Publications by authors named "Pramod K Sahu"

30 Publications

  • Page 1 of 1

Restructuring the Cellular Responses: Connecting Microbial Intervention With Ecological Fitness and Adaptiveness to the Maize ( L.) Grown in Saline-Sodic Soil.

Front Microbiol 2020 12;11:568325. Epub 2021 Feb 12.

Plant-Microbe Interaction and Rhizosphere Biology Lab, ICAR-National Bureau of Agriculturally Important Microorganisms, Kushmaur, India.

Salt stress hampers plant growth and development. It is now becoming one of the most important threats to agricultural productivity. Rhizosphere microorganisms play key roles in modulating cellular responses and enable plant tolerant to salt stress, but the detailed mechanisms of how this occurs need in-depth investigation. The present study elucidated that the microbe-mediated restructuring of the cellular responses leads to ecological fitness and adaptiveness to the maize ( L.) grown in saline-sodic soil. In the present study, effects of seed biopriming with MF-01, MF-15, and MF-08 singly and in consortium on different growth parameters were recorded. Soil biochemical and enzymatic analyses were performed. The activity and gene expression of High-Affinity K Transporter (), Sodium/Hydrogen exchanger 1 (), and antioxidant enzymes (, , , , , and ) were studied. The expression of genes related to lateral root development (, , and ) and root architecture were also carried out. Seeds bioprimed with consortium of all three strains have been shown to confer increased seed germination (23.34-26.31%) and vigor indices (vigor index I: 38.71-53.68% and vigor index II: 74.11-82.43%) as compared to untreated control plant grown in saline-sodic soil at 30 days of sowing. Results indicated that plants treated with consortium of three strains induced early production of adventitious roots (tips: 4889.29, forks: 7951.57, and crossings: 2296.45) in maize compared to plants primed with single strains and untreated control (tips: 2019.25, forks: 3021.45, and crossings: 388.36), which was further confirmed by assessing the transcript level of (7.20 folds), (4.50 folds), and (12.00 folds) genes using the qPCR approach. The uptake and translocation of Na, K, and Ca significantly varied in the plants treated with bioagents alone or in consortium. qRT-PCR analysis also revealed that the and expression levels varied significantly in the maize root upon inoculation and showed a 6- to 11-fold increase in the plants bioprimed with all the three strains in combination. Further, the activity and gene expression levels of antioxidant enzymes were significantly higher in the leaves of maize subjected seed biopriming with bioagents individually or in combination (3.50- to 12.00-fold). Our research indicated that and expression could effectively enhance salt tolerance by maintaining an optimal Na/K balance and increasing the antioxidant activity that keeps reactive oxygen species at a low accumulation level. Interestingly, up-regulation of , , , , and and genes encoding antioxidants regulates the cellular responses that could effectively enhance the adaptiveness and ultimately leads to better plant growth and grain production in the maize crop grown in saline-sodic soil.
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http://dx.doi.org/10.3389/fmicb.2020.568325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907600PMC
February 2021

Sustainable Synthesis and Characterization of Ni-Al-Containing Double-Layered Nanocatalysts and Their Catalytic Activity.

ACS Omega 2018 Dec 31;3(12):18976-18983. Epub 2018 Dec 31.

School of Studies in Chemistry and Department of Industrial Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India.

Sustainable synthesis of Ni-Al double-layered catalysts by the coprecipitation method is described. Synthesized double-layered catalysts have been characterized by X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared, and thermogravimetric analyses, which confirmed a hydrotalcite-like structure. In addition, the impact of aging time and temperature on the activity of catalyst has been investigated. Furthermore, it has been confirmed by SEM and TEM analyses that the recovered catalyst has retained its structure. It has also been observed that the prepared material has potency to catalyze the reaction without loss in the yield. To explore the reactivity of the material, the catalyst has been examined in the synthesis of -(2-hydroxyphenyl)benzamide under solvent-free conditions. The overall process afforded the product with high purity and high yields within short time.
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http://dx.doi.org/10.1021/acsomega.8b01994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643471PMC
December 2018

Metal-Free Construction of Fused Pyrimidines via Consecutive C-C and C-N Bond Formation in Water.

ACS Omega 2018 Nov 7;3(11):15035-15042. Epub 2018 Nov 7.

School of Studies in Chemistry and Department of Industrial Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India.

