Publications by authors named "Maliheh Safavi"

57 Publications

Phytochemical constituents and biological activities of Salvia macrosiphon Boiss.

BMC Chem 2021 Jan 19;15(1). Epub 2021 Jan 19.

Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Salvia macrosiphon Boiss. is an aromatic perennial herb belonging to the family Lamiaceae. Phytochemical studies and biological activities of this plant have been rarely documented in the literature. The current study aimed to investigate antibacterial and cytotoxic activity of different fractions of aerial parts of S. macrosiphon. Also, we tried to isolate and identify cytotoxic compounds from the plant. In this respect, the hydroalcoholic extract of the corresponding parts of the plant was fractionated into four fractions. Then, antibacterial and cytotoxic activity of each fraction were examined. It was found that the chloroform fraction had a good antibacterial activity against gram-positive and gram-negative bacteria. The most potent cytotoxicity was also obtained by the n-hexane fraction comparing with etoposide as the reference drug which was selected for the study and characterization of secondary metabolites. Accordingly, 13-epi manoyl oxide (1), 6α-hydroxy-13-epimanoyl oxide (2), 5-hydroxy-7,4'-dimethoxyflavone (3), and β-sitosterol (4) were isolated and evaluated for their cytotoxic activity. Among them, compound 1 revealed significant cytotoxicity against A549, MCF-7, and MDA-MB-231. It merits mentioning that it showed high selectivity index ratio regarding the low cytotoxic effects on Human Dermal Fibroblast which can be considered as a promising anticancer candidate.
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http://dx.doi.org/10.1186/s13065-020-00728-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814726PMC
January 2021

HPLC methods for quantifying anticancer drugs in human samples: A systematic review.

Anal Biochem 2020 12 5;610:113891. Epub 2020 Aug 5.

Department of Biotechnology, Iranian Research Organization for Science and Technology (IROST), Tehran, Iran. Electronic address:

Pharmacokinetic (PK) study of anticancer drugs in cancer patients is highly crucial for dose selection and dosing intervals in clinical applications. Once an anticancer drug is administered, it undergoes various metabolic pathways; to determine these pathways, it is necessary to follow the administered drug in biological samples via different analytical methods. In addition, multi-drug quantification methods in patients undergoing multi-drug regimens of cancer therapy can have several benefits, such as reduced sampling time and analysis costs. In order to collect and categorize these studies, we conducted a systematic review of HPLC methods reported for the analysis of anticancer drugs in biological samples. A systematic search was performed on PubMed Medline, Scopus, and Web of Science databases, and 116 studies were included. In summary of included studies, when the objective of a method was to quantify a single drug, MS, or UV detectors were utilized equivalently. On the other hand, in methods with the aim of quantifying drug and metabolite(s) in a single run, MS detectors were the most utilized. This review can provide a comprehensive insight for researchers prior to developing a quantification method and selecting a detector.
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http://dx.doi.org/10.1016/j.ab.2020.113891DOI Listing
December 2020

Thieno[2,3-b]pyridine amines: Synthesis and evaluation of tacrine analogs against biological activities related to Alzheimer's disease.

Arch Pharm (Weinheim) 2020 Oct 13;353(10):e2000101. Epub 2020 Jul 13.

Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.

In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (βA) aggregation and β-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.
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http://dx.doi.org/10.1002/ardp.202000101DOI Listing
October 2020

A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy.

Bioorg Chem 2020 06 2;99:103811. Epub 2020 Apr 2.

Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

The identification of molecular agents inhibiting specific functions in cancer cells progression is considered as one of the most successful plans in cancer treatment. The epidermal growth factor receptor (EGFR) over-activation is observed in a vast number of cancers, so, targeting EGFR and its downstream signaling cascades are regarded as a rational and valuable approach in cancer therapy. Several synthetic EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in recent years, mostly exhibited clinical efficacy in relevant models and categorized into first, second, third and fourth-generation. However, studies are still ongoing to find more efficient EGFR inhibitors in light of the resistance to the current inhibitors. In this review, the importance of targeting EGFR signaling pathway in cancer therapy and related epigenetic mutations are highlighted. The recent advances on the discovery and development of different EGFR inhibitors and the use of various therapeutic strategies such as multi-targeting agents and combination therapies have also been reviewed.
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http://dx.doi.org/10.1016/j.bioorg.2020.103811DOI Listing
June 2020

Alteration in inflammatory mediators in seriously eye-injured war veterans, long-term after sulfur mustard exposure.

Int Immunopharmacol 2020 Mar 1;80:105897. Epub 2019 Nov 1.

Immunoregulation Research Center, Shahed University, Tehran 3319118651, Iran; Department of Immunology, Shahed University, Tehran 3319118651, Iran. Electronic address:

Background: Sulfur mustard (SM) exposure produces extensive systemic and ocular adverse effects on the victims. One of the most important effects is immunological insults that can lead to other organ damages, including the eyes.

Methods: In this descriptive study, 128 SM-exposed veterans with severe eye injury were compared with 31 healthy controls. Tear levels of tumor necrosis factor (TNF)-α and serum concentrations of interleukin (IL)-1α, IL-1β, IL1Ra, IL-6, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and Fas Ligand (FasL) were compared between the two groups.

