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Sharma S.,Guru Nanak Dev University | Gupta M.K.,Lloyd Institute of Management and Technology | Saxena A.K.,Indian Institute of Integrative Medicine | Bedi P.M.S.,Guru Nanak Dev University
Anti-Cancer Agents in Medicinal Chemistry | Year: 2017

Background: Microtubules act as a useful and strategic molecular target for various anticancer drugs that binds to its distinct sites in tubulin subunits and inhibits its polymerization and ultimately leads to cell death. Moreover, numerous reports highlight the cytotoxic effects of constraint Combretastatin analogs and thiazolidinone derivatives. Objective: Therefore, the present study investigates the potential of thiazolidinone constraint combretastatin analogs as tubulin inhibitors. Method: By incorporating silica supported fluroboric acid, a series of thiazolidinone constraint combretastatin analogs were synthesized in a microwave reactor under solvent free conditions. To optimize the reaction conditions, the detailed investigation was done for the catalytic influence of HBF4-SiO2. All the synthesized analogs were assessed for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. Top hits were further examined for their tubulin polymerization inhibition and their effect on microtubule assembly. The significant cytotoxicity and tubulin polymerization inhibition of the most potent structure was further rationalized by molecular modelling studies. Results: The results stated that CS-2, CS-3 and CS-20 possessed significant cytotoxic potential with the IC50 values ranging from 1.21 to 5.50 µM against THP-1, COLO-205, HCT-116 human cancer cell lines. Established structure activity relationship revealed that the nature of Ring A substantially influences the cytotoxic potential of the compounds. Placement of methoxy substituents on the phenyl ring (Ring A) was found to be the most preferred structural feature. Compound CS-2 was found to considerably inhibit the tubulin polymerization (IC50 value 2.12 µM) and caused disruption of microtubule assembly as demonstrated by immunoflourescence technique. In molecular modelling studies, CS-2 exhibited various hydrophobic as well as hydrogen bonding interactions at colchicine binding site and was found to be stabilized in this cavity. Conclusion: This work provides an efficient methodology for the synthesis of antitubulin thiazolodinone- combretastatin hybrids. © 2017 Bentham Science Publishers.


Gupta M.K.,Lloyd Institute of Management and Technology
European Journal of Medicinal Chemistry | Year: 2017

Dihydropyrimidines are the most important heterocyclic ring systems which play an important role in the synthesis of DNA and RNA. Synthetically they were synthesized using Multi-component reactions like Biginelli reaction and Hantzschdihydropyridine. In the past decades, such Biginelli type dihydropyrimidones have received a considerable amount of attention due to the interesting pharmacological properties associated with this heterocyclic scaffold. In this review, we highlight recent developments in this area, with a focus on the DHPMs, recently developed as anti-inflammatory, anti-HIV, anti-tubercular, antifungal anticancer, antibacterial, antifilarial, antihyperglycemic, antihypertensive, analgesic, anti-convulsant, antioxidant, anti-TRPA1, anti-SARS, and anti-cancer activity and α1a binding affinity. © 2017 Elsevier Masson SAS


Singh H.,Guru Nanak Dev University | Sharma S.,Guru Nanak Dev University | Ojha R.,Guru Nanak Dev University | Gupta M.K.,Lloyd Institute of Management and Technology | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the enzyme with IC50 values ranging from 0.62 to 41.2 μM. Structure activity relationship indicated that the nature and placement of substituents on the phenyl ring at 2nd position remarkably influences the inhibitory activity. Substitution of halo and nitro groups at ortho and para position of the phenyl ring (2nd position) remarkably favored the activity. NF-4 with p-fluoro phenyl ring was the most potent inhibitor with IC50 value of 0.62 μM. Enzyme kinetics study was also performed to investigate the inhibition mechanism and it was found that the naphthoflavones displayed mixed type inhibition. The basis of significant inhibition of xanthine oxidase by NF-4 was rationalized by molecular modeling studies. © 2014 Elsevier Ltd. All rights reserved.


Sharma V.K.,Gurukul Kangri University | Nautiyal V.,Gurukul Kangri University | Goel K.K.,Gurukul Kangri University | Sharma A.,Lloyd Institute of Management and Technology
Asian Journal of Chemistry | Year: 2010

Metformin hydrochloride is a drug of choice of biguanide category in the management of diabetes mellitus. The drug sample was scanned for λmax by spectrophotometer and also by HPLC. The FTIR spectrum of the sample drug was compared with reference for genuinety. The thermal stability of the drug was studied at 30, 40, 50 and 70 °C in aqueous medium as it is freely soluble in water. The data obtained was treated by Arrhenius, zero order and first order kinetics. Metformin followed zero order kinetics in thermal degradation and covered 208 h to be decomposed up to 10%.


Oberoi L.,University of Arkansas for Medical Sciences | Oberoi L.,Lloyd Institute of Management and Technology | Akiyama T.,University of North Caroline | Lee K.-H.,University of North Caroline | Liu S.J.,University of Arkansas for Medical Sciences
Phytomedicine | Year: 2011

