Publications by authors named "Rakesh K Tiwari"

33 Publications

Cyclic Peptides as Protein Kinase Inhibitors: Structure-Activity Relationship and Molecular Modeling.

J Chem Inf Model 2021 06 17;61(6):3015-3026. Epub 2021 May 17.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, United States.

Under-expression or overexpression of protein kinases has been shown to be associated with unregulated cell signal transduction in cancer cells. Therefore, there is major interest in designing protein kinase inhibitors as anticancer agents. We have previously reported [WR], a peptide containing alternative arginine (R) and tryptophan (W) residues as a non-competitive c-Src tyrosine kinase inhibitor. A number of larger cyclic peptides containing alternative hydrophobic and positively charged residues [WR] ( = 6-9) and hybrid cyclic-linear peptides, [RK]W and [RK]W, containing R and W residues were evaluated for their protein kinase inhibitory potency. Among all the peptides, cyclic peptide [WR] was found to be the most potent tyrosine kinase inhibitor. [WR] showed higher inhibitory activity (IC = 0.21 μM) than [WR], [WR], [WR], and [WR] with IC values of 0.81, 0.57, 0.35, and 0.33 μM, respectively, against c-Src kinase as determined by a radioactive assay using [γ-P]ATP. Consistent with the result above, [WR] inhibited other protein kinases such as Abl kinase activity with an IC value of 0.35 μM, showing 2.2-fold higher inhibition than [WR] (IC = 0.79 μM). [WR] also inhibited PKCa kinase activity with an IC value of 2.86 μM, approximately threefold higher inhibition than [WR] (IC = 8.52 μM). A similar pattern was observed against Braf, c-Src, Cdk2/cyclin A1, and Lck. [WR] exhibited IC values of <0.25 μM against Akt1, Alk, and Btk. These data suggest that [WR] is consistently more potent than other cyclic peptides with a smaller ring size and hybrid cyclic-linear peptides [RK]W and [RK]W against selected protein kinases. Thus, the presence of R and W residues in the ring, ring size, and the number of amino acids in the structure of the cyclic peptide were found to be critical in protein kinase inhibitory potency. We identified three putative binding pockets through automated blind docking of cyclic peptides [WR]. The most populated pocket is located between the SH2, SH3, and N-lobe domains on the opposite side of the ATP binding site. The second putative pocket is formed by the same domains and located on the ATP binding site side of the protein. Finally, a third pocket was identified between the SH2 and SH3 domains. These results are consistent with the non-competitive nature of the inhibition displayed by these molecules. Molecular dynamics simulations of the protein-peptide complexes indicate that the presence of either [WR] or [WR] affects the plasticity of the protein and in particular the volume of the ATP binding site pocket in different ways. These results suggest that the second pocket is most likely the site where these peptides bind and offer a plausible rationale for the increased affinity of [WR].
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http://dx.doi.org/10.1021/acs.jcim.1c00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238896PMC
June 2021

siRNA Therapeutics for the Therapy of COVID-19 and Other Coronaviruses.

Mol Pharm 2021 06 4;18(6):2105-2121. Epub 2021 May 4.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, United States.

The ongoing pandemic of global concern has killed about three million humans and affected around 151 million people worldwide, as of April 30, 2021. Although recently approved vaccines for COVID-19 are engendering hope, finding new ways to cure the viral pandemic is still a quest for researchers worldwide. Major pandemics in history have been of viral origin, such as SARS, MERS, H1NI, Spanish flu, and so on. A larger emphasis has been on discovering potential vaccines, novel antiviral drugs, and agents that can mitigate the viral infection symptoms; however, a relatively new area, RNA interference (RNAi), has proven effective as an antiviral agent. The RNAi phenomenon has been largely exploited to cure cancer, neurodegenerative diseases, and some rare diseases. The U.S. Food and Drug Administration has recently approved three siRNA products for human use that garner significant hope in siRNA therapeutics for coronaviruses. There have been some commentaries and communications addressing this area. We have summarized and illustrated the significance and the potential of the siRNA therapeutics available as of April 30, 2021 to combat the ongoing viral pandemic and the emerging new variants such as B.1.1.7 and B.1.351. Numerous successful studies and several investigations to address the clinical application of siRNA therapeutics provide great hope in this field. This seminal Review describes the significance of siRNA-based therapy to treat diverse viral infections in addition to the current coronavirus challenge. In addition, we have thoroughly reviewed the patents approved for coronaviruses, the major challenges in siRNA therapy, and the potential approaches to address them, followed by innovation and prospects.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01239DOI Listing
June 2021

Applications of amphipathic and cationic cyclic cell-penetrating peptides: Significant therapeutic delivery tool.