A facile and efficient protocol has been developed for mild construction of fused pyrimidines via l-proline-catalyzed reaction of 4-hydroxy coumarins, aldehydes, and 2-aminobenzothiazoles/urea. The reaction has been carried out rapidly and efficiently in water under mild and metal-free conditions. Current etiquette has efficiently synthesized the heterocycles and avoids the use of hazardous solvents over conventional organic solvents. A plausible reaction mechanism has been established in this study. This study represents the first case in which l-proline as a homogeneous catalyst has been explored in the synthesis of fused pyrimidines in water in view of simple procedure and acceptable efficiency. This method gives the target product in excellent yield with ease of workup.
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http://dx.doi.org/10.1021/acsomega.8b01993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643823PMC
November 2018

- and Methyl Jasmonate-Induced Resistance to Through Enhanced Phenylpropanoid Activities in Bread Wheat ( L.).

Front Microbiol 2019 31;10:1697. Epub 2019 Jul 31.

Plant-Microbe Interaction and Rhizosphere Biology Lab, ICAR-National Bureau of Agriculturally Important Microorganisms, Mau, India.

The aim of the present study was to evaluate the impact of UBSTH-501- and methyl jasmonate-induced systemic resistance and their integration on the spot blotch pathogen, through enhanced phenylpropanoid activities in bread wheat ( L.). It was found that the application of MeJA (>100 mg L) inhibits the germination of spores under controlled laboratory conditions. To assess the effect of MeJA (150 mg L) in combination with the biocontrol agent UBSTH-501 , a green house experiment was conducted. For this, biocontrol agent UBSTH-501 was applied as seed treatment, whereas MeJA (150 mg L) was applied 5 days prior to pathogen inoculation. Results indicated that application of MeJA (150 mg L) did not affect the root colonization of wheat by UBSTH-501 in the rhizosphere. The combined application of UBSTH-501 and MeJA also enhanced indole acetic acid production in the rhizosphere (4.92 μg g of soil) which in turn helps in plant growth and development. Further, the combined application found to enhance the activities of defense related enzymes catalase (5.92 EU min g fresh wt.), ascorbate peroxidase [μmol ascorbate oxidized (mg prot) min], phenylalanine ammonia lyase (102.25 μmol cinnamic acid h mg fresh wt.) and peroxidase (6.95 Unit mg min fresh wt.) significantly in the plants under treatment which was further confirmed by assessing the transcript level of and genes using semi-quantitative PCR approach. The results showed manifold increase in salicylic acid (SA) along with enhanced accumulation of total free phenolics, ferulic acid, caffeic acid, coumaric acid, and chlorogenic acid in the leaves of the plants treated with the biocontrol agent alone or in combination with MeJA. A significant decrease in the disease severity (17.46%) and area under disease progress curve (630.32) were also observed in the treatments with biocontrol agent and MeJA in combination as compared to alone treated plant (56.95% and 945.50, respectively). Up-regulation of phenylpropanoid cascades in response to exogenous application of MeJA and the biocontrol agent was observed. It was depicted from the results that PAL is the primary route for lignin production in wheat which reduces cell wall disruption and tissue disintegration and increases suberization and lignification of the plant cell as seen by Scanning Electron microphotographs. These results clearly indicated that exogenous application of MeJA with inducing JA- and/or SA-dependent defense signaling after pathogen challenge may increase the resistance to spot blotch by stimulating enzymatic activities and the accumulation of phenolic compounds in a cooperative manner. This study apparently provides the evidence of biochemical cross-talk and physiological responses in wheat following MeJA and biocontrol agent treatment during the bio-trophic infection.
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http://dx.doi.org/10.3389/fmicb.2019.01697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685482PMC
July 2019

Presenile cataract and its risk factors: A case control study.

J Family Med Prim Care 2019 Jun;8(6):2120-2123

UCMS and Guru Teg Bahadur Hospital, Dilshad Garden, New Delhi, India.

Purpose: Early onset opacification of the lens (cataract) has been observed to be on the rise globally. This study was conducted to determine the various types of presenile cataract and to determine the probable risk factors associated with the occurrence of presenile cataract.

Materials And Methods: Patients in the age group of 18-40 years attending the Out-Patient Clinic of the Ophthalmology Department who were found to have presenile cataract were recruited as cases. An equal number of consecutive patients of the same age group were included in the control group. Those who gave consent to participate in the study were interviewed through a preformed questionnaire and underwent a complete ocular examination and set of blood investigations. The type of cataract was noted, data obtained were compiled, and examination and investigations done were documented and analyzed using frequency distribution and Chi-squared test.

