Publications by authors named "Burcu Çalışkan"

19 Publications

  • Page 1 of 1

Synthesis and biological evaluation of novel isoxazole-piperazine hybrids as potential anti-cancer agents with inhibitory effect on liver cancer stem cells.

Eur J Med Chem 2021 Oct 24;221:113489. Epub 2021 Apr 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey. Electronic address:

In our effort for the development of novel anticancer therapeutics, a series of isoxazole-piperazine analogues were prepared, and primarily screened for their antiproliferative potential against hepatocellular carcinoma (HCC; Huh7/Mahlavu) and breast (MCF-7) cancer cells. All compounds demonstrated potent to moderate cytotoxicity on all cell lines with IC values in the range of 0.09-11.7 μM. Further biological studies with 6a and 13d in HCC cells have shown that both compounds induced G1 or G2/M arrests resulting in apoptotic cell death. Subsequent analysis of proteins involved in cell cycle progression as well as proliferation of HCC cells revealed that 6a and 13d may affect cellular survival pathways differently depending on the mutation profiles of cells (p53 and PTEN), epidermal/mesenchymal characteristics, and activation of cell mechanisms through p53 dependent/independent pathways. Lastly, we have demonstrated the potential anti-stemness properties of these compounds in which the proportion of liver CSCs in Huh7 cells (CD133+/EpCAM+) were significantly reduced by 6a and 13d. Furthermore, both compounds caused a significant reduction in expression of stemness markers, NANOG or OCT4 proteins, in Mahlavu and Huh7 cells, as well as resulted in a decreased sphere formation capacity in Huh7 cells. Together, these novel isoxazole-piperazine derivatives may possess potential as leads for development of effective anti-cancer drugs against HCC cells with stem cell-like properties.
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http://dx.doi.org/10.1016/j.ejmech.2021.113489DOI Listing
October 2021

Simple heteroaryl modifications in the 4,5-diarylisoxazol-3-carboxylic acid scaffold favorably modulates the activity as dual mPGES-1/5-LO inhibitors with in vivo efficacy.

Bioorg Chem 2021 Jul 24;112:104861. Epub 2021 Mar 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06560 Ankara, Turkey. Electronic address:

Microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC mPGES-1 = 0.16 µM; IC 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents.
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http://dx.doi.org/10.1016/j.bioorg.2021.104861DOI Listing
July 2021

Antimigratory effect of pyrazole derivatives through the induction of STAT1 phosphorylation in A549 cancer cells.

J Pharm Pharmacol 2021 Apr;73(6):808-815

Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.

Objectives: In cancer treatment, it is important to prevent or slow down metastasis as well as preventing the proliferation of cancer cells. In this study, we aimed to find pyrazole compounds with antimigratory properties.

Methods: The 'PASSonline' programme was used to determine the possible pharmacological activities of the pyrazole compounds selected from the library, and two pyrazole derivatives were identified as a transcription factor STAT inhibitor with a high probability. There are studies known that JAK/STAT pathway is related to cancer cell migration, thus the possible antimigratory effects of these two synthesized pyrazole compounds were examined in A549 cancer cells.

Key Findings: Our data demonstrated that compound-2 at different concentrations significantly inhibited cell migration in A549 cells. Then, the effects of these compounds on STAT activation were evaluated. We reported that 10 µM compound-2 induced a significant phosphorylation of STAT1 suggesting that STAT1 activation may be responsible for the antimigratory effect of compound-2.

Conclusions: Taken together, the compound-2 is a promising compound with the antimigratory activity for cancer treatment, and further studies are needed to synthesize more active derivatives by evaluating the structure-activity relationship of leading compound-2.
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http://dx.doi.org/10.1093/jpp/rgab022DOI Listing
April 2021

A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate.

Mol Cancer Ther 2020 06 26;19(6):1243-1254. Epub 2020 Mar 26.

Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.

TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint-dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3-TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0957DOI Listing
June 2020

Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors.

Bioorg Chem 2020 01 28;95:103544. Epub 2019 Dec 28.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3 Yenimahalle, 06560 Ankara, Turkey. Electronic address:

We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a-d, 7a-c and 10) as well as hydroxamic acid (15a-b), carboxylic acid (16a-b), carboxamide (17a-b) and boronic acid (22a-b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with K values in the range of 5.2-29.3 nM and 9.9-41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (K = 6.6 nM) and XII (K = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4-25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1-121.5 although with K values in lower micromolar potency (Ks = 0.36-0.85 μM for CA IX/XII).
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http://dx.doi.org/10.1016/j.bioorg.2019.103544DOI Listing
January 2020

A Multi-step Virtual Screening Protocol for the Identification of Novel Non-acidic Microsomal Prostaglandin E Synthase-1 (mPGES-1) Inhibitors.

ChemMedChem 2019 01 20;14(2):273-281. Epub 2018 Dec 20.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, 06560, Turkey.