Peptides 2021 Jul 29;141:170542. Epub 2021 Mar 29.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, 92618, USA. Electronic address:

A new class of peptides, cyclic cell-penetrating peptides (CPPs), has great potential for delivering a vast variety of therapeutics intracellularly for treating diverse ailments. CPPs have been used previously; however, their further use is limited due to instability, toxicity, endosomal degradation, and insufficient cellular penetration. Cyclic CPPs are being investigated in delivering therapeutics to treat various ailments, including multi-drug resistant microbial infections, HIV, and cancer. They can act as a carrier for a variety of cargos and target intracellularly. Approximately 40 cyclic peptides-based therapeutics are available in the market, and annually one cyclic peptide-based drug enters the market. Numerous research and review articles have been published in the last decade about linear and cyclic peptides separately. This review is the first to provide a comprehensive deliberation about cationic and amphipathic cyclic CPPs. Herein, we highlights their structures, significant advantages, translocation mechanisms, and delivery application in the area of biomedical sciences.
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http://dx.doi.org/10.1016/j.peptides.2021.170542DOI Listing
July 2021

Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs Against Human Coronavirus 229E (HCoV-229E).

Molecules 2020 May 17;25(10). Epub 2020 May 17.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA.

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'--fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC value of 0.07 µM against HCoV-229E with TC of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'--fatty acyl conjugates of NRTIs, 5'--tetradecanoyl ester conjugate of FTC showed modest activity with EC and TC values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.
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http://dx.doi.org/10.3390/molecules25102343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287735PMC
May 2020

Comparative Molecular Transporter Efficiency of Cyclic Peptides Containing Tryptophan and Arginine Residues.

ACS Omega 2018 Nov 29;3(11):16281-16291. Epub 2018 Nov 29.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, California 92618, United States.

Cyclic peptides containing tryptophan (W) and arginine (R) residues, [WR], [WR], [WR], [WR], and [WR], were synthesized through Fmoc solid-phase chemistry to compare their molecular transporter efficiency. The in vitro cytotoxicity of the peptides was evaluated using human leukemia carcinoma cell line (CCRF-CEM) and normal kidney cell line (LLC-PK1). [WR], [WR], [WR], and [WR] were not significantly cytotoxic to LLC-PK1cells at a concentration of 10 μM after 3 h incubation. Among all the peptides, [WR] was found to be a more efficient transporter than [WR], [WR], [WR], and [WR] in CCRF-CEM cells for delivery of a cell-impermeable fluorescence-labeled negatively charged phosphopeptide (F'-GpYEEI). [WR] (10 μM) improved the cellular uptake of F'-GpYEEI (2 μM) by 20-fold. The cellular uptake of a fluorescent conjugate of [WR], F'-[WRK], was increased in a concentration- and time-dependent pattern in CCRF-CEM cells. The uptake of F'-[WRK] was slightly reduced in CCRF-CEM cells in the presence of different endocytic inhibitors, such as nystatin, 5-(-ethyl--isopropyl)amiloride, chlorpromazine, chloroquine, and methyl β-cyclodextrin. Furthermore, the uptake of F'-[WRK] was shown to be temperature-dependent and slightly adenosine 5'-triphosphate-dependent. The intracellular/cellular localization (in the nucleus and cytoplasm) of F'-[WRK] was confirmed by fluorescent microscopy in CCRF-CEM cells. These studies suggest that large cyclic peptides containing arginine and tryptophan can be used as a molecular transporter of specific compounds.
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http://dx.doi.org/10.1021/acsomega.8b02589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643651PMC
November 2018

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives.

Arch Pharm (Weinheim) 2017 Apr 20;350(3-4). Epub 2017 Mar 20.

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

In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.
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http://dx.doi.org/10.1002/ardp.201600390DOI Listing
April 2017

Palladium-Catalyzed Intramolecular Cross-Dehydrogenative Coupling: Synthesis of Fused Imidazo[1,2-]pyrimidines and Pyrazolo[1,5-]pyrimidines.

ACS Omega 2017 Jan 4;2(1):11-19. Epub 2017 Jan 4.

Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California 92618-1908, United States.

A palladium-catalyzed intramolecular dehydrogenative coupling reaction was developed for the synthesis of fused imidazo[1,2-]pyrimidines and pyrazolo[1,5-]pyrimidines. The developed protocol provides a practical approach for the synthesis of biologically important substituted pyrimidines from easily available substrates, with a broad substrate scope under mild reaction conditions.
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http://dx.doi.org/10.1021/acsomega.6b00417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641030PMC
January 2017

Design, Synthesis, and Evaluation of Dasatinib-Amino Acid and Dasatinib-Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors.