Results: In total, 90 cases and 90 controls that fulfilled the inclusion criteria were recruited. Most common type of cataract was found to be posterior subcapsular cataract. Presenile cataract was observed to be significantly associated with tobacco intake ( = 0.035), hypercholesterolemia ( = 0.002), fuel exposure ( = 0.004), and lower socioeconomic status ( = <0.001).

Conclusions: Tobacco chewing, hypercholesterolemia, and excessive fuel exposure are risk factors for early development of cataract.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_267_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618174PMC
June 2019

Design, Synthesis, and Anti-RNA Virus Activity of 6'-Fluorinated-Aristeromycin Analogues.

J Med Chem 2019 07 20;62(13):6346-6362. Epub 2019 Jun 20.

Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 151-742 , Korea.

The 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell -adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and -methyladenosine analogues showed potent inhibition against SAH hydrolase, while only the adenosine derivatives exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin () showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075649PMC
July 2019

Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species.

Sci Rep 2019 03 13;9(1):4346. Epub 2019 Mar 13.

National Research Laboratory of Molecular Microbiology and Toxicology, Department of Agricultural Biotechnology and Center for Food Safety and Toxicology, Seoul National University, Seoul, 08826, South Korea.

Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.
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http://dx.doi.org/10.1038/s41598-019-39554-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416295PMC
March 2019

Evaluation of intravitreal bevacizumab as monotherapy and in combination with macular grid laser photocoagulation in diffuse diabetic macular edema.

Oman J Ophthalmol 2018 Sep-Dec;11(3):248-253

Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi University, New Delhi, India.

Background And Objective: The objective of the study was to compare the efficacy of intravitreal bevacizumab (IVB) as monotherapy versus combination with modified macular grid (MMG) laser photocoagulation in the primary treatment of diffuse diabetic macular edema (DDME).

Materials And Methods: A prospective randomized trial was carried out in sixty eyes with DDME after Institutional Ethical clearance. Group A received three doses of IVB at a 1-month interval. Group B received MMG in addition to IVB. Complete examination including best-corrected visual acuity (BCVA) (Snellen's), central macular thickness (CMT) using spectral domain-optical coherence tomography was carried out at 0, 1, 4, 8, 12, and 24 weeks.

Results: mean CMT at baseline, 12 and 24 weeks in Group A was 401 (±76), 280 (±49), and 307 (±46) and in Group B, 405 (±73), 237 (±33), and 242 (±45), respectively. Group B had significantly greater reductions ( < 0.001) from 12 weeks onward. BCVA and contrast sensitivity showed improvements with no significant difference.

Conclusion: Combined therapy has more advantage in primary DDME by reducing CMT on longer follow-up.
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http://dx.doi.org/10.4103/ojo.OJO_196_2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219322PMC
December 2018

Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents.

Chem Cent J 2018 Nov 1;12(1):110. Epub 2018 Nov 1.

Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21500, Egypt.

Background: Nitrogen heterocyclic rings and sulfonamides have attracted attention of several researchers.

Results: A series of regioselective imidazole-based mono- and bis-1,4-disubstituted-1,2,3-triazole-sulfonamide conjugates 4a-f and 6a-f were designed and synthesized. The first step in the synthesis was a regioselective propargylation in the presence of the appropriate basic catalyst (EtN and/or KCO) to afford the corresponding mono-2 and bis-propargylated imidazoles 5. Second, the ligation of the terminal C≡C bond of mono-2 and/or bis alkynes 5 to the azide building blocks of sulfa drugs 3a-f using optimized conditions for a Huisgen copper (I)-catalysed 1,3-dipolar cycloaddition reaction yielded targeted 1,2,3-triazole hybrids 4a-f and 6a-f. The newly synthesized compounds were screened for their in vitro antimicrobial and antiproliferative activities. Among the synthesized compounds, compound 6a emerged as the most potent antimicrobial agent with MIC values ranging between 32 and 64 µg/mL. All synthesized molecules were evaluated against three aggressive human cancer cell lines, PC-3, HepG2, and HEK293, and revealed sufficient antiproliferative activities with IC values in the micromolar range (55-106 μM). Furthermore, we conducted a receptor-based electrostatic analysis of their electronic, steric and hydrophobic properties, and the results were in good agreement with the experimental results. In silico  ADMET prediction studies also supported the experimental biological results and indicated that all compounds are nonmutagenic and noncarcinogenic.