Results: Meibomian gland dysfunction (MGD); tear breakup time (TBUT < 10″); and conjunctival, limbal, and corneal abnormalities were more frequent among the cases (MS-exposed veterans) than the controls. Ocular involvement was mild in 14.8%, moderate in 24.2%, and severe in 60.9% of the cases. Serum levels of IL-1α and FasL were significantly higher among the cases than among the controls (P < 0.001 and P = 0.037, respectively). Also, a significant decrease was observed in serum and tear levels of TNF-α in the cases as compared with controls (P < 0.001, P < 0.001, respectively). Serum levels of FasL were significantly higher in cases with severe ocular involvement than in the controls (P = 0.03). Nonetheless, serum levels of IL-1β, IL-1Ra, IL-1α/IL-1Ra, and IL-6 were not significantly different between the two groups.

Conclusion: Serum levels of IL-1α and FasL may cause different ocular surface abnormalities in SM-exposed patients. Lower tear TNF-α concentration may be due to lower serum levels of this cytokine in these patients.
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http://dx.doi.org/10.1016/j.intimp.2019.105897DOI Listing
March 2020

Anti-algal activity of FeO-TiO photocatalyst on Chlorella vulgaris species under visible light irradiation.

Chemosphere 2020 Mar 15;242:125119. Epub 2019 Oct 15.

Department of Environmental Engineering, Technical University of Denmark, Kgs. Lyngby, DK-2800, Denmark. Electronic address:

Many industries located in coastal areas use a large amount of seawater. Algal biofouling can be a major problem that hinders the efficiency of these industrial facilities. In most cases, seawater requires algal removal pre-treatment to avoid or mitigate biofilm formation. To remediate green microalgae, FeO-TiO nanoparticles with 2.5% w/w FeO were applied as a visible light driven photocatalyst. The anti-algal activity of the photocatalytic pre-treatment using green microalgae, Chlorella vulgaris was tested. The experiments were carried out in freshwater, artificial seawater, and real seawater. Effect of photocatalyst dosage, visible light intensity, and water salinity on the removal of microalgae was investigated. The highest inactivation efficiency of Chlorella vulgaris was achieved under 55 W/m visible light irradiation when 0.25 g/L of FeO-TiO photocatalyst was used. The photocatalytic removal kinetics of Chlorella vulgaris followed the pseudo first order Langmuir-Hinshelwood model. The results revealed that the efficiency of photocatalytic removal of algae decreased with increasing of seawater salinity. The anti-algal activity of FeO-TiO nanoparticles was attributed to the generation of reactive oxygen species (ROS) through the photocatalytic process. H radical was shown to be the most important ROS that nanoparticles produced in the aqueous media. Using FeO-TiO nanoparticles in photocatalytic pre-treatment could be an efficient environmental-friendly method for micro-algal remediation in seawater under visible light.
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http://dx.doi.org/10.1016/j.chemosphere.2019.125119DOI Listing
March 2020

Tear and serum MMP-9 and serum TIMPs levels in the severe sulfur mustard eye injured exposed patients.

Int Immunopharmacol 2019 Dec 31;77:105812. Epub 2019 Oct 31.

Department of Immunology, Shahed University, Tehran, Iran; Immunoregulation Research Center, Shahed University, Tehran, Iran. Electronic address:

Introduction: Sulfur mustard (SM) intoxication produces local and systemic changes in the human body. In this study, the relationship between tear and serum matrix metalloproteinase (MMP)-9 and serum tissue inhibitors of metalloproteinases (TIMPs) are assessed in serious eye-injured SM-exposed casualties.

Methods: A group of 128 SM-exposed patients with serious ocular injuries in three subgroups (19 mild, 31 moderate, and 78 severe cases) is compared with 31 healthy controls. Tear and ocular status and serum MMPs and MMP-9/TIMPs complex levels were evaluated using enzyme-linked immunosorbent assay (ELISA).

Results: Serum level of MMP-9 was significantly higher in the SM-exposed group compared to the control group (P = 0.009). Mean serum MMP-9 level in the SM-exposed group with ocular abnormalities was significantly higher than that in the SM-exposed group without ocular abnormalities. SM-exposed people with corneal calcification had significantly higher serum MMP-9/TIMP-1 level compared to the SM-exposed ones without this problem (P = 0.045). The SM-exposed group with severe ocular injuries had significantly higher MMP-9/TIMP-1 than the controls (P = 0.046). The SM-exposed group had significantly lower levels of MMP-9/TIMP-4 complex than the controls (P < 0.001). The SM-exposed group with tear meniscus and fundus abnormality had significantly higher MMP-9/TIMP-4 levels than the SM-exposed group without these problems (P = 0.009 and P = 0.020).

Conclusion: Serum MMP-9 level had increased in SM-exposed groups with ocular problems, while TIMP-1 and TIMP-2 levels had remained unchanged. Serum TIMP-4 drastically decreased in SM-exposed group, which clearly explains the severity of the systemic and ocular damages.
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http://dx.doi.org/10.1016/j.intimp.2019.105812DOI Listing
December 2019

Apoptosis Induction of Armeniacae Semen Extractin Human Acute Leukemia (NALM-6 and KG-1) Cells.

