Publication Date: 2022
Hacettepe University Journal of the Faculty of Pharmacy (13000608)(4)pp. 228-237
Cancer is the second leading cause of death in the world. Due to toxicity and resistance to common therapies, the attempt to develop new anticancer agents has become a major challenge. Oxadiazole and thiadiazole are of interest building blocks used in drug design. Hybrids of thiadiazole-oxadiazole have been synthesized with significant cytotoxic effects. Considering importance of mentioned scaffolds some of the thiadiazole-oxadiazole derivatives were synthesized by three steps in this study. Firstly, thiol function of 2-amino-5-mercapto-1, 3, 4-thiadiazole was alkylated by benzyl chloride derivatives to give compounds (1a-c). The reaction of chloroacetyl chloride with amine group of compounds (1a–c) terminates to amide derivatives (2a-c). Definitive products were produced by treatment of corresponding amide derivatives with 5-(4-chlorophenyl)-1, 3, 4-oxadiazole-2-thiol. Synthesized compounds were evaluated by MTT assay against three cell lines. The final molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to assay the possible interactions. Final products showed range of cytotoxic activity of moderate to good against tested cell lines. Compound (3a) demonstrated a higher cytotoxic activity against MCF-7 (IC50: 26 µM) and Lncap (IC50: 37 µM) cell lines in comparison with other compounds. The highest docking score was-10.55 kcal/mol for compound 3a. © 2022, Hacettepe University, Faculty of Pharmacy. All rights reserved.
Hassanzadeh, F.,
Sadeghi, H.,
Nikooei, S.,
Jafari e., E.,
Vaseghi, G. Publication Date: 2019
Research In Pharmaceutical Sciences (17355362)(2)pp. 130-137
Triazoles and quinazolinones are important heterocyclic structures with diverse biological properties including cytotoxic, antibacterial, antifungal and anticonvulsant activities. Due to valuable cytotoxic effects of both triazole and quinazoline derivatives, in this study a series of quinazolinone-triazole hybrids were synthesized in a multiple-step reaction procedure. 3-Amino-quinazolinone derivatives were treated with chloroacetyl chloride in the presence of dichloromethane/triethylamine to afford 2-chloro-N-(4-oxo-2-quinazolin3 (3H)-yl) acetamide derivatives. The reaction of resultants with 4-mehyl-4-H-1, 2, 4-triazole-3-thiol in dry acetone and potassium carbonate led to the formation of final products. Synthesized compounds were evaluated for their cytotoxic effects against MCF-7 and Hela cell lines using MTT colorimetric assay. Amongst tested compounds, 6a showed the highest cytotoxic activity against MCF7 cell line at all tested concentrations while compounds 6b and 6c indicated mild cytotoxic effects against Hela cell line at highest tested concentration reducing cell viability about 40%. The IC50 values of tested compounds revealed that the MCF-7 is more susceptible to the compound 6a. © 2019 Medknow Publications.All rights reserved.
Mohamad reza nazifi s., ,
Sadeghi, H.,
Fassihi, A.,
Saghaei, L. Publication Date: 2019
Structural Chemistry (15729001)(1)pp. 175-184
High toxicity of anticancer drugs led to development of targeted drug delivery directly to the specific organs. Polyamine transport system (PTS) of mammalian cells is one of the targets for a cell-selective drug delivery of polyamine–drug conjugates into specific organs. Even without having a 3D structure for mammalian PTS, synthesis of polyamine derivatives and evaluation of their cytotoxic effects are potential practical approaches to find optimal polyamine moieties to be transported from the PTSs. Chinese hamster ovary (CHO) and its mutant cell line (CHO-MG) are two important cells for evaluation of polyamine transportation by polyamine transporters (PAT). If a polyamine conjugate ligand demonstrates a high IC50 ratio on CHO-MG/CHO cells, this indicates a high selectivity of such compound toward PAT. This study discussed the structural requirements (charge, linker, vector, cargo) of polyamine conjugates in order to be transported into the cells by the mean of PTS. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
Ardestani, M.,
Khorsandi, Z.,
Keshavarzipour, F.,
Iravani, S.,
Sadeghi, H.,
Varma, R.S. Publication Date: 2022
Pharmaceutics (19994923)(10)
Heat shock proteins (Hsps) have garnered special attention in cancer therapy as molecular chaperones with regulatory/mediatory effects on folding, maintenance/stability, maturation, and conformation of proteins as well as their effects on prevention of protein aggregation. Hsp90 ensures the stability of various client proteins needed for the growth of cells or the survival of tumor cells; therefore, they are overexpressed in tumor cells and play key roles in carcinogenesis. Accordingly, Hsp90 inhibitors are recognized as attractive therapeutic agents for investigations pertaining to tumor suppression. Natural Hsp90 inhibitors comprising geldanamycin (GM), reclaimed analogs of GM including 17-AAG and DMAG, and radicicol, a natural macrocyclic antifungal, are among the first potent Hsp90 inhibitors. Herein, recently synthesized heterocyclic compounds recognized as potent Hsp90 inhibitors are reviewed along with the anticancer effects of heterocyclic compounds, comprising purine, pyrazole, triazine, quinolines, coumarin, and isoxazoles molecules. © 2022 by the authors.