ChemMedChem 2017 01 5;12(1):86-99. Epub 2016 Dec 5.

Department of Cell & Molecular Biology, University of Rhode Island, 389 CBLS Building, 120 Flagg Road, Kingston, RI, 02881, USA.

Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib-l-arginine derivative (Das-R, 7) was found to be the most potent of the inhibitors tested, with IC values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C ) with an IC value of 3.2 μm for Csk compared with 35 nm for Src. Furthermore, many compounds displayed increased selectivity toward Src over Abl. Compounds 15 (Das-glutamic acid) and 13 (Das-cysteine) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC ratios). Das-R (IC =2.06 μm) was significantly more potent than the parent dasatinib (IC =26.3 μm) against Panc-1 cells, whereas both compounds showed IC <51.2 pm against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed good agreements with the experimental results and rationalized the differences in selectivity among the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of the dasatinib scaffold, providing useful insight into mechanisms of kinase selectivity.
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http://dx.doi.org/10.1002/cmdc.201600387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224969PMC
January 2017

Regio- and Stereoselective Domino Synthesis of Oxazolo Fused Pyridoindoles and Benzofurooxazolo Pyridines from ortho-Alkynylarylaldehydes.

J Org Chem 2016 10 26;81(19):9356-9371. Epub 2016 Sep 26.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi , Delhi 110007, India.

An environmentally benign Au(III)-catalyzed regio- and stereoselective domino synthesis of oxazolo fused pyridoindoles 7a-v and benzofurooxazolo pyridines 8a-n by the reaction of o-alkynylaldehydes 4a-t and 5a-k with (S)-phenylglycinol 6a and (R)-phenylglycinol 6b under mild reaction conditions using water as reaction medium is reported. The reaction proceeded via selective C-N bond formation on the more electrophilic alkynyl carbon through 6-endo-dig cyclization. The reaction tolerates a wide variety of functional groups. The developed chemistry has been successfully extended for the synthesis of a diverse class of γ-carbolines and benzofuro[3,2-c]pyridines using corresponding ester hydrochlorides of serine, threonine, and cystine as a nitrogen source.
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http://dx.doi.org/10.1021/acs.joc.6b02062DOI Listing
October 2016

Novel pH-Sensitive Cyclic Peptides.

Sci Rep 2016 08 12;6:31322. Epub 2016 Aug 12.

Department of Physics, University of Rhode Island, Kingston, RI 02881, US.

A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4WC], and asymmetric, c[E4W5C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH- and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4W5C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4W5C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.
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http://dx.doi.org/10.1038/srep31322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981864PMC
August 2016

Pd-catalyzed one-pot sequential unsymmetrical cross-coupling reactions of aryl/heteroaryl 1,2-dihalides.

Org Biomol Chem 2016 Jul;14(27):6487-96

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India.

Efficient, step-economic, Pd(ii)-catalyzed one-pot sequential Sonogashira/Sonogashira, Sonogashira/Suzuki, Sonogashira/Heck, Suzuki/Sonogashira, Suzuki/Suzuki, Suzuki/Heck, Heck/Sonogashira, Heck/Suzuki and Heck/Heck cross coupling reactions of sterically hindered aryl/heteroaryl 1,2-dihalides have been developed. The present methodology allows the conversion of easily available aryl/heteroaryl 1,2-dihalides into synthetically useful unsymmetrically substituted arenes/heteroarenes in good to excellent yields under mild reaction conditions. This methodology is a powerful tool for building a versatile substrate which can be utilized for the synthesis of various organic scaffolds.
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http://dx.doi.org/10.1039/c6ob01049kDOI Listing
July 2016

Design, synthesis, and evaluation of chitosan conjugated GGRGDSK peptides as a cancer cell-targeting molecular transporter.

Int J Biol Macromol 2016 Jun 11;87:611-22. Epub 2016 Mar 11.

Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, United States. Electronic address:

Targeting cancer cells using integrin receptor is one of the promising targeting strategies in drug delivery. In this study, we conjugated an integrin-binding ligand (GGRGDSK) peptide to chitosan oligosaccharide (COS) using sulfo-SMCC as a bifunctional linker to afford COS-SMCC-GGRGDSK. The conjugated polymer was characterized by FT-IR, (1)H NMR, (13)C NMR, and SEM. COS-SMCC-GGRGDSK did not show cytotoxicity up to a concentration of 1mg/mL in the human leukemia cell line (CCRF-CEM). The conjugate was evaluated for its ability to enhance the cellular uptake of a cell-impermeable cargo (e.g., F'-G(pY)EEI phosphopeptide) in CCRF-CEM, and human ovarian carcinoma (SK-OV-3) cancer cell lines. Additionally, RGD modified and unmodified COS polymers were used to prepare nanoparticles by ionic gelation and showed particle size ranging from 187 to 338nm, and zeta potential of 12.2-18.3mV using dynamic light scattering. The efficiency of COS-NPs and COS-SMCC-RGDSK NPs was assayed for translocation of two synthetic cytotoxic agents ((2-(2-aminoethylamino)-4-(4-chlorophenyl)-6-(1H-indol-3-yl) nicotinonitrile (ACIN), and 2-(2-aminoethylamino)-6-(1H-indol-3-yl)-4-(4-methoxyphenyl)-nicotinonitrile (AMIN)) into CCRF-CEM and human prostate (DU-145) cancer cell lines. The results showed a dramatic reduction in the cell viability on their treatment with RGD targeted COS NPs in comparison to paclitaxel (PTX), free drug, and drug-loaded COS NPs.
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http://dx.doi.org/10.1016/j.ijbiomac.2016.03.020DOI Listing
June 2016

Cysteine and arginine-rich peptides as molecular carriers.

Bioorg Med Chem Lett 2016 Jan 17;26(2):656-661. Epub 2015 Nov 17.

Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, United States. Electronic address:

A number of linear and cyclic peptides containing alternative arginine and cysteine residues, namely linear (CR)3, linear (CR)4, linear (CR)5, cyclic [CR]4, and cyclic [CR]5, were synthesized. The peptides were evaluated for their ability to deliver two molecular cargos, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F'-GpYEEI) and fluorescence-labeled lamivudine (F'-3TC), intracellularly in human leukemia cancer (CCRF-CEM) cells. We investigated the role of cyclization and the number of amino acids in improving the transporting ability of the peptides. The flow cytometry studies suggested that the synthesized peptides were able to work efficiently as transporters for both cargos. Among all compounds, cyclic [CR]4 was found to be the most efficient peptide in transporting the cargo into cells. For instance, the cellular uptake of F'-3TC (5μM) and F'-GpYEEI (5μM) was enhanced by 16- and 20-fold, respectively, in the presence of cyclic [CR]4 compared to that of the parent compound alone. The mechanism of F'-GpYEEI uptake by cells was found to be energy-independent. The results showed that the number of amino acids and their cyclic nature can impact the efficiency of the peptide in transporting the molecular cargos.
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http://dx.doi.org/10.1016/j.bmcl.2015.11.052DOI Listing
January 2016

Tandem Approach to Benzothieno- and Benzofuropyridines from o-Alkynyl Aldehydes via Silver-Catalyzed 6-endo-dig Ring Closure.

J Org Chem 2015 Nov 26;80(21):10548-60. Epub 2015 Oct 26.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi , Delhi 110007, India.

An operationally simple silver-catalyzed tandem strategy for the synthesis of benzothienopyridines 7a-t and benzofuropyridines 8a-p by the reaction of o-alkynyl aldehyde 4a-t and 5a-p with tert-butylamine 6 under mild reaction conditions is described. The present methodology provides a facile conversion of easily accessible o-alkynyl aldehydes into medicinally useful heterocycles in good to excellent yields under mild and environmentally friendly reaction conditions with excellent regioselectivity. The developed chemistry has been successfully extended for the selective synthesis of C-4 deuterated benzothienopyridines 7u-v and benzofuropyridines 8q-r. The role of the ethanolic proton in the reaction was validated by deuterium-labeling experiments.
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http://dx.doi.org/10.1021/acs.joc.5b01647DOI Listing
November 2015

Design, synthesis, antiviral activity, and pre-formulation development of poly-L-arginine-fatty acyl derivatives of nucleoside reverse transcriptase inhibitors.

Nucleosides Nucleotides Nucleic Acids 2015 ;34(1):1-15

a Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy , University of Rhode Island , Kingston , RI , United States.

The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.
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http://dx.doi.org/10.1080/15257770.2014.945649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269296PMC
July 2015

Cyclic peptide-selenium nanoparticles as drug transporters.

Mol Pharm 2014 Oct 17;11(10):3631-41. Epub 2014 Sep 17.

Chao Family Comprehensice Cancer Center, School of Medicine, University of California, Irvine , Shanbrom Hall, 101 The City Drive South, Orange, California 92868, United States.

