Publications by authors named "Narsimha Mamidi"

17 Publications

  • Page 1 of 1

Polyhydroxybutyrate-Based Nanocomposites for Bone Tissue Engineering.

Pharmaceuticals (Basel) 2021 Nov 15;14(11). Epub 2021 Nov 15.

Department of Chemistry and Nanotechnology, School of Engineering and Science, Tecnologico de Monterrey, Monterrey 64849, Mexico.

Bone-related diseases have been increasing worldwide, and several nanocomposites have been used to treat them. Among several nanocomposites, polyhydroxybutyrate (PHB)-based nanocomposites are widely used in drug delivery and tissue engineering due to their excellent biocompatibility and biodegradability. However, PHB use in bone tissue engineering is limited due to its inadequate physicochemical and mechanical properties. In the present work, we synthesized PHB-based nanocomposites using a nanoblend and nano-clay with modified montmorillonite (MMT) as a filler. MMT was modified using trimethyl stearyl ammonium (TMSA). Nanoblend and nano-clay were fabricated using the solvent-casting technique. Inspection of the composite structure revealed that the basal spacing of the polymeric matrix material was significantly altered depending on the loading percentage of organically modified montmorillonite (OMMT) nano-clay. The PHB/OMMT nanocomposite displayed enhanced thermal stability and upper working temperature upon heating as compared to the pristine polymer. The dispersed (OMMT) nano-clay assisted in the formation of pores on the surface of the polymer. The pore size was proportional to the weight percentage of OMMT. Further morphological analysis of these blends was carried out through FESEM. The obtained nanocomposites exhibited augmented properties over neat PHB and could have an abundance of applications in the industry and medicinal sectors. In particular, improved porosity, non-immunogenic nature, and strong biocompatibility suggest their effective application in bone tissue engineering. Thus, PHB/OMMT nanocomposites are a promising candidate for 3D organ printing, lab-on-a-chip scaffold engineering, and bone tissue engineering.
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http://dx.doi.org/10.3390/ph14111163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622693PMC
November 2021

Design, fabrication and drug release potential of dual stimuli-responsive composite hydrogel nanoparticle interfaces.

Colloids Surf B Biointerfaces 2021 Aug 4;204:111819. Epub 2021 May 4.

Department of Chemistry and Nanotechnology, School of Engineering and Science, Tecnologico de Monterrey, Monterrey, Nuevo Leon, 64849, Mexico.

Nanocomposite hydrogel particles grasp considerable attention in nanotechnology and nanomedicine as one of the potential drug delivery platforms. However, prevail a coveted drug delivery strategy with sustain and stimuli-drug release is still challenging. Herein, poly (N-(4-aminophenyl) methacrylamide))-carbon nano-onions (PAPMA-CNOs = f-CNOs)/diclofenac-complex integrated chitosan (CS) nanocomposite hydrogel nanoparticles (CNPs) were fabricated using an ionic gelation strategy. CNPs possess several conducive physicochemical properties, including spherical morphology and uniform particle distribution.In vitro drug release from CNPs was vetted in different pHs of gastrointestinal (GI) tract environment at a temperature range of 37-55 °C and found dual (pH and thermo)-responsive controlled drug release. Under pH 7.4, CNPs exhibited the highest drug release at 55 °C in 15 days. The drug release results disclose that the structure of CNPs was disassembled at 55 °C to release the encapsulated drug molecules in a controlled fashion. The CNPs also displayed good cell viability against human fibroblast cells. Thus, all the results together unveil that CNPs would thrive as a promising pH and temperature-triggered drug delivery platform for the GI tract and colon targeted drug delivery.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111819DOI Listing
August 2021

Manufacture and mechanical properties of knee implants using SWCNTs/UHMWPE composites.

J Mech Behav Biomed Mater 2021 08 24;120:104554. Epub 2021 Apr 24.

Tecnologico de Monterrey, Campus Monterrey, School of Engineering and Science, Eugenio Garza Sada 2501 Sur, Col Tecnológico C.P., 64849, Monterrey, Nuevo León, Mexico.