Publication Date: 2019
Advanced Pharmaceutical Bulletin (22517308)(4)pp. 649-654
Purpose: Several attempts have been made to identify the mechanisms by which mesenchymal stem cells (MSCs)-derived secretome exert anti-tumor or tumorigenic effects, but still further investigations are needed to explore this subject. Thus, in this study we want to examine the expression of different cytokines in secretome of hWJ-MSCs and their effects on cytokine expression profile of the MCF-7 tumor cells. Methods: The hWJ-MSCs were isolated and characterized according to the International Society for Cellular Therapy criteria. Then, secretome of hWJ-MSCs was collected and freeze-dried, and 20 mg/mL of the freeze-dried secretome was used to treat MCF-7 cancer cells for 48 hours. Afterwards, the expression levels of 12 cytokines including IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, TNFα, IFNγ and GM-CSF in secretome of hWJ-MSCs alone as well as in supernatant of tumor cells before and after treatment with hWJ-MSCs secretome were evaluated. Results: Our results indicate that MCF-7 cells express significant amount of IL-6 and IL-8. Moreover, significant amounts of IL-1a, IL-1b, IL-8, IL-6 and GM-CSF were detected in secretome of hWJ-MSCs. Furthermore, IL-1a, IL-2 and IL-4 were expressed significantly by MCF-7 cells after their treatment with hWJ-MSCs-derived secretome. Conclusion: According to our findings, the hWJ-MSCs derived secretome contains different cytokines which can exert either anti-tumor or tumorigenic effects. © 2019 The Author (s).
Khorsandi, Z.,
Keshavarzipour, F.,
Varma, R.S.,
Hajipour, A.R.,
Sadeghi, H. Publication Date: 2022
Molecular Catalysis (24688231)
Herein, chitosan as an inexpensive, abundant, and biodegradable bio-material, produced from a key constituent of the exoskeletons of crustaceans, was used to generate the cobalt-based magnetic silica nanocomposite for the performance of the C-N cross-coupling reaction as the main step of the synthesis of Abemaciclib and Fedratinibs. Several derivatives of these recently FDA-approved anti-cancer drugs were synthesized for the first time by using Pd/Cu-free co-catalyzed under both, the conventional heating and microwave (MW) irradiation conditions. The potential anticancer activity of synthesized compounds was investigated by molecular docking study. © 2021
Khorsandi, Z.,
Afshinpour, M.,
Molaei, F.,
Askandar, R.H.,
Keshavarzipour, F.,
Abbasi, M.,
Sadeghi, H. Publication Date: 2022
Journal of Biomolecular Structure and Dynamics (07391102)(17)pp. 7940-7948
In response to the current pandemic caused by the novel SARS-CoV-2, we design new compounds based on Lopinavir structure as an FDA-approved antiviral agent which is currently under more evaluation in clinical trials for COVID-19 patients. This is the first example of the preparation of Lopinavir isosteres from the main core of Lopinavir conducted to various heterocyclic fragments. It is proposed that main protease inhibitors play an important role in the cycle life of coronavirus. Thus, the protease inhibition effect of synthesized compounds was studied by molecular docking method. All of these 10 molecules, showing a good docking score compared. Molecular dynamics (MD) simulations also confirmed the stability of the best-designed compound in Mpro active site. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
Azimi, F.,
Ghasemi, J.B.,
Saghaei, L.,
Hassanzadeh, F.,
Mahdavi, M.,
Sadeghi, H.,
Scotti, M.T.,
Scotti, L. Publication Date: 2019
Current Topics In Medicinal Chemistry (15680266)(13)pp. 1092-1120
Background: Tubulin polymerization inhibitors interfere with microtubule assembly and their functions lead to mitotic arrest, therefore they are attractive target for design and development of novel anticancer compounds. Objective: The proposed novel and effective structures following the use of three-dimensional-quantitative structure activity relationship (3D-QSAR) pharmacophore based virtual screening clearly demonstrate the high efficiency of this method in modern drug discovery. Methods: Combined computational approach was applied to extract the essential 2D and 3D features requirements for higher activity as well as identify new anti-tubulin agents. Results: The best quantitative pharmacophore model, Hypo1, exhibited good correlation of 0.943 (RMSD=1.019) and excellent predictive power in the training set compounds. Generated model AHHHR, was well mapped to colchicine site and three-dimensional spatial arrangement of their features were in good agreement with the vital interactions in the active site. Total prediction accuracy (0.92 for training set and 0.86 for test set), enrichment factor (4.2 for training set and 4.5 for test set) and the area under the ROC curve (0.86 for training set and 0.94 for the test set), the developed model using Extended Class FingerPrints of maximum diameter 4 (ECFP_4) was chosen as the best model. Conclusion: Developed computational platform provided a better understanding of requirement features for colchicine site inhibitors and we believe the results of this study might be useful for the rational design and optimization of new inhibitors. © 2019 Bentham Science Publishers.