Conclusion: In summary, we have successfully synthesized novel targeted benzimidazole-1,2,3-triazole-sulfonamide hybrids through 1,3-dipolar cycloaddition reactions between the mono- or bis-alkynes based on imidazole and the appropriate sulfonamide azide under the optimized Cu(I) click conditions. The structures of newly synthesized sulfonamide hybrids were confirmed by means of spectroscopic analysis. All newly synthesized compounds were evaluated for their antimicrobial and antiproliferative activities. Our results showed that the benzimidazole-1,2,3-triazole-sulfonamide hybrids inhibited microbial and fungal strains within MIC values from 32 to 64 μg/mL. The antiproliferative evaluation of the synthesized compounds showed sufficient antiproliferative activities with IC values in the micromolar range (55-106 μM). In conclusion, compound 6a has remarkable antimicrobial activity. Pharmacophore elucidation of the compounds was performed based on in silico ADMET evaluation of the tested compounds. Screening results of drug-likeness rules showed that all compounds follow the accepted rules, meet the criteria of drug-likeness and follow Lipinski's rule of five. In addition, the toxicity results showed that all compounds are nonmutagenic and noncarcinogenic.
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http://dx.doi.org/10.1186/s13065-018-0479-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768023PMC
November 2018

Design, Synthesis and Anticancer Screening of Novel Benzothiazole-Piperazine-1,2,3-Triazole Hybrids.

Molecules 2018 Oct 27;23(11). Epub 2018 Oct 27.

Faculty of Science, Al al-Bayt University, Al-Mafraq 25113, Jordan.

A library of novel regioselective 1,4-di and 1,4,5-trisubstituted-1,2,3-triazole based benzothiazole-piperazine conjugates were designed and synthesized using the click synthesis approach in the presence and absence of the Cu(I) catalyst. Some of these 1,2,3-triazole hybrids possess in their structures different heterocyclic scaffold including 1,2,4-triazole, benzothiazole, isatin and/or benzimidazole. The newly designed 1,2,3-triazole hybrids were assessed for their antiproliferative inhibition potency against four selected human cancer cell lines (MCF7, T47D, HCT116 and Caco2). The majority of the synthesized compounds demonstrated moderate to potent activity against all the cancer cell lines examined. Further, we have established a structure activity relationship with respect to the in silico analysis of ADME (adsorption, distribution, metabolism and excretion) analysis and found good agreement with in vitro activity.
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http://dx.doi.org/10.3390/molecules23112788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278665PMC
October 2018

Orally active, species-independent novel A adenosine receptor antagonist protects against kidney injury in db/db mice.

Exp Mol Med 2018 04 20;50(4):1-14. Epub 2018 Apr 20.

Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, AAR, AAR, AAR, and AAR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective AAR antagonist, LJ-1888, ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for AAR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective AAR antagonist, may become a novel therapeutic agent against DKD.
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http://dx.doi.org/10.1038/s12276-018-0053-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938017PMC
April 2018

Comparative Evaluation of Corneal Endothelium in Patients with Diabetes Undergoing Phacoemulsification.

Middle East Afr J Ophthalmol 2017 Apr-Jun;24(2):74-80

Department of Ophthalmology, UCMS and GTB Hospital, New Delhi, India.

Purpose: The purpose of this study is to determine if phacoemulsification with posterior chamber foldable intraocular lens implantation has a greater impact on the corneal endothelium of type 2 diabetic patients as compared to nondiabetic controls.

Materials And Methods: This study compared the corneal endothelial status in sixty patients with diabetes with good glycemic control and sixty nondiabetic controls before and after (1 week, 1 month, 2 month, and 3 month) uneventful phacoemulsification. Central corneal endothelial cell density, percentage hexagonality, and coefficient of variation were measured using a noncontact specular microscope. Central corneal thickness was taken as a surrogate marker for endothelium functional status.

Results: Data were age and sex matched. Patients with diabetes showed significantly higher loss in endothelial cell count as compared to nondiabetic controls. Furthermore, the patients with diabetes showed a slower recovery trend in the endothelial healing response as evidenced by lower change in the coefficient of variation. Significant correlation was found between energy used and change in endothelial count as well as coefficient of variation in nondiabetics only.