This article focuses on obtaining ultra high molecular weight polyethylene (UHMWPE) material reinforced with functionalized single-walled carbon nanotubes (f-SWCNTs) and the manufacturing of unicompartmental knee implants via Single-Point Incremental Forming process (SPIF). The physicochemical properties of the developed UHMWPE reinforced with 0.01 and 0.1 wt% concentrations of f-SWCNTs are investigated using Raman and Thermogravimetic Analysis (TGA). Tensile mechanical tests performed in the nanocomposite material samples reveal a 12% improvement in their Young's modulus when compare to that of the pure UHMWPE material samples. Furthermore, the surface biocompatibility of the UHMWPE reinforced with f-SWCNTs materials samples was evaluated with human osteoblast cells. Results show cell viability enhancement with good cell growth and differentiation after 14 incubation days, that validates the usefulness of the developed nanocomposite material in the production of hip and knee artificial implants, and other biomedical applications.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104554DOI Listing
August 2021

Covalently Functionalized Carbon Nano-Onions Integrated Gelatin Methacryloyl Nanocomposite Hydrogel Containing γ-Cyclodextrin as Drug Carrier for High-Performance pH-Triggered Drug Release.

Pharmaceuticals (Basel) 2021 Mar 25;14(4). Epub 2021 Mar 25.

Department of Materials Science and Nanoengineering, Rice University, Houston, TX 77005, USA.

Herein, poly (-(4-aminophenyl) methacrylamide)) carbon nano-onions (PAPMA-CNOs = f-CNOs) and γ-cyclodextrin/DOX-complex (CD) reinforced gelatin methacryloyl (GelMA)/f-CNOs/CD supramolecular hydrogel interfaces were fabricated using the photo-crosslinking technique. The physicochemical properties, morphology, biodegradation, and swelling properties of hydrogels were investigated. The composite hydrogels demonstrated enriched drug release under the acidic conditions (pH 4.5 = 99%, and pH 6.0 = 82%) over 18 days. Owing to the f-CNOs inclusion, GelMA/f-CNOs/CD supramolecular hydrogels presented augmented tensile strength (σ = 356.1 ± 3.4 MPa), toughness (K = 51.5 ± 0.24 Jg), and Young's modulus (E = 41.8 ± 1.4 GPa). The strengthening of GelMA/f-CNOs/CD hydrogel systems indicates its good dispersion and the degree of polymer enveloping of f-CNOs within GelMA matrixes. Furthermore, the obtained hydrogels showed improved cell viability with human fibroblast cells. Nevertheless, the primed supramolecular hydrogels would pave the way for the controlled delivery systems for future drug delivery.
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http://dx.doi.org/10.3390/ph14040291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064464PMC
March 2021

Engineering of carbon nano-onion bioconjugates for biomedical applications.

Mater Sci Eng C Mater Biol Appl 2021 Jan 4;120:111698. Epub 2020 Nov 4.

Tecnologico de Monterrey, Department of Chemistry and Nanotechnology, School of Engineering and Sciences, Ave. Eugenio Garza Sada 2501, Monterrey 64849, NL, Mexico.

Engineered stimuli-responsive drug delivery strategies grasp enormous potential in biomedical applications for disease treatment due to their exploited therapeutic efficiency. In the current study, we developed poly 4-hydroxyphenyl methacrylate-carbon nano-onions (PHPMA-CNOs = f-CNOs) embedded bovine serum albumin (BSA) nanocomposite fibers by Forcespinning® (FS) technology for stimuli-responsive release of cargo, using doxorubicin (DOX) as a model drug. Nanocomposite fiber system showed thermosensitive drug release and exhibited around 72 and 95% of drug release at 37 and 43 °C, respectively. A slow and prolonged DOX release was observed over a 15-day study. The amount of drug released was determined by the concentration of the DOX payload, incubation temperature, and pH of the released medium. Owing to the f-CNOs incorporation, the mechanical strength (18.23 MPa) of hybrid BSA nanocomposite fibers was enhanced significantly. Besides, in vitro degradation, water contact angles, and thermal properties of nanocomposite fibers have augmented. During the in vitro cytotoxicity assessment, nanocomposite fibers exhibited improved cell viability against human fibroblast cells. Nonetheless, the external-stimuli-dependent and sustained DOX release perhaps reduces its circumventing side effects and show potential applications in biomedical research.
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http://dx.doi.org/10.1016/j.msec.2020.111698DOI Listing
January 2021

Carbon Nano-Onions Reinforced Multilayered Thin Film System for Stimuli-Responsive Drug Release.

Pharmaceutics 2020 Dec 13;12(12). Epub 2020 Dec 13.

Department of Materials Science and Nanoengineering, Rice University, Houston, TX 77005, USA.