A cyclic peptide composed of five tryptophan, four arginine, and one cysteine [W5R4C] was synthesized. The peptide was evaluated for generating cyclic peptide-capped selenium nanoparticles (CP-SeNPs) in situ. A physical mixing of the cyclic peptide with SeO3(-2) solution in water generated [W5R4C]-SeNPs via the combination of reducing and capping properties of amino acids in the peptide structure. Transmission electron microscopy (TEM) images showed that [W5R4C]-SeNPs were in the size range of 110-150 nm. Flow cytometry data revealed that a fluorescence-labeled phosphopeptide (F'-PEpYLGLD, where F' = fluorescein) and an anticancer drug (F'-dasatinib) exhibited approximately 25- and 9-times higher cellular uptake in the presence of [W5R4C]-SeNPs than those of F'-PEpYLGLD and dasatinib alone in human leukemia (CCRF-CEM) cells after 2 h of incubation, respectively. Confocal microscopy also exhibited higher cellular delivery of F'-PEpYLGLD and F'-dasatinib in the presence of [W5R4C]-SeNPs compared to the parent fluorescence-labeled drug alone in human ovarian adenocarcinoma (SK-OV-3) cells after 2 h of incubation at 37 °C. The antiproliferative activities of several anticancer drugs doxorubicin, gemcitabine, clofarabine, etoposide, camptothecin, irinotecan, epirubicin, fludarabine, dasatinib, and paclitaxel were improved in the presence of [W5R4C]-SeNPs (50 μM) by 38%, 49%, 36%, 36%, 31%, 30%, 30%, 28%, 24%, and 17%, respectively, after 48 h incubation in SK-OV-3 cells. The results indicate that CP-SeNPs can be potentially used as nanosized delivery tools for negatively charged biomolecules and anticancer drugs.
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http://dx.doi.org/10.1021/mp500364aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186687PMC
October 2014

Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives.

Bioorg Chem 2014 Apr 17;53:75-82. Epub 2014 Feb 17.

Department of Chemistry, University of Delhi, Delhi 110007, India. Electronic address:

Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25μM. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5μM. Furthermore, the kinase inhibitory activity of compound 36 was studied against EGFR, MAPK and PDK, however no significant activity was observed at the highest tested concentration (300μM). These results provide insights for further optimization of this scaffold for designing the next generation of 2-pyridone derivatives as candidate Src kinase inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2014.02.001DOI Listing
April 2014

Base-mediated chemo- and stereoselective addition of 5-aminoindole/tryptamine and histamines onto alkynes.

J Org Chem 2014 Jan 20;79(1):172-86. Epub 2013 Nov 20.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi , Delhi 110007, India.

Transition-metal-free chemo- and stereoselective addition of 5-aminoindole (1a), tryptamine (1b), and histamine (1c) to alkynes 2a-s to synthesize the indolyl/imidazolyl enamines 3a-p, 5a-o, and 6a-e using superbasic solutions of alkali-metal hydroxides in DMSO is described. The addition of N-heterocycles onto alkynes takes places chemoselectively without affecting the 1° amino groups (aromatic and aliphatic) of 5-aminoindole, tryptamine, and histamine. The stereochemistry of the products was found to be dependent upon reaction time; an increase in reaction time leads to the formation of a mixture of E/Z isomers and the thermodynamically stable E addition product. The chemoselective addition of N-heterocycle 1a onto alkyne over thiophenol 7 and phenol 8 is supported by control experiments. Competitive experiments showed that 5-aminoindole was more reactive than tryptamine, and histamine was found to be the least reactive. The present methodology provides an efficient chemoselective method to synthesize a variety of (Z)-enamines of 5-aminoindole, tryptamine, and histamine without affecting the 1° amino group. The presence of the free amino group in enamines could be further used for synthetic elaboration, which proved to be highly advantageous for structural and biological activity assessments.
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http://dx.doi.org/10.1021/jo402352vDOI Listing
January 2014

Self-Assembled Surfactant Cyclic Peptide Nanostructures as Stabilizing Agents.

Soft Matter 2013 Oct 7;9(39). Epub 2013 Aug 7.

