed azide-alkyne cycloaddition (AgAAC): assessing the mechanism by density functional theory calculations.

R Soc Open Sci 2016 Sep 14;3(9):160090. Epub 2016 Sep 14.

Structural Biology and Bioinformatics Division , CSIR-Indian Institute of Chemical Biology; 4 , Raja S.C. Mullick Road, Kolkata , India.

'Click reactions' are the copper catalysed dipolar cycloaddition reaction of azides and alkynes to incorporate nitrogens into a cyclic hydrocarbon scaffold forming a triazole ring. Owing to its efficiency and versatility, this reaction and the products, triazole-containing heterocycles, have immense importance in medicinal chemistry. Copper is the only known catalyst to carry out this reaction, the mechanism of which remains unclear. We report here that the 'click reactions' can also be catalysed by silver halides in non-aqueous medium. It constitutes an alternative to the well-known CuAAC click reaction. The yield of the reaction varies on the type of counter ion present in the silver salt. This reaction exhibits significant features, such as high regioselectivity, mild reaction conditions, easy availability of substrates and reasonably good yields. In this communication, the findings of a new catalyst along with the effect of solvent and counter ions will help to decipher the still obscure mechanism of this important reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsos.160090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043300PMC
September 2016

A Novel Spirooxindole Derivative Inhibits the Growth of Leishmania donovani Parasites both In Vitro and In Vivo by Targeting Type IB Topoisomerase.

Antimicrob Agents Chemother 2016 10 23;60(10):6281-93. Epub 2016 Sep 23.

Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India

Visceral leishmaniasis is a fatal parasitic disease, and there is an emergent need for development of effective drugs against this neglected tropical disease. We report here the development of a novel spirooxindole derivative, N-benzyl-2,2'α-3,3',5',6',7',7α,α'-octahydro-2methoxycarbonyl-spiro[indole-3,3'-pyrrolizidine]-2-one (compound 4c), which inhibits Leishmania donovani topoisomerase IB (LdTopIB) and kills the wild type as well as drug-resistant parasite strains. This compound inhibits catalytic activity of LdTopIB in a competitive manner. Unlike camptothecin (CPT), the compound does not stabilize the DNA-topoisomerase IB cleavage complex; rather, it hinders drug-DNA-enzyme covalent complex formation. Fluorescence studies show that the stoichiometry of this compound binding to LdTopIB is 2:1 (mole/mole), with a dissociation constant of 6.65 μM. Molecular docking with LdTopIB using the stereoisomers of compound 4c produced two probable hits for the binding site, one in the small subunit and the other in the hinge region of the large subunit of LdTopIB. This spirooxindole is highly cytotoxic to promastigotes of L. donovani and also induces apoptosis-like cell death in the parasite. Treatment with compound 4c causes depolarization of mitochondrial membrane potential, formation of reactive oxygen species inside parasites, and ultimately fragmentation of nuclear DNA. Compound 4c also effectively clears amastigote forms of wild-type and drug-resistant parasites from infected mouse peritoneal macrophages but has less of an effect on host macrophages. Moreover, compound 4c showed strong antileishmanial efficacies in the BALB/c mouse model of leishmaniasis. This compound potentially can be used as a lead for developing excellent antileishmanial agents against emerging drug-resistant strains of the parasite.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00352-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038232PMC
October 2016
-->