Herein, poly (-(4-aminophenyl) methacrylamide))-carbon nano-onions (PAPMA-CNOs = f-CNOs) and anilinated-poly (ether ether ketone) (AN-PEEK) have synthesized, and AN-PEEK/f-CNOs composite thin films were primed via layer-by-layer (LbL) self-assembly for stimuli-responsive drug release. The obtained thin films exhibited pH-responsive drug release in a controlled manner; pH 4.5 = 99.2% and pH 6.5 = 59.3% of doxorubicin (DOX) release was observed over 15 days. Supramolecular π-π stacking interactions between f-CNOs and DOX played a critical role in controlling drug release from thin films. Cell viability was studied with human osteoblast cells and augmented viability was perceived. Moreover, the thin films presented 891.4 ± 8.2 MPa of the tensile strength (σult), 43.2 ± 1.1 GPa of Young's modulus (E), and 164.5 ± 1.7 Jg of toughness (K). Quantitative scrutiny revealed that the well-ordered aligned nanofibers provide critical interphase, and this could be responsible for augmented tensile properties. Nonetheless, a pH-responsive and mechanically robust biocompatible thin-film system may show potential applications in the biomedical field.
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http://dx.doi.org/10.3390/pharmaceutics12121208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764530PMC
December 2020

Engineering and evaluation of forcespun functionalized carbon nano-onions reinforced poly (ε-caprolactone) composite nanofibers for pH-responsive drug release.

Mater Sci Eng C Mater Biol Appl 2020 Jul 3;112:110928. Epub 2020 Apr 3.

Tecnologico de Monterrey, Department of Chemistry and Nanotechnology, School of Engineering and Science, Eugenio Garza Sada 2501 Sur, Col. Tecnologico, C.P. 64849 Monterrey, Nuevo León, Mexico.

Nanofibers and smart polymers are potentially fascinating biomaterials for the sustained release of therapeutic agents and tissue engineering applications. The current study describes a new class of pH-controlled polycaprolactone/mercaptophenyl methacrylate functionalized carbon nano-onions (PCL/f-CNOs) composite nanofibers by Forcespinning® (FS) with a sustained drug release profile. The morphology and structural characteristics of PCL/f-CNOs nanofibers were scrutinized by Scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR), respectively. The morphological results revealed that FS provided homogeneous and bead free nanofibers with average diameters from approximately 215 nm to 596 nm. PCL/f-CNOs composite fibers exhibited pH-responsive release of DOX over 15 days; pH 6.5 showed 87%, and pH 5.0 presented around 99% of DOX release. Drug release measurements showed that the π-π stacking interactions between DOX and f-CNOs have led to a controlled DOX release from forcespun PCL/f-CNOs fibers. Owing to the f-CNOs amalgamation, PCL/f-CNOs fibers unveiled enhanced tensile strength (3.16 MPa) as compared to pristine PCL fibers. It reveals the magnitude of colloidal stability and physisorption of f-CNOs within the PCL matrix. Besides, the in-vitro cell viability was measured with human fibroblast cells, and good viability was observed. Nevertheless, DOX embedded pH-responsive PCL/f-CNOs composite nanofibers may show potential applications in the biomedical research area.
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http://dx.doi.org/10.1016/j.msec.2020.110928DOI Listing
July 2020

Rational design and engineering of carbon nano-onions reinforced natural protein nanocomposite hydrogels for biomedical applications.

J Mech Behav Biomed Mater 2020 04 11;104:103696. Epub 2020 Feb 11.

Tecnologico de Monterrey, Department of Chemistry and Nanotechnology, School of Engineering and Science, Monterrey, Nuevo Leon, 64849, Mexico.

In the current study, poly 4-hydroxyphenyl methacrylate-carbon nano-onions (PHPMA-CNOs = f-CNOs) are synthesized and reinforced with natural protein gelatin (GL) to engineer GL/f-CNOs composite hydrogels under the sonochemical method. The influence of f-CNOs content on the mechanical properties of hydrogels is examined. Cytotoxicity of hydrogels is measured with the human osteoblast cells. The results revealed good cell viability, cell growth, and attachment on the surface of the hydrogels, and results are f-CNOs dose-dependent. Specifically, the GL/f-CNOs (2 mg/mL) hydrogel showed the highest cell viability, enhanced tensile strength, elastic modulus, and yield strength as compared to pristine GL and GL/f-CNOs (1 mg/mL) hydrogels. It reveals the extent of physisorption and degree of colloidal stability of f-CNOs within the gel matrix. Furthermore, GL/f-CNOs hydrogels efficiently load the 5-fluorouracil (5-FU) and show a pH-responsive sustained drug release over 15 days. Nevertheless, these CNOs based composite hydrogels offer a potential prospect to use them in diverse biomedical applications.
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http://dx.doi.org/10.1016/j.jmbbm.2020.103696DOI Listing
April 2020

Development of Functionalized Carbon Nano-Onions Reinforced Zein Protein Hydrogel Interfaces for Controlled Drug Release.