Conclusion: In spite of good glycemic control, patients with diabetes have significantly more endothelial damage in comparison to nondiabetic controls with similar nuclear grading and phaco energy used. This warrants a more careful use of phaco energy in patient with diabetes.
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http://dx.doi.org/10.4103/meajo.MEAJO_242_15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598306PMC
October 2017

Determination and validation of LJ-2698, a potent human A adenosine receptor antagonist, in rat plasma by liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic study.

Arch Pharm Res 2017 Aug 29;40(8):952-961. Epub 2017 Jul 29.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

LJ-2698, a highly potent human A adenosine receptor antagonist with nucleoside structure, was designed to have a minimal species dependence. For further pre-clinical studies, analytical method for the detection of LJ-2698 in rat plasma was developed by liquid chromatography-tandem mass. Plasma samples were processed by protein precipitation method with acetonitrile, using losartan as the internal standard (IS). Chromatographic separation was carried out using a Kinetex C18 column (100 × 4.6 mm; 100 Å; 2.6 μ) with acetonitrile/water with 0.2% (v/v) formic acid (65:35, v/v) in the isocratic mode at a flow rate of 0.4 mL/min. Mass spectrometric detection in multiple reaction monitoring mode was performed with positive electrospray ionization. The mass transitions of LJ-2698 and IS were m/z 412.3 → 294.1 and m/z 423.1 → 207.2, respectively. The calibration curves were linear in the range 5.00-5000 ng/mL (r  ≥ 0.998). The lower limit of quantification was established as 5.00 ng/mL. Within- and between-run precisions were <7.01%, as relative standard deviation; and accuracies were in the range 3.37-3.64%, as relative error. The validated method was successfully applied to its pharmacokinetic evaluation after intravenous and oral administration in rats, and the dose-dependent pharmacokinetic behavior of LJ-2698 was elucidated for the first time.
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http://dx.doi.org/10.1007/s12272-017-0935-9DOI Listing
August 2017

Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents.

Molecules 2017 Jul 12;22(7). Epub 2017 Jul 12.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

A series of acyclic selenopurine nucleosides - and - were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir () exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC = 1.47 µM) and HSV-2 (EC = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives - exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative , indicating that they might act as prodrugs of seleno-ganciclovir ().
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http://dx.doi.org/10.3390/molecules22071167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152377PMC
July 2017

Stereoselective Synthesis of 4'-Selenonucleosides via the Seleno-Michael Reaction.

Curr Protoc Nucleic Acid Chem 2017 06 19;69:14.13.1-14.13.15. Epub 2017 Jun 19.

Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, South Korea.

5'-Homo-4'-selenonucleosides, a class of next-generation nucleosides, are synthesized from D-ribose via a 4-selenosugar intermediate. The key step in synthesizing this intermediate is a seleno-Michael reaction. 5'-Homo-4'-selenouridine and -adenosine are prepared using Pummerer-type and Vorbrüggen condensation, respectively. © 2017 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpnc.27DOI Listing
June 2017

N-Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation.

J Med Chem 2017 04 19;60(8):3422-3437. Epub 2017 Apr 19.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.

Potent and selective A adenosine receptor (AR) agonists were identified by the replacement of 4'-oxo- or 4'-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4'-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N-3-iodobenzyl analogue 3d was found to be the most potent AAR full agonist (K = 0.57 nM), which was ≥800- and 1900-fold selective for AAR and AAR, respectively. In the N-cycloalkyl series, 2-Cl analogues generally exhibited better hAAR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N-3-halobenzyl series. N isomers 3t and 3u were much weaker in binding than corresponding N isomers, but compound 3t lacked AAR activation, appearing to be a weak antagonist. 2-Cl-N-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential for the development of 4'-selenonucleoside AAR agonists as novel antistroke agents.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479327PMC
April 2017

Abiotic Stress Responses and Microbe-Mediated Mitigation in Plants: The Omics Strategies.

Front Plant Sci 2017 9;8:172. Epub 2017 Feb 9.

Department of Microbiology, School of Edaphic Stress Management, National Institute of Abiotic Stress Management, Indian Council of Agricultural Research Baramati, India.