7 Greenhouse Road, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, 02881, USA.

A number of cyclic peptides including [FR], [FK], [WR], [CR], [AK], and [WK] (n = 3-5) containing L-amino acids were produced using solid-phase peptide synthesis. We hypothesized that an optimal balance of hydrophobicity and charge could generate self-assembled nanostructures in aqueous solution by intramolecular and/or intermolecular interactions. Among all the designed peptides, [WR] (n = 3-5) generated self-assembled vesicle-like nanostructures at room temperature as shown by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and/or dynamic light scattering (DLS). This class of peptides represents the first report of surfactant-like cyclic peptides that self-assemble into nanostructures. A plausible mechanistic insight into the self-assembly of [WR] was obtained by molecular modeling studies. Modified [WR] analogues, such as [WR], [WR], [WR], and [WR], exhibited different morphologies to [WR] as shown by TEM observations. [WR] exhibited a significant stabilizing effect for generated silver nanoparticles and glyceraldehyde-3-phosphate dehydrogenase activity. These studies established a new class of surfactant-like cyclic peptides that self-assembled into nanostructures and could have potential applications for the stabilization of silver nanoparticles and protein biomolecules.
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http://dx.doi.org/10.1039/C3SM50764EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811951PMC
October 2013

Synthesis and antiproliferative activities of quebecol and its analogs.

Bioorg Med Chem Lett 2013 Oct 2;23(19):5329-31. Epub 2013 Aug 2.

Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India.

Simple and efficient synthesis of quebecol and a number of its analogs was accomplished in five steps. The synthesized compounds were evaluated for antiproliferative activities against human cervix adenocarcinoma (HeLa), human ovarian carcinoma (SK-OV-3), human colon carcinoma (HT-29), and human breast adenocarcinoma (MCF-7) cancer cell lines. Among all the compounds, 7c, 7d, 7f, and 8f exhibited antiproliferative activities against four tested cell lines with inhibition over 80% at 75 μM after 72 h, whereas, compound 7b and 7g were more selective towards MCF-7 cell line. The IC50 values for compounds 7c, 7d, and 7f were 85.1 μM, 78.7 μM, and 80.6 μM against MCF-7 cell line, respectively, showing slightly higher antiproliferative activtiy than the synthesized and isolated quebecol with an IC50 value of 104.2 μM against MCF-7.
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http://dx.doi.org/10.1016/j.bmcl.2013.07.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816661PMC
October 2013

On water: silver-catalyzed domino approach for the synthesis of benzoxazine/oxazine-fused isoquinolines and naphthyridines from o-alkynyl aldehydes.

J Org Chem 2013 Jul 19;78(13):6657-69. Epub 2013 Jun 19.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India.

An operationally simple domino approach for the silver-catalyzed synthesis of oxazine/benzoxazine-fused isoquinolines 5a-q and naphthyridines 6a-v by the reaction of o-alkynyl aldehydes 3a-aa with amines having embedded nucleophiles 4a-d under mild reaction condition in water is described. The reaction shows selective C-N bond formation on the more electrophilic alkynyl carbon resulting in the formation of 6-endo-dig cyclized product. The competitive experiments show the viability of an intramolecular nucleophilic attack over an intermolecular attack of the external nucleophile. This methodology accommodates wide functional group variation, which proves to be useful for structural and biological assessment.
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http://dx.doi.org/10.1021/jo4009639DOI Listing
July 2013

Tandem synthesis of pyrroloacridones via [3 + 2] alkyne annulation/ring-opening with concomitant intramolecular aldol condensation.

J Org Chem 2013 Jun 14;78(11):5372-84. Epub 2013 May 14.

Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India.

An efficient cascade strategy for the direct synthesis of pyrrolo[3,2,1-de]acridones 4a-v, 5a-h from iodo-pyranoquinolines 2a-i by the palladium-catalyzed regioselective [3 + 2] alkyne annulation/ring-opening followed by intramolecular aldol condensation under microwave irradiation is described. The chemistry involves the in situ formation of pyrroloquinolines Y, via palladium-catalyzed selective [3 + 2] annulation of iodopyranoquinolines and internal akynes with ring-opening and successive intramolecular cross-aldol condensation. Both the symmetrical and unsymmetrical internal alkynes were reacted smoothly to provide the desired pyrroloacridones in good yields. This methodology provides the facile conversion of easily accessble iodopyranoquinoline into highly functionalized biologically important pyrroloacridones in a single process.
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http://dx.doi.org/10.1021/jo400539xDOI Listing
June 2013

Silver-catalyzed tandem synthesis of naphthyridines and thienopyridines via three-component reaction.

J Org Chem 2013 May 17;78(9):4386-401. Epub 2013 Apr 17.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India.