Pharmaceutics 2019 Nov 20;11(12). Epub 2019 Nov 20.

Department of Materials Science and NanoEngineering, Rice University, Houston, TX 77005, USA.

In the current study, poly 4-mercaptophenyl methacrylate-carbon nano-onions (PMPMA-CNOs = f-CNOs) reinforced natural protein (zein) composites (zein/f-CNOs) are fabricated using the acoustic cavitation technique. The influence of f-CNOs inclusion on the microstructural properties, morphology, mechanical, cytocompatibility, in-vitro degradation, and swelling behavior of the hydrogels are studied. The tensile results showed that zein/f-CNOs hydrogels fabricated by the acoustic cavitation system exhibited good tensile strength (90.18 MPa), compared with the hydrogels fabricated by the traditional method and only microwave radiation method. It reveals the magnitude of physisorption and degree of colloidal stability of f-CNOs within the zein matrix under acoustic cavitation conditions. The swelling behaviors of hydrogels were also tested and improved results were noticed. The cytotoxicity of hydrogels was tested with osteoblast cells. The results showed good cell viability and cell growth. To explore the efficacy of hydrogels as drug transporters, 5-fluorouracil (5-FU) release was measured under gastric and intestinal pH environment. The results showed pH-responsive sustained drug release over 15 days of study, and pH 7.4 showed a more rapid drug release than pH 2.0 and 4.5. Nonetheless, all the results suggest that zein/f-CNOs hydrogel could be a potential pH-responsive drug transporter for a colon-selective delivery system.
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http://dx.doi.org/10.3390/pharmaceutics11120621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956117PMC
November 2019

Cytotoxicity evaluation of unfunctionalized multiwall carbon nanotubes-ultrahigh molecular weight polyethylene nanocomposites.

J Biomed Mater Res A 2017 Nov 14;105(11):3042-3049. Epub 2017 Aug 14.

Tecnologico de Monterrey, Departamento de Ingeniería Biomédica, Av. Eugenio Garza Sada 2501 Sur, C.P. 64849, Monterrey, Nuevo León, México.

The carbon nanotubes were chosen for this study since long, small to medium diameter, and unfunctionalized nanotubes are considered less favorable for nontoxic applications. The intent of the study is to expand the use of CNTs beyond current understood nontoxic means. Multiwall carbon nanotube/ultrahigh molecular weight polyethylene (MWCNT/UHMWPE) nanocomposites were prepared by reinforcing long chain UHMWPE with MWCNTs. These nanocomposites were prepared to study their cytotoxicity assessments with human fibroblast cell lines. Cell adhesion, proliferation, and differentiation were studied with human fibroblast cell lines. In vitro studies revealed good cell viability on the surface of MWCNT/UHMWPE composites even after 72 h. The nanocomposites showed better cell attachment for fibroblasts than pristine UHMWPE. Overall, the results showed that MWCNT/UHMWPE composites displayed good cellular growth and biocompatibility indicating another way CNTs can be nontoxic. These nanocomposites offer nontoxic conditions that can be used in biomedical devices because the long chain UHMWPE is entangled with long MWCNTs. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3042-3049, 2017.
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http://dx.doi.org/10.1002/jbm.a.36168DOI Listing
November 2017

Aromatic Sulfonium Polyoxomolybdates: Solid-State Photochromic Materials with Tunable Properties.

Chemistry 2015 Dec 10;21(51):18557-62. Epub 2015 Nov 10.

School of Basic Sciences, Indian Institute of Technology Mandi, Mandi 175005, Himachal Pradesh (India) http://faculty.iitmandi.ac.in/∼pradeep/.