Abiotic stresses are the foremost limiting factors for agricultural productivity. Crop plants need to cope up adverse external pressure created by environmental and edaphic conditions with their intrinsic biological mechanisms, failing which their growth, development, and productivity suffer. Microorganisms, the most natural inhabitants of diverse environments exhibit enormous metabolic capabilities to mitigate abiotic stresses. Since microbial interactions with plants are an integral part of the living ecosystem, they are believed to be the natural partners that modulate local and systemic mechanisms in plants to offer defense under adverse external conditions. Plant-microbe interactions comprise complex mechanisms within the plant cellular system. Biochemical, molecular and physiological studies are paving the way in understanding the complex but integrated cellular processes. Under the continuous pressure of increasing climatic alterations, it now becomes more imperative to define and interpret plant-microbe relationships in terms of protection against abiotic stresses. At the same time, it also becomes essential to generate deeper insights into the stress-mitigating mechanisms in crop plants for their translation in higher productivity. Multi-omics approaches comprising genomics, transcriptomics, proteomics, metabolomics and phenomics integrate studies on the interaction of plants with microbes and their external environment and generate multi-layered information that can answer what is happening in real-time within the cells. Integration, analysis and decipherization of the big-data can lead to a massive outcome that has significant chance for implementation in the fields. This review summarizes abiotic stresses responses in plants in-terms of biochemical and molecular mechanisms followed by the microbe-mediated stress mitigation phenomenon. We describe the role of multi-omics approaches in generating multi-pronged information to provide a better understanding of plant-microbe interactions that modulate cellular mechanisms in plants under extreme external conditions and help to optimize abiotic stresses. Vigilant amalgamation of these high-throughput approaches supports a higher level of knowledge generation about root-level mechanisms involved in the alleviation of abiotic stresses in organisms.
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http://dx.doi.org/10.3389/fpls.2017.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299014PMC
February 2017

Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues.

Authors:
Pramod K Sahu

Eur J Med Chem 2016 Oct 21;121:510-516. Epub 2016 May 21.

School of Studies in Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India; Department of Industrial Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India. Electronic address:

New fourteen 3,4-dihydropyrimidine derivatives/analogues of curcumin (2a-2n) were designed, synthesized and biologically evaluated for their cytotoxicity and antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines HeLa, HCT-116 and QG-56 by MTT assay method. From SAR study, it has been revealed that particularly, compound 2e and 2j (IC50 value 12.5 μM) have shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 3,4-dihydropyrimidines of curcumin, 2c, 2d, 2j and 2n exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally. Therefore, we conclude that physico-chemical analyses may prove structural features of curcumin analogues with their promising combined cytotoxicity/antioxidant activity and it is also concluded from virtual and practical screening that the compounds were varied to possess a broad range of lipophilic character, revealed by Log P values.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.037DOI Listing
October 2016

Design, synthesis, and anticancer activity of C8-substituted-4'-thionucleosides as potential HSP90 inhibitors.

Bioorg Med Chem 2016 08 20;24(16):3418-28. Epub 2016 May 20.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address:

A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100μM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity.
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http://dx.doi.org/10.1016/j.bmc.2016.05.041DOI Listing
August 2016

Structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives.

Bioorg Med Chem Lett 2016 Feb 7;26(4):1342-7. Epub 2015 Dec 7.

School of Studies in Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India; Department of Industrial Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India.

Series of curcumin derivatives/analogues were designed and efficient method for synthesis thereof is described. All the synthesized compounds have been screened for their cytotoxicity and evaluated their antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines Hep-G2, HCT-116 and QG-56 by MTT assay method. Structure activity relationship has revealed that particularly, compound 3c, (IC50 value 6.25 μM) has shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 4H-pyrimido[2,1-b]benzothiazole derivatives (2e and 2f), pyrazoles (3a, 3b, 3c and 3d) benzylidenes (4d) exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally.
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http://dx.doi.org/10.1016/j.bmcl.2015.12.013DOI Listing
February 2016

Selenoacyclovir and Selenoganciclovir: Discovery of a New Template for Antiviral Agents.

J Med Chem 2015 Nov 23;58(21):8734-8. Epub 2015 Oct 23.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.

On the basis of the potent antiviral activity of acyclovir and ganciclovir, selenoacyclovir (2a) and selenoganciclovir (2b) were designed based on bioisoteric rationale and synthesized via the diselenide 7 as the key intermediate. Compound 2a exhibited potent anti-HSV-1 and -2 activities while 2b exerted moderate anti-HCMV activity, indicating that these nucleosides can serve as a novel template for the development of new antiviral agents.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00804DOI Listing
November 2015

Design, synthesis and cellular metabolism study of 4'-selenonucleosides.