Int J Hematol Oncol Stem Cell Res 2019 Jul;13(3):116-121

Department of Pharmacognosy and Medicinal Plants Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Prunusarmeniaca is a member of the Rosacea family. The most important ingredient of this family is amygdalin that is believed to have anti-tumor and analgesic properties. The aim of this study was to evaluate the anti-proliferative effects of Armeniacae semen extract on the acute leukemia, NALM-6, and KG-1 cell lines, and investigate the effect of the extract on apoptosis of these cell lines and caspase-3 gene expression. We prepared aqueous, ethyl acetate, and hydro alcoholic extracts of the Armeniacae semen. The NALM-6 and KG-1 cell lines and mononuclear cells (PBMCs) of healthy controls were treated with different doses of the extracts for 48 hours, and then cell viability was investigated with the MTT test. High-Performance Liquid Chromatography was done for amygdalin identification. The percentage of apoptotic cells was determined using the Annexin V-FITC/PI flow cytometric kit, and caspase-3 gene expression was evaluated. MTT test revealed that the strongest Inhibition Concentration (IC50) in KG-1 and NALM-6 cell lines was related to the ethyl acetate extract. This extract did not have toxic effects on PBMCs. Flow cytometric analysis showed that the ethyl acetate extract at its IC50 concentration led to almost 50% apoptosis in both cell lines after 48 hours. In the molecular examination, after treatment, a significant increase was seen in caspase-3 gene expression in NALM6 and KG1 cells compared to the control (P<0.001 and P <0.05, respectively). Our data confirmed that the ethyl acetate extract of Prunusarmeniaca could reduce the proliferation of KG-1 and NALM-6 cell lines probably by activating the apoptotic pathway.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801328PMC
July 2019

Synthesis, in vitro and cellular antioxidant activity evaluation of novel peptides derived from Saccharomyces cerevisiae protein hydrolysate: structure-function relationship : Antioxidant activity and synthetic peptides.

Amino Acids 2019 Aug 17;51(8):1167-1175. Epub 2019 Jun 17.

Department of Biotechnology, Iranian Research Organization for Science and Technology (IROST), Tehran, Iran.

The relationship between structure and function of primary antioxidant peptide, YR-10 (YGKPVAVPAR) was considered by synthesizing three analogues including YHR-10 (YGKHVAVHAR), GA-8 (GKPVAVPA) and PAR-3 (PAR). Antioxidant activity was determined through in vitro and cellular assays. Substitution of Pro with His in the structure of YR-10 led to significant (P < 0.05) higher ABTS radical scavenging and ferric reducing activity. Following in silico simulated gastrointestinal digestion, Tyr and Arg were omitted, respectively, from N and C-terminal positions and resulted in decreasing DPPH, ABTS radical scavenging, and ferric reducing activities. PAR-3 showed the best inhibitory activity on linoleic acid oxidation. Pretreatment of Caco-2 cells with YR-10, YHR-10, and GA-8 (1000 µM) before exposure to HO (160 µM) resulted in 34.10%, 39.66% and 29.159% reduction in malondialdehyde and 53.52%, 17.02% and 24.71% reduction in protein carbonyl levels. The peptide pretreatment reduced catalase level in cells and PAR-3 exhibited the most protective effects on the viability of cells exposed to oxidative stress.
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http://dx.doi.org/10.1007/s00726-019-02752-zDOI Listing
August 2019

, a Bioactive Essential Oil: Chemical Composition and Biological Activities.

Iran J Pharm Res 2019 ;18(1):412-421

Department of Pharmacognosy, Faculty of Pharmacy and Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.

is an aromatic plant traditionally used for treatment of infections and gastrointestinal diseases. In the present study, the volatile oil of the plant was obtained by hydrodistillation and analyzed by GC-MS. In addition, antibacterial and anti- activities of this essential oil were determined using disc diffusion and agar dilution methods, respectively. Insecticidal activity was assessed through topical and fumigation application of the essential oil to cabbage looper larvae. Acetylcholinesterase (AChE) inhibition by the essential oil was examined using Ellman's method. Furthermore, its cytotoxic potential against three different cancer cell lines was assessed using the MTT assay. The phenolic monoterpenoids, thymol (38.79%), and carvacrol (36.30%) were identified as major constituents of the essential oil. We observed significant antibacterial activity of the essential oil against (MIC=20.4 µg /mL) as well as other tested bacteria, except for . essential oil showed significant toxicity to cabbage looper larvae with LD value of 52.1 µg /larva following topical and fumigant administration. essential oil was considerably inhibitory to acetylcholinesterase activity (IC50 = 0.117 µg/mL). Cytotoxic assay of the volatile oil resulted in IC50 = 0.065, 0.104, and 0.141 μg/mL for MCF-7, T47D and MDA- MB-231 cell lines, respectively. According to our data, this species with high concentrations of thymol and carvacrol could be considered as a natural source for pharmaceutical products.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487399PMC
January 2019

In vitro and in silico studies of novel synthetic ACE-inhibitory peptides derived from Saccharomyces cerevisiae protein hydrolysate.

Bioorg Chem 2019 06 28;87:647-654. Epub 2019 Mar 28.

Department of Biotechnology, Iranian Research Organization for Science & Technology (IROST), Tehran, Iran.