Hassanzadeh, F.,
Jafari e., E.,
Shojaei, F.,
Sadeghi, H. Publication Date: 2021
Research In Pharmaceutical Sciences (17355362)(6)pp. 634-642
Background and purpose: In the last few decades, nitrogen-rich heterocyclic compounds such as 1, 3, 4-thiadiazoles, 1, 2, 4-triazoles and 1, 3, 4-oxadiazoles have received considerable attention because of their notable biological properties, especially cytotoxic effects. The small molecules of mentioned azole derivatives revealed very intensive antitumor activity. In addition, phthalimide-thiadiazole and naphthalimide-triazole hybrid derivatives have shown remarkable cytotoxic effects. According to these observations, some of the hybrid derivatives containing the phthalimide-five-membered azoles were prepared in three steps in this research. Experimental approach: The thiol group of azoles was treated with ethyl chloroacetate which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. Subsequently, the corresponding acid hydrazides were utilized to prepare the final derivatives through the reaction with phthalic anhydride. Cytotoxic activity of final compounds was evaluated against MCF-7 and HeLa cell lines using MTT assay. Findings/Results: Compound 3d containing two phthalimide moieties in its structure showed a significant improvement in cytotoxic activity with an IC 50 value of 29 μM against HeLa cell line. Compounds 3a-3c showed less cytotoxic effects against both cell lines. Conclusion and implications: The combination of the thiadiazole nucleus with two phthalimide structures increased the cytotoxic activity against the HeLa cell line. This increase in cytotoxic activity is probably due to its being more lipophilic characteristic and interaction of this derivative with the biological targets of two directions. © 2021 Wolters Kluwer Medknow Publications. All rights reserved.
Publication Date: 2018
Food Chemistry (0308-8146)pp. 9-15
The aim of this study was to establish a new dispersive liquid-liquid microextraction (DLLME) technique for the determination of iron concentration in aqueous solutions and fruit juices based on the reaction between iron and 3-hydroxy-1-(3-hydroxyphenyl)-2-methylpyridin-4(1H)-one (3-OH-PMPO) as a chelating agent. A central composite design (CCD) was applied to optimize the effects of independent parameters (pH, volume of disperser solvent and extractant solvent and chelating agent concentration) on extraction efficiency. Under the optimized conditions, the analytical curve is linear in a concentration range of 10–750 μgL−1 with a detection limit of 5 μgL−1. The relative standard deviation (RSD) for ten repeated determinations of iron concentrations at 40 and 200 μgL−1 was calculated to be 4.2% and 1.2%, respectively. Relative recovery of iron in several water samples was investigated and the average was obtained in the range of 91–108%. © 2018 Elsevier Ltd
Publication Date: 2021
Iranian Journal Of Pharmaceutical Research (17350328)(4)pp. 125-136
The coronavirus disease-2019 (COVID-19) was first recognized in Wuhan, China, and quickly spread worldwide. Between all proposed research guidelines, inhibition of the main protease (Mpro) protein of the virus will be one of the main strategies for COVID-19 treatment. The present work was aimed to perform a computational study on FDA-approved drugs, similar to piperine scaffold, to find possible Mpro inhibitors. Firstly, virtual screening studies were performed on a library of FDA-approved drugs (43 medicinal compounds, similar to piperine scaffold). Among imported 43 drugs to virtual screening, 34 compounds were extracted. Four top-ranked drugs in terms of the highest interactions and the lowest binding energy were selected for the IFD study. Among these selections, lasofoxifene showed the lowest IFD score (-691.743 kcal mol-1). The stability of lasofoxifene in the COVID-19 Mpro protein active site was confirmed with 100 ns MD simulation. Lasofoxifene binding free energy was obtained-107.09 and-173.97 kcal mol-1, using Prime MM-GBSA and g_mmpbsa methods, respectively. The identified lasofoxifene by the presented computational approaches could be a suitable lead for inhibiting Mpro protein and COVID-19 treatment. © 2021, Briefland. All rights reserved.