A new aromatic sulfonium counter-ion motif for polyoxometalate (POM) clusters with potential for structural and electronic fine-tuning has been designed. Its two derivatives 4-hydroxyphenyl dimethylsulfonium triflate (HPDST) and 4-(allyloxy)phenyl dimethylsulfonium triflate (APDST) exhibit ionic liquid behaviors under ambient conditions. HPDST and APDST are used to develop a series of aromatic sulfonium POM hybrids (HPDS/APDS)n[XMo12 O40] (HPDS and APDS are the cations of HPDST and APDST, respectively; X=P or Si; n=3 or 4), which are tested for photochromic behavior. On exposure to UV light, these POM hybrids undergo color change from yellow to green/blue. The coloration kinetics half lives (t1/2) are less for APDS-based hybrids than for HPDS-based hybrids, suggesting that alkyl substitution on the phenolic group helps to fine-tune the electron availability on the sulfonium moiety and hence to control the photochromic behavior of the POM hybrids. The t1/2 values of these hybrids are considerably lower than those of the reported aliphatic sulfonium POM hybrids. We have also demonstrated the application of photoreduced POM hybrids as catalysts for the reduction of 4-nitrophenol to 4-aminophenol.
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http://dx.doi.org/10.1002/chem.201503574DOI Listing
December 2015

Elucidating the interaction of γ-hydroxymethyl-γ-butyrolactone substituents with model membranes and protein kinase C-C1 domains.

Mol Biosyst 2015 May;11(5):1389-99

Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.

The protein kinase C (PKC) family of proteins is an attractive drug target. Dysregulation of PKC-dependent signalling pathways is related to several human diseases like cancer, immunological and other diseases. We approached the problem of altering PKC activities by developing C1 domain-based PKC ligands. In this report γ-hydroxymethyl-γ-butyrolactone (HGL) substituents were investigated in an effort to develop small molecule-based PKC regulators with higher specificity for C1 domain than the endogenous diacylglycerols (DAGs). Extensive analysis of membrane-ligands interaction measurements revealed that the membrane-active compounds strongly interact with the lipid bilayers and the hydrophilic parts of compounds localize at the bilayer/water interface. The pharmacophores like hydroxymethyl, carbonyl groups and acyl-chain length of the compounds are crucial for their interaction with the C1 domain proteins. The potent compounds showed more than 17-fold stronger binding affinity for the C1 domains than DAG under similar experimental conditions. Nonradioactive kinase assay confirmed that these potent compounds have similar or better PKC dependent phosphorylation capabilities than DAG under similar experimental conditions. Hence, our findings reveal that these HGL analogues represent an attractive group of structurally simple C1 domain ligands that can be further structurally altered to improve their potencies.
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http://dx.doi.org/10.1039/c5mb00100eDOI Listing
May 2015

Synthesis and protein kinase C (PKC)-C1 domain binding properties of diacyltetrol based anionic lipids.

Mol Biosyst 2014 Nov;10(11):3002-13

Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.

The protein kinase C (PKC) family of lipid-activated kinases plays a significant role in the regulation of diverse cellular functions including tumor promotion, apoptosis, differentiation, and others. The lipophilic second messenger diacylglycerols (DAGs) act as endogenous ligands for the PKCs in the presence of anionic phospholipids. To develop effective PKC regulators and understand the importance of anionic phospholipids in DAG binding of PKC isoforms, we conveniently synthesized octanoic acid containing diacyltetrol (DAT) based hybrid lipids with both DAG and anionic phospholipid headgroups within the same molecule. We also used palmitic and oleic acid containing hybrid lipids for additional understanding of the PKC-C1 domain binding mechanism. Biophysical studies showed that hydrophobic side chains, DAG and anionic phospholipids headgroups are necessary for their interaction with the C1-domain of PKC isoforms. The hybrid lipids DAT-PS and DAT-PA specifically interact with the PKCδ-C1b and PKCθ-C1b subdomains and showed 5- and 2.5-fold stronger binding affinity compared with DAG, respectively. Whereas, the PKCα-C1a subdomain interacts with the hybrid lipids, without any significant specificity. The present results show that hybrid lipids bind to the PKC C1b/a subdomains and can be further studied to decipher their binding mechanism and biological activities. This study proposes a new concept of developing PKC activators by using tetrol-based anionic hybrid lipids having both phospholipids and diacylglycerol headgroups within the same molecule. This study also supplies useful information for the binding potencies of hybrid lipids with PKC-C1 domains.
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http://dx.doi.org/10.1039/c4mb00382aDOI Listing
November 2014

Zn(OTf)2-promoted chemoselective esterification of hydroxyl group bearing carboxylic acids.

J Org Chem 2013 Mar 6;78(6):2386-96. Epub 2013 Feb 6.

Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.