The structure-function relation of YR-10 (YGKPVAVPAR) was investigated by synthesizing four structural analogs of that including YHR-10 (YGKHVAVHAR), GA-8 (GKPVAVPA), GHA-8 (GKHVAVHA), and PAR-3 (PAR). GA-8 (GKPVAVPA) was synthesized on the basis of simulated enzymatic gastrointestinal digestion performed by bioinformatics tools (expasy-peptide cutter). This study explains the molecular mechanisms for the interaction of synthetic peptides with ACE. The IC values of each were 139.554 ± 2.3, 61.91 ± 1.2, 463.230 ± 3.56, 135.135 ± 2.1, 514.024 ± 5.86 µM, respectively. Results indicated that Pro replacement with His in YR-10 and GA-8 increased ACE inhibitory activity respectively, by 55.63% and 70.82%. Removal of Tyr and Arg from respectively N and C terminal positions of YR-10, following in silico simulated gastrointestinal digestion caused the 3.31 fold decrease in ACE inhibitory activity. YHR-10 showed the best docking poses, and GHA-8 exhibited interaction with Zn. Lineweaver-Burk plots of most active peptides suggest that they act as noncompetitive inhibitors against ACE.
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http://dx.doi.org/10.1016/j.bioorg.2019.03.057DOI Listing
June 2019

Design and Synthesis of Novel Cytotoxic Indole-Thiosemicarbazone Derivatives: Biological Evaluation and Docking Study.

Chem Biodivers 2019 Apr 3;16(4):e1800470. Epub 2019 Apr 3.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, 1417653761, Tehran, Iran.

In this work, two novel series of indole-thiosemicarbazone derivatives were designed, synthesized, and evaluated for their cytotoxic activity against MCF-7, A-549, and Hep-G2 cell lines in comparison to etoposide and colchicine as the reference drugs. Generally, the synthesized compounds showed better cytotoxicity towards A-549 and Hep-G2 than MCF-7. Among them, (2E)-2-{[2-(4-chlorophenyl)-1H-indol-3-yl]methylidene}-N-(4-methoxyphenyl)hydrazinecarbothioamide (8l) was found to be the most potent compound against A-549 and Hep-G2, at least three times more potent than etoposide. The morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that compound 8l induced apoptosis in A-549 cells. Moreover, molecular docking methodology was exploited to elucidate the details of molecular interactions of the studied compounds with putative targets.
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http://dx.doi.org/10.1002/cbdv.201800470DOI Listing
April 2019

Design and synthesis of novel quinazolinone-1,2,3-triazole hybrids as new anti-diabetic agents: In vitro α-glucosidase inhibition, kinetic, and docking study.

Bioorg Chem 2019 03 11;83:161-169. Epub 2018 Oct 11.

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A novel series of quinazolinone-1,2,3-triazole hybrids 10a-p were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory activity leading to efficient anti-diabetic agents. All synthesized compounds exhibited good inhibitory activity against yeast α-glucosidase (IC values in the range of 181.0-474.5 µM) even much more potent than standard drug acarbose (IC = 750.0). Among them, quinazolinone-1,2,3-triazoles possessing 4-bromobenzyl moiety connected to 1,2,3-triazole ring (10g and 10p) demonstrated the most potent inhibitory activity towards α-glucosidase. Compound 10g inhibited α-glucosidase in a competitive manner with K value of 117 µM. Furthermore, the binding modes of the most potent compounds 10g and 10p in the α-glucosidase active site was studied through in silico docking studies. Also, lack of cytotoxicity of compounds 10g and 10p was confirmed via MTT assay.
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http://dx.doi.org/10.1016/j.bioorg.2018.10.023DOI Listing
March 2019

In-vitro evaluation of apoptotic effect of OEO and thymol in 2D and 3D cell cultures and the study of their interaction mode with DNA.

Sci Rep 2018 10 25;8(1):15787. Epub 2018 Oct 25.

Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.

Oliveria decumbens is an Iranian endemic plant used extensively in traditional medicine. Recently, some studies have been performed on biological effects of Oliveria essential oil (OEO). However, to our knowledge, the anticancer activity of OEO has not been reported. Based on our GC/MS analysis, the basic ingredients of OEO are thymol, carvacrol, p-cymene and γ-terpinene. Therefore, we used OEO and its main component, thymol, to explore their effects on cell growth inhibition and anticancer activity. Despite having a limited effect on L929 normal cells, OEO/thymol induced cytotoxicity in MDA-MB231 breast cancer monolayers (2D) and to a lesser extent in MDA-MB231 spheroids (3D). Flow cytometry, caspase-3 activity assay in treated monolayers/spheroids and also fluorescence staining and DNA fragmentation in treated monolayers demonstrated apoptotic death mode. Indeed, OEO/thymol increased the Reactive Oxygen Species (ROS) level leading to mitochondrial membrane potential (MMP, ΔΨm) loss, caspase-3 activation and DNA damage caused S-phase cell cycle arrest. Furthermore, immunoblotting studies revealed the activation of intrinsic and maybe extrinsic apoptosis pathways by OEO/thymol. Additionally, in-vitro experiments, indicated that OEO/thymol interacts with DNA via minor grooves confirmed by docking method. Altogether, our reports underlined the potential of OEO to be considered as a new candidate for cancer therapy.
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http://dx.doi.org/10.1038/s41598-018-34055-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202332PMC
October 2018

Identification and anti-cancer activity in 2D and 3D cell culture evaluation of an Iranian isolated marine microalgae Picochlorum sp. RCC486.