Maleknia, L.,
Dilamian, M.,
Pilehrood, M.,
Sadeghi, H.,
Hekmati, A. Publication Date: 2018
Research In Pharmaceutical Sciences (17355362)(3)pp. 273-282
In this paper, polyurethane (PU), chitosan (Cs)/polyethylene oxide (PEO), and core-shell PU/Cs nanofibers were produced at the optimal processing conditions using electrospinning technique. Several methods including SEM, TEM, FTIR, XRD, DSC, TGA and image analysis were utilized to characterize these nanofibrous structures. SEM images exhibited that the core-shell PU/Cs nanofibers were spun without any structural imperfections at the optimized processing conditions. TEM image confirmed the PU/Cs core-shell nanofibers were formed apparently. It that seems the inclusion of Cs/PEO to the shell, did not induce the significant variations in the crystallinity in the core-shell nanofibers. DSC analysis showed that the inclusion of Cs/PEO led to the glass temperature of the composition increased significantly compared to those of neat PU nanofibers. The thermal degradation of core-shell PU/Cs was similar to PU nanofibers degradation due to the higher PU concentration compared to other components. It was hypothesized that the core-shell PU/Cs nanofibers can be used as a potential platform for the bioactive scaffolds in tissue engineering. Further biological tests should be conducted to evaluate this platform as a three dimensional scaffold with the capabilities of releasing the bioactive molecules in a sustained manner. © 2018 Herpetologist's League Inc. All rights reserved.
Publication Date: 2018
Journal of Biomolecular Structure and Dynamics (07391102)(6)pp. 1463-1478
Heat shock protein 90(Hsp90), as a molecular chaperone, play a crucial role in folding and proper function of many proteins. Hsp90 inhibitors containing isoxazole scaffold are currently being used in the treatment of cancer as tumor suppressers. Here in the present studies, new compounds based on isoxazole scaffold were predicted using a combination of molecular modeling techniques including three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamic (MD) simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were also done. The steric and electrostatic contour map of CoMFA and CoMSIA were created. Hydrophobic, hydrogen bond donor and acceptor of CoMSIA model also were generated, and new compounds were predicted by CoMFA and CoMSIA contour maps. To investigate the binding modes of the predicted compounds in the active site of Hsp90, a molecular docking simulation was carried out. MD simulations were also conducted to evaluate the obtained results on the best predicted compound and the best reported Hsp90 inhibitors in the 3D-QSAR model. Findings indicate that the predicted ligands were stable in the active site of Hsp90. © 2017 Informa UK Limited, trading as Taylor & Francis Group.