Future Med Chem 2015 24;7(13):1643-55. Epub 2015 Sep 24.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.

Background: 4'-seleno-homonucleosides were synthesized as next-generation nucleosides, and their cellular phosphorylation was studied to confirm the hypothesis that bulky selenium atom can sterically hinder the approach of cellular nucleoside kinase to the 5'-OH for phosphorylation.

Results: 4'-seleno-homonucleosides (n = 2), with one-carbon homologation, were synthesized through a tandem seleno-Michael addition-SN2 ring cyclization. LC-MS analysis demonstrated that they were phosphorylated by cellular nucleoside kinases, resulting in anticancer activity.

Conclusion: The bulky selenium atom played a key role in deciding the phosphorylation by cellular nucleoside kinases. [Formula: see text].
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http://dx.doi.org/10.4155/fmc.15.102DOI Listing
July 2016

Stereoselective Synthesis of D-5-Homo-4-selenoribose as a Versatile Intermediate for 4'-Selenonucleosides.

Org Lett 2015 Sep 8;17(18):4636-9. Epub 2015 Sep 8.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.

Stereoselective synthesis of D-5-homo-4-selenoribose, serving as a versatile intermediate for the synthesis of 4'-selenonucleosides 12a-c, was accomplished using Sharpless asymmetric epoxidation, regioselective cleavage of the α,β-epoxide, and stereoselective reduction of the ketone as the key steps.
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http://dx.doi.org/10.1021/acs.orglett.5b02393DOI Listing
September 2015

Regio- and stereoselective synthesis of 2'-β-substituted-fluoroneplanocin A analogues as potential anticancer agents.

Org Biomol Chem 2015 Sep 30;13(35):9236-48. Epub 2015 Jul 30.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.

A series of 2'-β-substituted-6'-fluoro-cyclopentenyl-pyrimidines and -purines 8 and 9 were successfully synthesized from d-ribose in a regio- and stereoselective manner. The functionalization at the C2-position of 6'-fluoro-cyclopentenyl nucleosides was achieved via regioselective protection of a hydroxyl group at the C3-position and stereoselective formation of C2-triflate followed by direct SN2 reaction with a fluoro or azido nucleophile. All the synthesized compounds were evaluated for their anticancer activities in several tumor cell lines, but were found to be neither active nor toxic.
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http://dx.doi.org/10.1039/c5ob01348hDOI Listing
September 2015

Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities.

J Med Chem 2015 Jun 5;58(12):5108-20. Epub 2015 Jun 5.

†Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.

On the basis of the potent inhibitory activity of neplanocin A (1) against S-adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure-activity relationships by modifying the adenine and carbasugar moiety of 1 to find the pharmacophore in the active site of the enzyme. The introduction of 7-deazaadenine instead of adenine eliminated the inhibitory activity against the AdoHcy hydrolase, while 3-deazaadenine maintained the inhibitory activity of the enzyme, indicating that N-7 is essential for its role as a hydrogen bonding acceptor. The substitution of hydrogen at the 6'-position with fluorine increased the inhibitory activity of the enzyme. The one-carbon homologation at the 5'-position generally decreased the inhibitory activity of the enzyme, indicating that steric repulsion exists. A molecular docking study also supported these experimental data. In this study, 6'-fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC50 = 0.24 μM). It showed a potent anti-VSV activity (EC50 = 0.43 μM) and potent anticancer activity in all the human tumor cell lines tested.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00553DOI Listing
June 2015

Stereoselective synthesis of 4'-selenonucleosides via seleno-Michael reaction as potent antiviral agents.

Org Lett 2014 Nov 23;16(21):5796-9. Epub 2014 Oct 23.

College of Pharmacy, Seoul National University , Seoul, 151-742, Korea.

Based on the hypothesis that the bulky selenium atom, with 4p orbitals, can sterically hinder the approach of a cellular kinase to 5'-OH for phosphorylation, 4'-selenonucleosides with one-carbon homologation were designed and synthesized via a novel seleno-Michael reaction, with the stereoselectivity controlled by steric effects. 5'-Homo-4'-selenonucleosides (n = 2) demonstrated potent antiherpes simplex virus (HSV-1) activity, indicating that the bulky selenium atom might play a key role in preventing phosphorylation by cellular kinases, resulting in no antiviral activity.
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http://dx.doi.org/10.1021/ol502899bDOI Listing
November 2014

Synthesis and anti-renal fibrosis activity of conformationally locked truncated 2-hexynyl-N(6)-substituted-(N)-methanocarba-nucleosides as A3 adenosine receptor antagonists and partial agonists.