Daru 2018 Dec 21;26(2):105-116. Epub 2018 Sep 21.

Department of Biotechnology, Iranian Research Organization for Science and Technology, P. O. Box 3353-5111, Tehran, Iran.

Purpose: Cancer disease is the second cause of death in the world. Now a days, high percentage of drugs, which are involved in treatment of cancers, have natural origin. Introduction of microalgae strains as anti-cancer drugs origin is a valuable approach for cancer therapy.

Methods: In the present study we describe the isolation, characterization, and anti-proliferative activity of a new microalga strain (Picochlorum sp. RCC486) from Iran. The cytotoxic activity of four different algal extracts including methanol, ethyl acetate, chloroform, and hexane were evaluated against MDA-MB-231, MCF-7, Hep-G2, and A-549 cell liens. Cell viability was determined using MTT assay in both monolayer and spheroids 3D cultures. The apoptosis was confirmed by different methods such as AO/EB and Annexin V-FITC/PI double staining, caspase-3 colorimetric assay, ROS and MMP assay.

Results: The results of MTT assay and fluorescent double staining confirmed that methanol and ethyl acetate extracts showed the best cytotoxic activity against the cancer cell lines. The production of ROS, caspase-3 activity and depolarized MMP were quite significant in MDA-MB-231 cell line treated with methanol and ethyl acetate extracts.

Conclusion: In this research we revealed that cytotoxicity and apoptotic effects of the methanol and ethyl acetate extracts in human cancer cells make them good candidates for further pharmacological studies to discover effective drugs for cancer therapy. Graphical abstract The present study describes the isolation, characterization, and anti-proliferative activity of different extracts of a new microalga strain (Picochlorum sp. RCC486) from Iran. The antiproliferative and apoptosis inducing activity of ethyl acetate and methanol extracts with high content of phenol and carotenoid make them as good candidates for further pharmacological studies to discover effective drugs for cancer therapy.
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http://dx.doi.org/10.1007/s40199-018-0213-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279668PMC
December 2018

Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety.

Eur J Med Chem 2018 Jul 7;155:483-491. Epub 2018 Jun 7.

The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of new coumarin-containing compounds 3a-l and 4a-c was designed and synthesized based on the chalcone-type 4-amino-5-cinnamoylthiazole scaffold 2, and screened for their in vitro anticancer and antioxidant activities. Representatively, the 2-thiomorpholinothiazole derivative 3k with IC values of 7.5-16.9 μg/ml demonstrated good cytotoxic effects against tested cell lines MCF-7, HepG2 and SW480. Further investigation by flow cytometric analysis confirmed that this compound induces apoptotic cell death in MCF-7 cells and cause G1-phase arrest in the cell cycle. Moreover, most of compounds had intrinsic potential for radical scavenging activity and ferric-reducing power as investigated by DPPH and FRAP assays.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.015DOI Listing
July 2018

Novel quinazolin-4(3H)-one linked to 1,2,3-triazoles: Synthesis and anticancer activity.

Chem Biol Drug Des 2018 07 18;92(1):1373-1381. Epub 2018 May 18.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

In this work, a wide range of novel quinazolin-4(3H)-one linked to 1,2,3-triazoles was designed, synthesized, and evaluated against a panel of three human breast (MDA-MB-231, MCF-7, T-47D), lung (A549), and prostate (PC3) cancer cell lines. Our results revealed that the anticancer activity of the synthesized compounds was selectively affected by the presence of methoxy group on the linker between quinazolinone and 1,2,3-triazole moieties. According to the calculated IC values, compounds 6q, 6w, and 6x showed good cytotoxicity against breast cancer cell lines even more effective than the reference drug, etoposide. Compounds 6q and 6u were found to be potent compounds against A549, non-small-cell lung cancer (NSCLC), comparing with erlotinib. Also, the morphological analysis by acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that potent compounds induced apoptosis in human cancer cell lines. Molecular docking studies were performed to clarify the inhibition mode of compounds 6g, 6u, 6w, and 6x over the EGFR active site. The most promising compounds, 6q and 6u, possessing 3-methoxy group were well oriented to the gatekeeper hydrophobic pocket of EGFR active site and interact well with Ala719, Val702, and Leu820 through hydrophobic interaction.
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http://dx.doi.org/10.1111/cbdd.13203DOI Listing
July 2018

Bio-guided isolation of subsp. cytotoxic components.

Nat Prod Res 2019 Jun 19;33(11):1687-1690. Epub 2018 Feb 19.

d Department of Biotechnology , Iranian Research Organization for Science and Technology , Tehran , Iran.

subsp was extracted by 80% ethanol. The total extract was then partitioned into four fractions including chloroform, ethyl acetate and methanol. Cytotoxic effect of fractions was examined by MTT assay in K562 (chronic myelogenous leukemia), AGS (gastric adenocarcinoma), MCF-7 (breast adenocarcinoma) and SW742 (colon adenocarcinoma) cell lines. The Chloroform fraction, with the lowest LC against K-562 cell lines, was partitioned into 14 subfractions and subjected to further purification by reversed-phase (C18) silica gel and sephadex LH-20 column chromatography. Three flavonoids including cirsimaritin, cirsilinelol and eupatilin were isolated for the first time from the species and the structures were confirmed by spectroscopic data. The high selectivity index of the purified flavonoids indicates valuable components with potential few side effects for normal cell lines. However, solubility tests for isolated components indicates the need for novel pharmaceutical dosage forms, in the case for using natural flavonoids as chemotherapeutic agents.
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http://dx.doi.org/10.1080/14786419.2018.1428590DOI Listing
June 2019

Synthesis and biological evaluation of 4-amino-5-cinnamoylthiazoles as chalcone-like anticancer agents.