An efficient approach for the silver-catalyzed regioselective tandem synthesis of highly functionalized 1,2-dihydrobenzo[1,6]naphthyridines 6a-z and 7a-e by the reaction of ortho-alkynylaldehydes 3a-n with amines 4a-d and ketones 5a-c/active methylene compounds 5d-g, under mild reaction conditions, is described. The scope of the developed chemistry was successfully extended for the direct synthesis of 1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridines 8a-e, which is known as the sulfur analogue of β-carbolines. Naphthyridines 6a-z and thienopyridines 8a-e were obtained via dual activation concept using l-proline as organocatalyst; however, naphthyridines 7a-e were synthesized without using organocatalyst. The reaction shows selective N-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized products. Reactivity behavior of electron-deficient and electron-rich ortho-alkynylaldehydes in the synthesis of naphthyridines and thienopyridine by three-component reaction is supported by the control experiment.
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http://dx.doi.org/10.1021/jo400400cDOI Listing
May 2013

Palladium-catalyzed Sonogashira-coupling conjoined C-H activation: a regioselective tandem strategy to access indolo- and pyrrolo[1,2-a]quinolines.

J Org Chem 2012 Nov 30;77(22):10382-92. Epub 2012 Oct 30.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India.

An operationally simple approach for the regioselective tandem synthesis of indolo[1,2-a]quinolines 4a-v and pyrrolo[1,2-a]quinolines 5a-k from 1-(2-bromophenyl)-1H-indole/pyrrole/imidazole 1a-c, 2a,b by the palladium-catalyzed sequential C-C bond formation is described. The developed approach involves the palladium-catalyzed Sonogashira coupling followed by the intramolecular C-C bond formation via C-H activation, which leads to the formation of 6-endo-dig cyclized product. This synthetic methodology accommodates wide functional group variation on alkyne, which proves to be advantageous for the structural and biological activity assessments.
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http://dx.doi.org/10.1021/jo302112aDOI Listing
November 2012

Ionic liquid as soluble support for synthesis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles.

J Org Chem 2012 Oct 8;77(20):9391-6. Epub 2012 Oct 8.

Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India.

A convenient synthesis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles was achieved using an ionic liquid as a novel soluble support. Ionic liquid-supported sulfonyl hydrazine was synthesized and reacted with a number of ketones to afford the corresponding ionic liquid-supported hydrazones that were converted to 1,2,3-thiadiazoles in the presence of thionyl chloride. The reaction of ionic liquid-supported hydrazones with selenium dioxide in acetonitrile afforded 1,2,3-selenadiazoles. The advantages of this methodology were the ease of workup, simple reaction conditions, and high purity.
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http://dx.doi.org/10.1021/jo301607aDOI Listing
October 2012

Palladium-catalyzed regioselective [3 + 2] annulation of internal alkynes and iodo-pyranoquinolines with concomitant ring opening.

Org Lett 2012 Oct 28;14(20):5184-7. Epub 2012 Sep 28.

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

A regioselective tandem synthesis of highly functionalized pyrrolo[1,2-a]quinolines has been developed through a novel strategy by palladium-catalyzed [3 + 2] annulation of iodo-pyranoquinolines and internal alkynes with subsequent ring opening. Pyranoquinoline with n-alkyl substitution at the 3-position leads to the formation of pyrrolo-acridones via [3 + 2] annulations/ring opening and successive intramolecular cross-aldol condensation.
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http://dx.doi.org/10.1021/ol3022935DOI Listing
October 2012

Cyclic peptide-capped gold nanoparticles as drug delivery systems.

Mol Pharm 2013 Feb 5;10(2):500-11. Epub 2012 Oct 5.

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, Rhode Island 02881, United States.

A number of cyclic peptides were synthesized and evaluated as simultaneous reducing and capping agents for generation of cyclic peptide-capped gold nanoparticles (CP-AuNPs). Among them, direct dissolution of cyclic peptides containing alternate arginine and tryptophan [WR](n) (n = 3-5) into an aqueous solution of AuCl(4)(-) led to the formation of CP-AuNPs, through the reducing activity of tryptophan residues and attraction of positively charged arginine residues toward chloroaurate anions in the reaction environment. Differential interference contrast microscopy of fluorescence-labeled lamivudine in the presence of [WR](4)-capped AuNPs showed significantly higher cellular delivery of antiviral drug versus that of parent drug alone. Flow cytometry studies also showed that the cellular uptake of fluorescence-labeled lamivudine, emtricitabine, and stavudine was significantly enhanced in human ovarian adenocarcinoma (SK-OV-3) cells in the presence of [WR](4)-AuNPs. For example, fluorescence labeled lamivudine-loaded [WR](4)-AuNPs exhibited approximately 12- and 15-times higher cellular uptake than that of fluorescence labeled lamivudine alone in CCRF-CEM cells and SK-OV-3 cells, respectively. Confocal microscopy revealed that the presence of the [WR](4)-AuNPs enhanced the retention and nuclear localization of doxorubicin in SK-OV-3 cells after 24 h. These data suggest that these complexes can be used as potential noncovalent prodrugs for delivery of antiviral and anticancer agents.
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http://dx.doi.org/10.1021/mp300448kDOI Listing
February 2013

Site-selective electrophilic cyclization and subsequent ring-opening: a synthetic route to pyrrolo[1,2-a]quinolines and indolizines.