Emami, J.,
Maghzi, P.,
Hassanzadeh, F.,
Sadeghi, H.,
Mirian, M.,
Rostami, M. Publication Date: 2018
Pharmaceutical Development and Technology (10837450)(1)pp. 41-54
To develop an effective therapeutic treatment, the potential of poly (lactic-co-glycolic acid)-polyethylene glycol-retinoic acid (PLGA-PEG-RA) polymeric micelles for targeted delivery of irinotecan to hepatocellular carcinoma (HepG2) and colorectal cancer cell lines (HT-29) was evaluated. PLGA-PEG-RA was synthesized by amide reaction of PLGA with NH2–PEG–NH2 and then PLGA-PEG-NH2 with RA and confirmed by FTIR and 1H NMR spectroscopy. Irinotecan-loaded nanomicelles were prepared using thin-film hydration method and the impact of various formulation variables on their particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), and mean release time (MRT) were assessed using a Taguchi design. TEM was used to observe morphology of the nanomicelles and the CMC was determined by fluorescence spectroscopy. Adopted PLGA-PEG-RA nanomicelle exhibited PS of 160 ± 9.13 nm, PDI of 0.20 ± 0.05, ZP of −24.9 ± 4.03 mV, EE of 83.9 ± 3.61%, MRT of 3.28 ± 0.35 h, and CMC value of 25.7 μg/mL. Cytotoxicity of the targeted nanomicelles on HepG2 and HT-29 cell lines was significantly higher than that of non-targeted nanomicelles and the free drug. These results suggest that PLGA-PEG-RA nanomicelles could be an efficient delivery system of irinotecan for targeted therapy of colorectal cancer and hepatocellular carcinoma. © 2017 Informa UK Limited, trading as Taylor & Francis Group.
Azimi, F.,
Azizian, H.,
Najafi, M.,
Hassanzadeh, F.,
Sadeghi, H.,
Ghasemi, J.B.,
Ali faramarzi, M.,
Mojtabavi, S.,
Larijani, B.,
Saghaei, L. Publication Date: 2021
Bioorganic Chemistry (00452068)
In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure–activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme. © 2021
Publication Date: 2018
Journal Of Pharmacy And Pharmaceutical Sciences (14821826)(1S)
In the present study, a transferrin-conjugated nanostructured lipid carrier (TF-NLCs) for brain delivery of artemisinin (ART) was developed. ART-loaded NLCs (ART-NLCs) were prepared using solvent evaporation method and the impact of various formulation or process variables on the responses were assessed using a Taguchi design. Optimized ART-NLC was then coupled with transferrin as targeting ligand and its in vitro cytotoxicity was investigated against U-87MG brain cancer cell line. As a result, the following values are suggested by the software to prepare the optimized formulation: 20 mg Compritol®, 0.25% Tween 80, 5 mg oleic acid, 2.5 mL dichloromethane and 4 min sonication. Mean particle size (PS), zeta potential (ZP), polydispersity index (PDI), entrapment efficiency (EE), mean release time (MRT) of adopted formulation were confirmed to be 145 ± 12.5 nm, 24.3 ± 1.5 mV, 0.513 ± 0.021, 82.3 ± 7.3 % and 24.0 ± 1.1 h, respectively. Following conjugation of optimized ART-NLCs with TF, PS and MRT were increased, while ZP, and EE were decreased significantly. TF-ART-NLCs showed higher cytotoxic activity compared to non-targeted NLCs and free drug. These results indicated that the TF-ART-NLCs could potentially be exploited as a delivery system for anticancer and antimalarial drug ART in brain tumors and malaria. © 2018, Canadian Society for Pharmaceutical Sciences. All rights reserved.
Ramezani-aliakbari, M.,
Varshosaz, J.,
Sadeghi, H.,
Hassanzadeh, F.,
Rostami, M. Publication Date: 2021
Langmuir (15205827)(21)pp. 6475-6489
This study is aimed at developing a micellar carrier for an Anderson-type manganese polyoxomolybdate (TRIS-MnPOMo) to improve the potency and reduce the general toxicity. The biotin-targeted stearic acid-polyethylene glycol (SPB) polymeric conjugate was selected for the first time as a micelle-forming basis for the delivery of TRIS-MnPOMo to breast cancer cells. The cytotoxicity of TRIS-MnPOMo and its nanomicellar form (TRIS-MnPOMo@SPB) was evaluated against MCF-7, MDA-MB-231 (breast cancer cell lines), and HUVEC (normal cell line) in vitro using the MTT assay. The quantity of cellular uptake and apoptosis level were studied properly using standard methods. The hydrodynamic size, zeta potential, and polydispersity index of the prepared micelles were 140 nm,-15.6 mV, and 0.16, respectively. The critical micelle concentration was about 30 μg/mL, which supports the colloidal stability of the micellar dispersion. The entrapment efficiency was interestingly high (about 82%), and a pH-responsive release of TRIS-MnPOMo was successfully achieved. The micellar form showed better cytotoxicity than the free TRIS-MnPOMo on cancer cells without any significant heme and normal cell toxicity. Biotin-targeted nanomicelles internalized into the MDA-MB-231 cells interestingly better than nontargeted micelles and TRIS-MnPOMo, most probably via the endocytosis pathway. Furthermore, at the same concentration, micelles remarkably increased the level of induced apoptosis in MDA-MB-231 cells. In conclusion, TRIS-MnPOMo@SPB could profoundly improve potency, safety, and cellular uptake; these results are promising for further evaluations in vivo. © 2021 American Chemical Society.