Eur J Med Chem 2018 Feb 6;145:404-412. Epub 2018 Jan 6.

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of 4-amino-5-cinnamoylthiazoles 3a-p were designed and synthesized as chalcone-like anticancer agents. The synthesized derivatives 3a-p were evaluated for their in vitro antiproliferative activities against three different human cancer cell lines including MCF-7, HepG2 and SW480. Most of compounds could significantly prevent proliferation of tested cell lines. In particular, the pyrrolidine derivative 3e namely (E)-1-(4-amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one showed promising activity, especially against HepG2 cells (IC = 10.6 μg/ml). Flow cytometric analyses revealed that the prototype compound 3e can prevent the proliferation of HepG2 cells by blockade of the cell cycle at the G2 phase and induction of apoptosis.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.015DOI Listing
February 2018

Caspase-dependent apoptosis induced by two synthetic halogenated flavanones, 3',7-dichloroflavanone and 3',6-dichloroflavanone, on human breast and prostate cancer cells.

In Vitro Cell Dev Biol Anim 2018 Feb 20;54(2):136-146. Epub 2017 Dec 20.

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

The destruction of cancer cells with chemotherapeutic agents is normally achieved through apoptosis. We previously introduced two synthetic halogenated flavanone derivatives, 3,7-dichloroflavanone (3'-7 DCF) and 3,6-dichloroflavanone (3'-6 DCF), as potential apoptosis-inducing agents. In the current study, we investigated the ability of these compounds in triggering intrinsic or/and extrinsic pathway of apoptosis in breast and prostate cancer cells. Also, the synergistic effect of 3'-7 DCF with TLR3 (Toll-like receptor 3) agonist in apoptosis induction was evaluated on PC3 and LNCaP human prostate cancer cells. The involved pathway of apoptosis in the treated cells was delineated by caspase-3 activity assay, PARP-1 (poly(ADP-ribose)polymerase-1) cleavage, and procaspase-9 cleavage as markers of the intrinsic pathway and procaspase-8 cleavage as the marker of the extrinsic pathway. With the exception of the normal cells, treatment of all cell lines with both 3'-7 DCF and 3'-6 DCF triggered the cleavage of procaspase-8 and procaspase-9. These results indicate that the intrinsic and the extrinsic pathways of apoptosis are the mechanisms of the toxicity of flavanones in these cancer cell lines. However, the cytoxicity of the compound 3'-7 DCF was not synergistic with TLR3 agonist. Interestingly, the activation of caspases-9 preceeded that of caspase-8 suggesting that the intrinsic pathway is the primary reason for apoptosis induction by the flavanones.
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http://dx.doi.org/10.1007/s11626-017-0209-3DOI Listing
February 2018

Facile synthesis and antiproliferative activity of 7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-amines.

Eur J Med Chem 2017 Feb 21;127:128-136. Epub 2016 Dec 21.

Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran; Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of 7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8-amines 6a-t were synthesized as new potential antiproliferative agents. The in vitro antiproliferative activity evaluation of title compounds using MTT assay revealed that most compounds showed significant activity against tested cancer cell lines (A549, MOLT-4, and HeLa). The 2-fluoro-aniline derivatives 6e and 6l were the most active compounds against A549 and MOLT-4 cells, respectively. The benzylamine analog 6h showed superior activity against HeLa cells. However, compound 6l with IC values of 5.2-6.9 μM had the best profile of activity against all tested cell lines. The morphological and flow cytometric analyses showed that compound 6l can induce apoptosis in the MOLT-4 cells.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.037DOI Listing
February 2017

Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer's disease.

Bioorg Chem 2017 02 24;70:86-93. Epub 2016 Nov 24.

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

In this work, novel chromenones linked to 1,2,3-triazole ring system were synthesized and evaluated for their anti-ChE activity. Among them, N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-5-yl)methyl)-8-methoxy-2-oxo-2H-chromene-3-carboxamide (6m) showed good anti-acetylcholinesterase activity (IC=15.42μM). Also, compound 6m demonstrated neuroprotective effect against HO-induced cell death in PC12 neurons, however, it showed no beta-secretase (BACE1) inhibitory activity. Docking and kinetic studies separately confirmed dual binding activity of compound 6m since it targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.
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http://dx.doi.org/10.1016/j.bioorg.2016.11.011DOI Listing
February 2017

Novel Tacrine-Based Pyrano[3',4':5,6]pyrano[2,3-b]quinolinones: Synthesis and Cholinesterase Inhibitory Activity.

Arch Pharm (Weinheim) 2016 Dec 7;349(12):915-924. Epub 2016 Nov 7.

Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.