The bark of Terminalia arjuna (TA) has been used for centuries in ayurvedic medicine as cardiotonics for treatment of cardiac disorders. It became recently available as over-the-counter supplements marketed for maintaining a healthy heart. However, the cellular mechanism of its cardiotonic effect remains undefined. The present study was designed to investigate the physicochemical property and inotropic effect of the aqueous extract of TA bark (TA AqE) on adult rat ventricular myocytes in comparison with extracts prepared sequentially with organic solvents (organic extracts). The kinetics of myocyte contraction and caffeine-induced contraction were analyzed to assess the effect of TA AqE on sarcoplasmic reticular (SR) function. The inotropic effect of TA AqE was also compared with that of known cardiotonics, isoproterenol (ISO) and ouabain (Ouab). We found that TA AqE decoctions exerted positive inotropy, accelerated myocyte relaxation and increased caffeine-induced contraction concentration-dependently. In contrast, TA organic extracts caused interruption of excitability and arrhythmias without consistent inotropic action. In conclusion, TA AqE-induced cardiotonic action via enhancing SR function, a unique action minimizing the occurrence of arrhythmias, makes TA AqE a promising and relatively safe cardiotonic beneficial to the healthy heart and the treatment for chronic heart disease. The cardiotonic effect of TA AqE is consistent with the therapeutic property of TA bark used in ayurvedic medicine. The method of administration and/or selective omission of hydrophobic components from bark powder could be crucial to the efficacy and safety of TA bark in cardiac therapy and uses as over-the-counter supplements. © 2010 Elsevier GmbH. All rights reserved.


Sharma S.,Guru Nanak Dev University | Gupta M.K.,Lloyd Institute of Management and Technology | Saxena A.K.,Indian Institute of Integrative Medicine | Bedi P.M.S.,Guru Nanak Dev University
Bioorganic and Medicinal Chemistry | Year: 2015

Keeping in view the limitations associated with currently available anticancer drugs, molecular hybrids of mono carbonyl curcumin and isatin tethered by triazole ring have been synthesized and evaluated for in vitro cytotoxicity against THP-1, COLO-205, HCT-116, A549, HeLa, CAKI-I, PC-3, MiaPaca-2 human cancer cell lines. The results revealed that the compounds SA-1 to SA-9, SB-2, SB-3, SB-4, SB-7 and SC-2 showed a good range of IC50 values against THP-1, COLO-205, HCT-116 and PC-3 cell lines, while the other four cell lines among these were found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and substitution at position R influences the activity. Methoxy substituted phenyl ring as Ring X and H as R were found to be the ideal structural features. The most potent compounds (SA-2, SA-3, SA-4, SA-7) were further tested for tubulin inhibition. Compound SA-2 was found to significantly inhibit the tubulin polymerization (IC50 = 1.2 μM against HCT-116). Compound SA-2, moreover, lead to the disruption of microtubules as confirmed by immunofluorescence technique. The significant cytotoxicity and tubulin inhibition by SA-2 was streamlined by molecular modeling studies where it was docked at the curcumin binding site of tubulin. © 2015 Elsevier Ltd. All rights reserved.


PubMed | Indian Institute of Integrative Medicine, Lloyd Institute of Management and Technology and Guru Nanak Dev University
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2015

Keeping in view the limitations associated with currently available anticancer drugs, molecular hybrids of mono carbonyl curcumin and isatin tethered by triazole ring have been synthesized and evaluated for in vitro cytotoxicity against THP-1, COLO-205, HCT-116, A549, HeLa, CAKI-I, PC-3, MiaPaca-2 human cancer cell lines. The results revealed that the compounds SA-1 to SA-9, SB-2, SB-3, SB-4, SB-7 and SC-2 showed a good range of IC50 values against THP-1, COLO-205, HCT-116 and PC-3 cell lines, while the other four cell lines among these were found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and substitution at position R influences the activity. Methoxy substituted phenyl ring as Ring X and H as R were found to be the ideal structural features. The most potent compounds (SA-2, SA-3, SA-4, SA-7) were further tested for tubulin inhibition. Compound SA-2 was found to significantly inhibit the tubulin polymerization (IC50=1.2 M against HCT-116). Compound SA-2, moreover, lead to the disruption of microtubules as confirmed by immunofluorescence technique. The significant cytotoxicity and tubulin inhibition by SA-2 was streamlined by molecular modeling studies where it was docked at the curcumin binding site of tubulin.


PubMed | Indian Institute of Integrative Medicine, Lloyd Institute of Management and Technology, Himachal Pradesh University and Guru Nanak Dev University
Type: | Journal: European journal of medicinal chemistry | Year: 2014

The present study involves the design of a series of 3-aryl-9-acetyl-pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76M. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41M against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions.


PubMed | Indian Institute of Integrative Medicine, Lloyd Institute of Management and Technology and Guru Nanak Dev University
Type: | Journal: European journal of medicinal chemistry | Year: 2016

Keeping in view the confines allied with presently accessible antitumor agents and success of C5-curcuminoid based bifunctional hybrids as novel antitubulin agnets, molecular hybrids of C5-curcuminoid and coumarin tethered by triazole ring have been synthesized and investigated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and PC-3 human tumor cell lines. The results revealed that the compounds A-2 to A-9, B-2, B-3, B-7 showed significant cytotoxic potential against THP-1, COLO-205 and HCT-116 cell lines, while the PC-3 cell line among these was found to be almost resistant. Structure activity relationship revealed that the nature of Ring X and the length of carbon-bridge (n) connecting triazole ring with coumarin moiety considerably influence the activity. Methoxy substituted phenyl ring as Ring X and two carbon-bridges were found to be the ideal structural features. The most potent compounds (A-2, A-3 and A-7) were further tested for tubulin polymerization inhibition. Compound A-2 was found to significantly inhibit the tubulin polymerization (IC50=0.82M in THP-1 tumor cells). The significant cytotoxicity and tubulin polymerization inhibition by A-2 was further rationalized by docking studies where it was docked at the curcumin binding site of tubulin.


PubMed | Lloyd Institute of Management and Technology and Guru Nanak Dev University
Type: | Journal: Bioorganic & medicinal chemistry letters | Year: 2017

A library of forty 7,8-benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showed the most promising activity with IC

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