Rezazadeh, M.,
Emami, J.,
Hassanzadeh, F.,
Sadeghi, H.,
Rostami, M.,
Mohammadkhani, H. Publication Date: 2017
Current Drug Delivery (15672018)(8)pp. 1189-1200
Objective: Low water solubility, high systemic toxicity and insignificant cellular uptake have limited efficient clinical applications of the anti-tumor agent Paclitaxel (PTX). To overcome these limitations, a Novel Nanostructured Lipid Carrier (NLC) modified with Folic Acid (FA) and polyethylene glycol (PEG) was prepared by emulsion solvent evaporation method using cholesterol, α-tocopherol, lecithin and Poloxamer. A partial factorial design was applied to determine the appropriate levels of variables for optimized formulation. Formulations were evaluated for Particle Size (PS), Zeta Potential (ZP), Entrapment Efficiency (EE), and release efficiency (RE72%). FA- and PEGconjugated octadecylamine (FA-ODA and PEG-ODA) were synthesized and confirmed by FTIR and H-NMR and incorporated either alone or in combination with the optimized formulation whose properties were also evaluated. PTX-loaded optimized, targeted, pegylated, targeted/pegylated NLCs, pure PTX, and Anzatax® along with their respective controls were selected for toxicity evaluation on human breast cancer cell line, MCF-7, using MTT assay. Methods: PS, ZP, EE%, and RE72% of the optimized formulation were 154.6 nm, -16.5 mv, 79.1% and 49.3%, respectively. Incorporation of α-tocopherol as the liquid lipid allowed for more efficient drug encapsulation, PS reduction, enhanced stability and sustained-release of the drug. Cytotoxicity of PTX-loaded NLCs modified with both FA-ODA and PEG-ODA was significantly enhanced compared to that of free PTX and other drug-loaded modified NLCs. Results and Conclusion: The results suggest that preparation of NLCs with synthesized conjugates might be a promising candidate for drug delivery of PTX to the cancerous cells and has a great potential as a carrier for tumor targeting in breast cancer. © 2017 Bentham Science Publishers.
Publication Date: 2017
Human Geographies (18436587)(2)pp. 213-229
Aiming to explain the socio-economic effects of reservoir dams on the sustainable development of rural areas, this paper, as a case study on Iran focuses on Karun 3 Dam, the largest arch dam of the Middle East. 350 rural household were studied through survey data collection. The households settled in 38 villages where questionnaires were distributed accordingly. The results showed that the dam has been effective in improving agriculture and boosting local economic indices, but has not affected on tourism, industrial development and employment. Also, it seems that the indices of quality of life, welfare and social capital correlate with inefficient dam performance in rural sustainable economic development. Evaluation of the effective social and economic variables of the dam in relation to the sustainable development of rural settlements shows that there is a duality in management based sustainable development that has prevented the positive effects of the dam on villages. © 2017 Human Geographies; The authors.
Abbasi, M.,
Amanlou, M.,
Aghaei, M.,
Hassanzadeh, F.,
Sadeghi, H. Publication Date: 2021
Anti-Cancer Agents In Medicinal Chemistry (18715206)(18)pp. 2583-2591
Background: Heat shock protein90 (Hsp90) is overexpressed in tumor cells, thus the inhibition of the Hsp90 ATPase activity would be a meaningfully effective strategy in cancer therapy. Objective: The present work was aimed at four steps: designing new Hsp90 inhibitors as anti-cancer by a virtual screening study; synthesize designed compounds; biological evaluation of them and finally molecular dynamic (MD) simulations of best compounds. Methods: A virtual screening study was performed on a library (100 compounds) of the ZINC database with benzimidazole scaffold; then an extracted compound and two derivatives were synthesized. The anti-proliferative and ATPase inhibitory activities of these compounds were evaluated by MTT and ATPase inhibition assays, respectively. The western blot analysis was performed to the evaluation of the expression level of Hsp70 and Her2 proteins. Finally, 200 ns molecular dynamic simulation was carried out to confirm the stability of the strongest synthesized compound in Hsp90 active site. Results: ZINC00173501 compound with an aminobenzimidazole scaffold was chosen by the virtual screening study. ZINC00173501 compound and two of its derivatives were synthesized. ATPase inhibitory activity of three synthesized compounds shown that ZINC00173501 compound was the most potent inhibitor (IC50= 8.6 μM) with the anti-proliferative activity 14.41 μM, 19.07 μM and more than 100 μM against MCF-7, HeLa and HUVEC cell lines, respectively. The high level of Hsp70 expression and low level of Her2 expression confirmed ZINC00173501 as an Hsp90 inhibitor. Finally, molecular dynamics simulation showed that ZINC00173501 was stable in Hsp90 active site during 200 ns simulation. Conclusion: The biological evaluation results show that 2-aminobenzimidazole scaffold could be suggested as a lead for inhibition of Hsp90. © 2021 Bentham Science Publishers.