In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC  = 0.37-5.62 μM) compared with rivastigmine (IC  = 11.07 μM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity. However, most of the synthesized compounds showed no anti-BChE activity and compounds 6b and 6f were found to be only moderate inhibitors. The most potent anti-AChE compound 6f had low and moderate inhibitory activity and neuroprotective effects against beta-secretase (BACE1) and oxidative stress-induced cell death, respectively. Also, kinetic and molecular docking studies of binding interactions elucidated that compound 6f bound to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.
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http://dx.doi.org/10.1002/ardp.201600123DOI Listing
December 2016

Synthesis and biological evaluation of novel imidazopyrimidin-3-amines as anticancer agents.

Chem Biol Drug Des 2017 05 29;89(5):797-805. Epub 2016 Dec 29.

Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Groebke-Blackburn-Bienayme reaction has been utilized for the synthesis of new imidazo[1,2-a]pyrimidine derivatives as novel anticancer agents. The cytotoxic activities of compounds were evaluated against human cancer cell lines including MCF-7, T-47D, and MDA-MB-231, compared with etoposide as the standard drug. Among the tested compounds, hydroxy- and/or methoxy-phenyl derivatives (6a-c and 6k) with IC values of 6.72-14.36 μm were more potent than etoposide against all cell lines. The acridine orange/ethidium bromide double staining and DNA fragmentation studies demonstrated that the cytotoxic effect of 3-hydroxy-4-methoxyphenyl derivative 6c is associated with apoptosis in cancer cells.
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http://dx.doi.org/10.1111/cbdd.12904DOI Listing
May 2017

In vitro and in vivo evaluation of paclitaxel-lapatinib-loaded F127 pluronic micelles.

Drug Dev Ind Pharm 2017 Mar 14;43(3):390-398. Epub 2016 Nov 14.

a Department of Pharmaceutics, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran.

The aim of this study was to evaluate the in vitro and in vivo efficacy of paclitaxel-lapatinib-loaded Pluronic micelles. Lapatinib and pluronic sensitize the cancerous cells to paclitaxel via efflux pump inhibition. In addition, pluronic polymers can trigger intrinsic apoptosis pathways. Furthermore, micellar system can passively target the chemotherapeutic agents by enhanced permeability and retention effect. The paclitaxel-lapatinib-loaded micelles were characterized in means of encapsulation efficacy and size. The in vitro analyses were performed by MTT assay and uptake studies. Real-time imaging and in vivo anti-tumor efficacy studies were also performed. The prepared micelles have acceptable encapsulation ratio and size. Hemolysis assay confirmed that the micelles are hemo-compatible. MTT assay demonstrated that drug-loaded micelles have superior cytotoxicity compared with the naked drugs. The confocal microscopy and flowcytometry analyses showed that micelles are mainly internalized by endocytosis. According to the results of the in vivo imaging, the micelles are accumulated within liver. In vivo anti-tumor efficacy studies confirmed that tumor inhibition of drug-loaded micelles was significant compared to Intaxel.
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http://dx.doi.org/10.1080/03639045.2016.1254238DOI Listing
March 2017

The development of biomarkers to reduce attrition rate in drug discovery focused on oncology and central nervous system.

Expert Opin Drug Discov 2016 Oct 3;11(10):939-56. Epub 2016 Aug 3.

b Faculty of Pharmacy and Pharmaceutical Sciences Research Center , Tehran University of Medical Sciences , Tehran , Iran.

Introduction: The task of discovery and development of novel therapeutic agents remains an expensive, uncertain, time-consuming, competitive, and inefficient enterprise. Due to a steady increase in the cost and time of drug development and the considerable amount of resources required, a predictive tool is needed for assessing the safety and efficacy of a new chemical entity.

Areas Covered: This study is focused on the high attrition rate in discovery and development of oncology and central nervous system (CNS) medicines, because the failure rate of these medicines is higher than others. Some approaches valuable in reducing attrition rates are proposed and the judicious use of biomarkers is discussed.

Expert Opinion: Unlike the significant progress made in identifying and characterizing novel mechanisms of disease processes and targeted therapies, the process of novel drug development is associated with an unacceptably high attrition rate. The application of clinically qualified predictive biomarkers holds great promise for further development of therapeutic targets, improved survival, and ultimately personalized medicine sets for patients. Decisions such as candidate selection, development risks, dose ranging, early proof of concept/principle, and patient stratification are based on the measurements of biologically and/or clinically validated biomarkers.
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http://dx.doi.org/10.1080/17460441.2016.1217196DOI Listing
October 2016

Anticancer effects of synthetic hexahydrobenzo [g]chromen-4-one derivatives on human breast cancer cell lines.

Breast Cancer 2017 Mar 1;24(2):299-311. Epub 2016 Jun 1.

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Cancer results from a series of molecular changes that alter the normal function of cells. Breast cancer is the second leading cause of cancer death in women. To develop novel anticancer agents, new series of chromen derivatives were synthesized and evaluated for their cytotoxic activity against human breast cancer cell lines.

Method: The growth inhibitory activities of synthesized hexahydrobenzo chromen-4-one were screened against six human cancer cell lines using an in vitro cell culture system (MTT assay). Fluorochrome staining (acridine orange/ethidium bromide double staining) and DNA fragmentation by the diphenylamine method were used to investigate the effects of most potent compounds on the process of apoptosis in breast cancer cell lines. To determine the mechanism of apoptosis, ROS and NOX production in treated breast cancer cells with compounds was evaluated.