Selective esterification of aliphatic and aromatic carboxylic acids with various alcohols is studied using triphenylphosphine, I2, and a catalytic amount of Zn(OTf)2. Use of this catalyst allows the formation of esters at a faster rate with good to excellent yield by activating the in situ generated acyloxyphosphonium ion intermediate. During the esterification process, both their aromatic and aliphatic hydroxyl groups are fully preserved from transesterification. The results show that the bulkiness and the reactivity of this doubly activated intermediate III control the selectivity and the rate of the reaction, respectively. The method is also useful for direct amidation reactions.
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http://dx.doi.org/10.1021/jo302502rDOI Listing
March 2013

Effects of ortho substituent groups of protocatechualdehyde derivatives on binding to the C1 domain of novel protein kinase C.

J Phys Chem B 2012 Sep 23;116(35):10684-92. Epub 2012 Aug 23.

Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.

Diacylglycerol (DAG) regulates a broad range of cellular functions including tumor promotion, apoptosis, differentiation, and growth. Thus, the DAG-responsive C1 domain of protein kinase C (PKC) isoenzymes is considered to be an attractive drug target for the treatment of cancer and other diseases. To develop effective PKC regulators, we conveniently synthesized (hydroxymethyl)phenyl ester analogues targeted to the DAG binding site within the C1 domain. Biophysical studies and molecular docking analysis showed that the hydroxymethyl group, hydrophobic side chains, and acyl group at the ortho position are essential for their interactions with the C1-domain backbone. Modifications of these groups showed diminished binding to the C1 domain. The active (hydroxymethyl)phenyl ester analogues showed more than 5-fold stronger binding affinity for the C1 domain than DAG. Therefore, our findings reveal that (hydroxymethyl)phenyl ester analogues represent an attractive group of C1-domain ligands that can be further structurally modified to improve their binding and activity.
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http://dx.doi.org/10.1021/jp304787jDOI Listing
September 2012

Alkyl cinnamates as regulator for the C1 domain of protein kinase C isoforms.

Chem Phys Lipids 2012 Apr 6;165(3):320-30. Epub 2012 Mar 6.

Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam, India.

The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target for the treatment of cancer and other diseases. Natural product curcumin is known to interact with PKC isoforms through the C1 domain and modulate PKC activity. The reported results demonstrate that the symmetric curcumin molecule might act as two separate units during its recognition of C1 domains. To understand the importance of the two halves of curcumin in PKC binding and to develop effective PKC regulators, we synthesized a series of alkyl cinnamates (1-8), characterized absorption and fluorescence properties and measured binding affinities with the C1b subdomains of PKC isoforms. The binding parameters of the monomeric compounds and liposomes containing compounds confirmed their interaction with the C1b subdomains of PKCδ and PKCθ. The molecular docking analysis with PKCδ and PKCθ C1b subdomains revealed that the alkyl cinnamates form hydrogen bond with the backbone of the protein at the same binding site as that of diacylglycerol and phorbol esters. The results show that the alkyl cinnamates bind to the activator binding site of PKCs and both methoxy and hydroxyl groups play important roles in the binding process.
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http://dx.doi.org/10.1016/j.chemphyslip.2012.02.010DOI Listing
April 2012

Development of diacyltetrol lipids as activators for the C1 domain of protein kinase C.

Mol Biosyst 2012 Apr 2;8(4):1275-85. Epub 2012 Feb 2.

Department of Chemistry, Indian Institute of Technology Guwahati, Assam 781039, India.

The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target for the treatment of cancer and other diseases. Diacylglycerol (DAG), phorbol esters and others act as ligands for the C1 domain of PKC isoforms. Inspection of the crystal structure of the PKCδ C1b subdomain in complex with phorbol-13-O-acetate shows that one carbonyl group and two hydroxyl groups play pivotal roles in recognition of the C1 domain. To understand the importance of two hydroxyl groups of phorbol esters in PKC binding and to develop effective PKC activators, we synthesized DAG like diacyltetrols (DATs) and studied binding affinities with C1b subdomains of PKCδ and PKCθ. DATs, with the stereochemistry of natural DAGs at the sn-2 position, were synthesized from (+)-diethyl L-tartrate in four to seven steps as single isomers. The calculated EC(50) values for the short and long chain DATs varied in the range of 3-6 μM. Furthermore, the fluorescence anisotropy values of the proteins were increased in the presence of DATs in a similar manner to that of DAGs. Molecular docking of DATs (1b-4b) with PKCδ C1b showed that the DATs form hydrogen bonds with the polar residues and backbone of the protein, at the same binding site, as that of DAG and phorbol esters. Our findings reveal that DATs represent an attractive group of C1 domain ligands that can be used as research tools or further structurally modified for potential drug development.
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http://dx.doi.org/10.1039/c2mb05452cDOI Listing
April 2012
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