Varshosaz, J.,
Khabbazian, E.,
Hassanzadeh, F.,
Sadeghi, H.,
Rostami, M.,
Taymouri, S. Publication Date: 2017
IET Nanobiotechnology (1751875X)(7)pp. 843-851
Biotinylated chitosan/poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) copolymer was synthesised by an amide reaction in two steps. Structural characterisation was performed using 1HNMR and Fourier transform infra-red (FTIR) spectra. Critical micelle concentration (CMC) of the copolymer was determined by pyrene as a fluorescent probe. Doxorubicin (DOX) was loaded in the micelles by the direct dissolution method. The effects of different variables including type of copolymer, copolymer concentration, stirring rate and stirring time were studied on the physicochemical properties of the micelles including: particle size, zeta potential, release efficiency and loading efficiency of nanoparticles using an irregular factorial design. The in vitro cytotoxicity of DOX-loaded biotin-targeted micelles was studied in HepG2 cells which over express biotin receptors by 3, 5-[dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay. The successful synthesis of the biotinylated copolymer of chitosan/PMVEMA was confirmed by FTIR and 1HNMR. The optimised micelles showed the CMC of 33 μg/ml, particle size of 247 ± 2 nm, zeta potential of +9.46 mV, polydispersity index of 0.22, drug-loading efficiency of 71% and release efficiency of 84.5 ± 1.6%. The synthesised copolymer was not cytotoxic. The cytotoxicity of DOX-loaded in targeted micelles on HepG2 cell line was about 2.2-fold compared with free drug. © The Institution of Engineering and Technology 2017.
Publication Date: 2017
Daru Journal Of Pharmaceutical Sciences (15608115)(1)
Background: Heat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy. Methods: In the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models' validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein. Results: The made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound. Conclusion: The QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites. © 2017 The Author(s).
Azimi, F.,
Ghasemi, J.B.,
Azizian, H.,
Najafi, M.,
Ali faramarzi, M.,
Saghaei, L.,
Sadeghi, H.,
Larijani, B.,
Hassanzadeh, F.,
Mahdavi, M. Publication Date: 2021
International Journal of Biological Macromolecules (01418130)pp. 1082-1095
A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC50 values in the range of 65.1–695.0 μM) even much more potent than standard drug acarbose (IC50 = 750.0 μM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC50 = 65.1 ± 0.3 μM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (Ki = 87.0 μM). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silico docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). © 2020
Shahsavari-alavijeh, S.,
Sadeghi, H.,
Jahanian-najafabadi, A.,
Mirian, M. Publication Date: 2017
Journal Of Reports In Pharmaceutical Sciences (23225106)(2)pp. 115-122
Previous studies showed that palladacycle complexes with three phenyl phosphine ligands and piperidine or biphosphinic based palladacycle complexes were cytotoxic on K562, HT29, and Hela cell lines. In the present study, in order to evaluate the efficacy of the compound on cisplatin resistant cells, first we made HT-29 cells resistant to cisplatin, and then evaluated the potential cytotoxicity of the mentioned plladacylce complex on them. In addition, it was evaluated whether cytotoxic effect of the compound is mediated via apoptosis or necrosis death mechanisms. In this regard, Annexin V/PI by staining followed by flow cytometric analysis was performed. Results showed that palladacycle complexes were 45 times more cytotoxic than cisplatin (P<0.05) on the resistant HT-29 cells. Flow cytometry results also revealed that apoptosis induction was the major cell death mechanism of these compounds. Therefore, it could be concluded that these compounds might be effectively cytotoxic for cisplatin resistant cells. However, further in vitro and in vivo preclinical studies on evaluation of specific and non-specific cytotoxic characteristics of these complexes are necessary. © 2017 by Kermanshah University of Medical Sciences.