J Org Chem 2012 Oct 17;77(19):8562-73. Epub 2012 Sep 17.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India.

An efficient strategy for the synthesis of pyrrolo[1,2-a]quinolines and indolizines from pyranoquinolines via site-selective electrophilic cyclization and subsequent opening of pyran ring using silver/iodine under mild reaction conditions is described. This approach involves the preferential attack of the pyridyl nitrogen over aryl ring and leads to the formation of 5-endo-dig cyclized products. Quantum chemical calculations between C-N (ΔE(a) = 9.01 kcal/mol) and C-C (ΔE(a) = 31.31 kcal/mol) bond formation were performed in order to rationalize the observed site selectivity. Structure of the products were confirmed by the X-ray crystallographic studies. Iodo-substituted compounds generated by the electrophilic iodocyclization were further diversified via Pd-catalyzed cross-coupling reactions.
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http://dx.doi.org/10.1021/jo3015374DOI Listing
October 2012

Copper-catalyzed tandem synthesis of indolo-, pyrrolo[2,1-a]isoquinolines, naphthyridines and bisindolo/pyrrolo[2,1-a]isoquinolines via hydroamination of ortho-haloarylalkynes followed by C-2 arylation.

J Org Chem 2012 Sep 4;77(18):8191-205. Epub 2012 Sep 4.

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India.

An efficient approach for the copper-catalyzed regioselective tandem synthesis of diversely substituted indolo[2,1-a]isoquinolines 11a-r, pyrrolo[2,1-a]isoquinolines 12a-d, and indolo-, pyrrolo[2,1-f][1,6]naphthyridines 14a-f via preferential addition of the heterocyclic amines onto the ortho-haloarylalkynes over N-arylation followed by intramolecular C-2 arylation is described. The scope of the developed chemistry was successfully extended for the direct synthesis of bisindolo-, pyrrolo[2,1-a]isoquinolines 15a-g, a regioisomer of the bisindolo[1,2-a]quinolines used as organic single-crystal field-effect transistor. Hydroxymethyl benzotriazole, which is an inexpensive and air stable compound, has been used as a ligand to carry out this one-step conversion of simple, readily available starting materials into an interesting class of heterocyclic compounds.
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http://dx.doi.org/10.1021/jo301572pDOI Listing
September 2012

Conformationally constrained peptides as protein tyrosine kinase inhibitors.

Curr Pharm Des 2012 ;18(20):2852-66

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, 02881, USA.

Protein kinases are enzymes that catalyze the transfer of the γ-phosphate group from ATP to the hydroxyl groups in side chains of tyrosine, serine, or threonine. Protein kinases are divided in two classes: tyrosine kinases (TKs) and serine/threonine kinases (STKs). Overexpression or activation of protein tyrosine kinases (PTKs) has been found to be responsible for the development of many diseases, including cancer, inflammation, and many cardiovascular and neurodegenerative disorders. Thus, the design of PTK inhibitors (PTKIs) has become a subject of a major interest for the pharmaceutical industry. A number of marketed PTKIs that target conserved ATP binding site of PTKs were found to demonstrate toxicity (e.g., imitanib and sorafenib) or to generate resistance (e.g., imitanib and vemurafenib in chronic myeloid leukemia and metastatic melanoma, respectively). Thus, alternative strategies are urgently required for designing novel PTKIs. Linear peptides designed based on the natural protein substrates of PTKs have been introduced to target unique and non conserved PTK regions, such as substrate binding site. These compounds are more specific than the small molecules that usually target conserved ATP binding site. On the other hand, linear peptides are susceptible to hydrolysis by endogenous peptidases. Cyclization of linear peptides has led to generation of diverse conformationally constrained structures as PTKIs. Introduction of the conformational constraints enhances the stability towards proteases, the free energy upon binding, and binding affinity, but reduces the conformational entropy penalty upon receptor binding. Herein, design strategies for conformationally constrained peptides and their application as PTKIs are discussed.
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http://dx.doi.org/10.2174/138161212800672714DOI Listing
October 2012
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