Results: The cytotoxicity data of tested compounds demonstrate these compounds had varying degree of toxicity. Compound 7h was the most potent compound with IC = 1.8 ± 0.6 µg/mL against T-47D cell line. Analyses of the compounds treated (MCF-7, MDA-MB-231, and T-47D) cells by acridine orange/ethidium bromide double staining and DNA fragmentation by the diphenylamine method showed that the synthetic compounds induce apoptosis in the cells. A significant increase in ROS production was observed in T-47D cells treated with IC value of compound 7g. Incubation with IC value of synthetic compounds increased the NOX production in cell lines, especially T-47D cells.

Conclusion: Our results show that most compounds have a significant anti-proliferative activity against six human cancer cell lines. The observations confirm that chromen derivatives have induced the cell death through apoptosis.
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http://dx.doi.org/10.1007/s12282-016-0704-5DOI Listing
March 2017

Treatment of Helicobacter pylori infection: Current and future insights.

World J Clin Cases 2016 Jan;4(1):5-19

Maliheh Safavi, Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran 13353-5111, Iran.

Helicobacter pylori (H. pylori) is an important major cause of peptic ulcer disease and gastric malignancies such as mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma worldwide. H. pylori treatment still remains a challenge, since many determinants for successful therapy are involved such as individual primary or secondary antibiotics resistance, mucosal drug concentration, patient compliance, side-effect profile and cost. While no new drug has been developed, current therapy still relies on different mixture of known antibiotics and anti-secretory agents. A standard triple therapy consisting of two antibiotics and a proton-pump inhibitor proposed as the first-line regimen. Bismuth-containing quadruple treatment, sequential treatment or a non-bismuth quadruple treatment (concomitant) are also an alternative therapy. Levofloxacin containing triple treatment are recommended as rescue treatment for infection of H. pylori after defeat of first-line therapy. The rapid acquisition of antibiotic resistance reduces the effectiveness of any regimens involving these remedies. Therefore, adding probiotic to the medications, developing anti-H. pylori photodynamic or phytomedicine therapy, and achieving a successful H. pylori vaccine may have the promising to present synergistic or additive consequence against H. pylori, because each of them exert different effects.
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http://dx.doi.org/10.12998/wjcc.v4.i1.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714294PMC
January 2016

Novel N-2-(Furyl)-2-(chlorobenzyloxyimino) Ethyl Piperazinyl Quinolones: Synthesis, Cytotoxic Evaluation and Structure-Activity Relationship.

Iran J Pharm Res 2015 ;14(4):1095-103

Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran. ; Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Quinolone antibacterials are one of the most important classes of pharmacological agents known as potent inhibitors of bacterial DNA gyrase and topoisomerase IV that efficiently inhibit DNA replication and transcription by generating several double-stranded DNA break. Some quinolone derivatives demonstrated inhibitory potential against eukaryote topoismarase II and substantial dose-dependent cytotoxic potential against some cancerous cells. In present study, synthesis and cytotoxic activity evaluation of new series of N-pipearzinyl quinolones containing N-2-(furyl-2 or 3-yl)-2-(chlorobenzyloxyimino) ethyl moiety 7a-i have been studied. Reaction of quinolone, with 2-bromo-1-(furan-2 or 3-yl)ethanone-O-substituted chlorobenzyloxime in DMF in presence of NaHCO3 at room temperature, gave the title compounds N-2-(furan-2 or 3-yl)-2-(chlorobenzyloxyiminoethyl) quinolone 7a-i. Synthesized compounds were further evaluated in-vitro against three human breast tumor cell lines. Preliminary screening indicated that compound 7 g demonstrated significant growth inhibitory potential against all evaluated cell lines. The results of structure-activity relationship study exhibited that quinolone derivatives are superior in cytotoxic potential compared to 1, 8-naphthyridone series. Furthermore, ethyl quinolone derivatives were more potent cytotoxic agents comparing with cyclopropyl quinolones.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673937PMC
December 2015

Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9(10H)-acridinone-1,2,3-triazoles.

Mol Divers 2015 Nov 14;19(4):787-95. Epub 2015 Jul 14.

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

A new series of 9(10H)-acridinone-1,2,3-triazole derivatives were designed, synthesized and evaluated for their cytotoxic activity against human breast cancer cell lines. The acridone skeleton was prepared through the Ullman condensation of 2-bromobenzoic acid and anilines. Subsequently, it was functionalized with propargyl bromide. Then, a click reaction of the latter compound and in situ prepared 1-(azidomethyl)-4-methoxybenzene derivatives led to the formation of the desired triazole products. Finally, all products were investigated for their capability to cause cytotoxicity against MCF-7, T-47D, and MDA-MB-231 cell lines. Among them, 2-methoxy-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one 8c exhibited the most potency [Formula: see text] against MCF-7 cells, being more potent than etoposide [Formula: see text]. Also, apoptosis induced by compound 8c was confirmed via acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide (PI) double staining.
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http://dx.doi.org/10.1007/s11030-015-9616-0DOI Listing
November 2015