J Med Chem 2014 Feb 5;57(4):1344-54. Epub 2014 Feb 5.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.

Truncated N(6)-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N(6) and/or C2 substituents were tolerated in A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N(6)-cycloalkyl group (4d) showed excellent binding affinity at the hA3AR and was better than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with Ki values of 7.8-16.0 nM. N(6)-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A3AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis.
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http://dx.doi.org/10.1021/jm4015313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954500PMC
February 2014

Synthesis and evaluation of antimicrobial activity of 4H-pyrimido[2,1-b]benzothiazole, pyrazole and benzylidene derivatives of curcumin.

Eur J Med Chem 2012 Aug 22;54:366-78. Epub 2012 May 22.

School of Studies in Chemistry, Jiwaji University, Gwalior 474011, Madhya Pradesh, India.

A novel, one-pot, simple, efficient procedure for 4H-pyrimido[2,1-b]benzothiazole (4a-h), pyrazole (6a-d) and benzylidene (7a-d) derivatives of curcumin under solvent and solvent free conditions in microwave with good yield is have been synthesized. The synthesized compounds were evaluated for their antibacterial activity against gram-positive and gram-negative bacteria viz. Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhi, Escherichia coli, Bacillus cereus and Providencia rettgeri and antifungal activity against fungi viz Aspergillus niger, Aspergillus fumigates, Aspergillus flavus. Detailed mechanistic study shows reaction proceeds through Knoevenagel type intermediate 3a which has been suggested as key intermediate for reaction (Fig. 3).
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http://dx.doi.org/10.1016/j.ejmech.2012.05.020DOI Listing
August 2012

Diels-Alder cycloaddition and ring-closing metathesis: a versatile, stereoselective, and general route to embellished bridged bicyclic systems, carbocyclic framework of secoatisanes, and homologues.

J Org Chem 2009 Aug;74(16):6092-104

Department of Chemistry, Indian Institute of Technology, Bombay, Mumbai 400 076, India.

A general and stereoselective methodology for the synthesis of bridged bicyclic octenones having various types of alkenyl chains and a tricyclic framework of secoatisanes and higher analogues is reported. In situ generation and cycloaddition of 2-allyl-6,6-spiroepoxycyclohexadienones with ethyl acrylate gave bicyclo[2.2.2]octanes having an allyl group at the bridgehead and other chemically distinguishable functionality in a regio- and stereoselective fashion. Selective manipulation of adducts led to the introduction of other olefinic chain of variable lengths at the carbon adjacent to the bridge head. Ring-closing metathesis in bicyclooctanes having olefin tethers provided an efficient route to tricyclic systems having bicyclo[2.2.2]octane framework having spiro-fused six-, seven-, and eight-membered rings.
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http://dx.doi.org/10.1021/jo901279gDOI Listing
August 2009

Molecular complexity from aromatics: a novel, stereoselective route to tricyclo[5.2.2.0(1,5)]undecenones, tricyclo[6.2.2.0(1,6)]dodecenones, and [n.3.3]propellanes.

J Org Chem 2007 Dec 30;72(26):10155-65. Epub 2007 Nov 30.

Department of Chemistry and National Single Crystal X-ray Diffraction Facility, Indian Institute of Technology, Bombay, Mumbai 400076, India.

A general stereoselective route to functionalized and substituted tricyclo [5.2.2.0(1,5)]undecenones, tricyclo[6.2.2.0(1,6)]dodecenones, and [3.3.3]- and [4.3.3]propellanes from simple aromatic precursors is reported. The methodology involves generation and cycloaddition of annulated cyclohexa-2,4-dienones with various acrylates followed by manipulation of the resulting tricyclic adducts, leading to functionalized tricyclo[5.2.2.0(1,5)]undecenones and tricyclo[6.2.2.0(1,6)]dodecenones endowed with a beta,gamma-enone chromophore. Photochemical reaction of the tricyclic chromophoric systems followed by reductive cleavage provided an efficient entry into propellanes.
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http://dx.doi.org/10.1021/jo702168sDOI Listing
December 2007
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