Hajhashemi, V.,
Ghanadian, M.,
Palizaban, A.,
Mahnam, K.,
Eshaghi, H.,
Gheisari, B.,
Sadeghi, H. Publication Date: 2020
Prostaglandins and Other Lipid Mediators (10988823)
Background and aims: Euphorbia is a large genus of flowering plants. In Iran, some plants of this family have been used in the treatment of inflammatory disorders and also to relieve back pain. Euphorbia spinidens is a rich source of Cycloarta-23-ene-3beta,25-diol. Cycloartane structures are the starting material for the synthesis of plant steroids, and the aim of this study is to demonstrate COX inhibitory activity, molecular docking and in vivo approach of anti-inflammatory activity of cycloartane compound isolated from Euphorbia spinidens. Material and Methods: Plant material was extracted with acetone-chloroform and submitted to column chromatography for fractionation. Based on preliminary 1H-NMR spectra, cycloartane fraction was selected and purified by repeated recycle HPLC system. The structure and purity of compound were determined by 1H and 13C-NMR, HPTLC, and mass spectra. Inhibitory activities of the tested compounds on COX-1 and COX-2 were evaluated by a colorimetric COX (ovine) inhibitor screening method. Vero cells were used to assess the toxicity against the normal cells, and calculate the selectivity index. COX inhibitory activity results were evaluated and confirmed by molecular docking experiments. In the in vivo approach, analgesic activity was assessed by acetic acid-induced abdominal writhing and formalin tests. Croton oil-induced ear edema in mice and carrageenan-induced rat paw edema in rats were used to evaluate anti-inflammatory activity. Pain tests were carried out on male Swiss mice (25–35 g). Male Wistar rats (160–200 g) were used for the carrageenan test. Results: Cycloart-23-ene-3β,25-diol showedin vitro cyclooxygenase 1 and 2 inhibitory activities with more selectivity for COX-2. Molecular docking by predicting binding energies in COX protein receptors confirmed in vitro COX inhibitory results, and determined the best position for ligand in COX receptors along with its residue interactions in receptor pockets, which must be considered for designing of their inhibitors. In the in vivo studies, cycloartane inhibited significantly acetic acid-induced abdominal contractions and formalin-induced licking behavior at a dose of 200 mg/kg. The same dose reduced croton oil ear edema in mice and carrageenan-induced paw edema in rats. Conclusion: Therefore, according to these findings, cycloart-23-ene-3beta,25-diol showed promising analgesic and anti-inflammatory effects with low toxicity against normal cells and can be suggested as a template lead for designing anti-inflammatory compounds with good selectivity index, and potency for COX-2 inhibitory activity. © 2020 Elsevier Inc.
Momtazi-borojeni, A.,
Sadeghi, H.,
Rabbani, M.,
Ghannadi, A.,
Abdollahi, E. Publication Date: 2017
Research In Pharmaceutical Sciences (17355362)(3)pp. 257-264
The objective of the present study was to evaluate the cognitive enhancing of pineapple juice and ethanolic extract in scopolamine-induced cognitive deficit mice. The ethanolic extract of pineapple (Ananas comosus (L.) Merr.) was prepared by maceration method and its juice was obtained by a homogenizer. Object recognition task was used to evaluate the mice memory. Exploration time in the first and second trial was recorded. The differences in exploration time between a familiar and a novel object in the second trial were taken as a memory index. Animals were randomly assigned into 15 groups of 6 each including: control group (normal saline + vehicle), positive control group (scopolamine + rivastigmine), seven experimental groups (received scopolamine alone or scopolamine + ethanolic extract of pineapple in different doses), six other experimental groups were treated by ethanolic extract or juice of pineapple in different doses. Scopolamine (100 μL, 1 mg/kg, i.p.) and pineapple juice or extract (50, 75 and 100 mg/kg, i.p.) were administered 40 and 30 min before starting the second trial in the experimental groups. Object discrimination was impaired after scopolamine administration. Results showed that juice and ethanolic extract of pineapple significantly restored object recognition ability in mice treated with scopolamine. These finding suggested that pineapple had a protective role against scopolamine-induced amnesia, indicating its ability in management of cognitive disorders.