Microsomal prostaglandin E synthase-1 (mPGES-1) is a potential therapeutic target for the treatment of inflammatory diseases and certain types of cancer. To identify novel scaffolds for mPGES-1 inhibition, we applied a virtual screening (VS) protocol that comprises molecular docking, fingerprints-based clustering with diversity-based selection, protein-ligand interactions fingerprints, and molecular dynamics (MD) simulations with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The hits identified were carefully analyzed to ensure the selection of novel scaffolds that establish stable interactions with key residues in the mPGES-1 binding pocket and inhibit the catalytic activity of the enzyme. As a result, we discovered two promising chemotypes, 4-(2-chlorophenyl)-N-[(2-{[(propan-2-yl)sulfamoyl]methyl}phenyl)methyl]piperazine-1-carboxamide (6) and N-(4-methoxy-3-{[4-(6-methyl-1,3-benzothiazol-2-yl)phenyl]sulfamoyl}phenyl)acetamide (8), as non-acidic mPGES-1 inhibitors with IC values of 1.2 and 1.3 μm, respectively. Minimal structural optimization of 8 resulted in three more compounds with promising improvements in inhibitory activity (IC : 0.3-0.6 μm). The unprecedented chemical structures of 6 and 8, which are amenable to further derivatization, reveal a new and attractive approach for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties.
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http://dx.doi.org/10.1002/cmdc.201800701DOI Listing
January 2019

Synthesis and cellular bioactivities of novel isoxazole derivatives incorporating an arylpiperazine moiety as anticancer agents.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1352-1361

a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Gazi University , Ankara , Turkey.

In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC values in the range of 0.3-3.7 μM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation.
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http://dx.doi.org/10.1080/14756366.2018.1504041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161610PMC
December 2018

Identification of multi-target inhibitors of leukotriene and prostaglandin E biosynthesis by structural tuning of the FLAP inhibitor BRP-7.

Eur J Med Chem 2018 Apr 17;150:876-899. Epub 2018 Mar 17.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330, Ankara, Turkey. Electronic address:

Leukotrienes (LTs) and prostaglandin (PG)E are enzymatically produced from arachidonic acid and represent highly bioactive lipid mediators with pro-inflammatory functions. Here, we report on novel multi-target inhibitors that potently and dually interfere with 5-lipoxygenase-activating protein (FLAP) and microsomal prostaglandin E synthase (mPGES)-1 in LT and PGE biosynthesis, based on the previously identified selective FLAP inhibitor BRP-7 (8, IC = 0.31 μM). C (5)-substitution of the benzimidazole ring of BRP-7 by carboxylic acid and its bioisosteres provided compounds, exemplified by 57 that potently suppress LT formation (IC = 0.05 μM) by targeting FLAP along with inhibition of mPGES-1 (IC = 0.42 μM). Besides FLAP, also 5-lipoxygenase (5-LO) and LTC synthase activities were inhibited by 57, albeit with lower potency (IC = 0.6 and 6.2 μM) than FLAP. Docking studies and molecular dynamic simulations with FLAP, mPGES-1 and 5-LO provide valuable insights into potential binding interactions of the inhibitors with their targets. Together, these novel benzimidazole derivatives may possess potential as leads for development of effective anti-inflammatory drugs with multi-target properties for dually inhibiting LT and PGE production.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.045DOI Listing
April 2018

Drug discovery approaches targeting 5-lipoxygenase-activating protein (FLAP) for inhibition of cellular leukotriene biosynthesis.

Eur J Med Chem 2018 Jun 13;153:34-48. Epub 2017 Jul 13.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey. Electronic address:

Leukotrienes are proinflammatory lipid mediators associated with diverse chronic inflammatory diseases such as asthma, COPD, IBD, arthritis, atherosclerosis, dermatitis and cancer. Cellular leukotrienes are produced from arachidonic acid via the 5-lipoxygenase pathway in which the 5-lipoxygenase activating protein, also named as FLAP, plays a critical role by operating as a regulatory protein for efficient transfer of arachidonic acid to 5-lipoxygenase. By blocking leukotriene production, FLAP inhibitors may behave as broad-spectrum leukotriene modulators, which might be of therapeutic use for chronic inflammatory diseases requiring anti-leukotriene therapy. The early development of FLAP inhibitors (i.e. MK-886, MK-591, BAY-X-1005) mostly concentrated on asthma cure, and resulted in promising readouts in preclinical and clinical studies with asthma patients. Following the recent elucidation of the 3D-structure of FLAP, development of new inhibitor chemotypes is highly accelerated, eventually leading to the evolution of many un-drug-like structures into more drug-like entities such as AZD6642 and BI665915 as development candidates. The most clinically advanced FLAP inhibitor to date is GSK2190918 (formerly AM803) that has successfully completed phase II clinical trials in asthmatics. Concluding, although there are no FLAP inhibitors reached to the drug approval phase yet, due to the rising number of indications for anti-LT therapy such as atherosclerosis, FLAP inhibitor development remains a significant research field. FLAP inhibitors reviewed herein are classified into four sub-classes as the first-generation FLAP inhibitors (indole and quinoline derivatives), the second-generation FLAP inhibitors (diaryl-alkanes and biaryl amino-heteroarenes), the benzimidazole-containing FLAP inhibitors and other FLAP inhibitors with polypharmacology for easiness of the reader. Hence, we meticulously summarize how FLAP inhibitors historically developed from scratch to their current advanced state, and leave the reader with a positive view that a FLAP inhibitor might soon reach to the need of patients who may require anti-LT therapy.
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http://dx.doi.org/10.1016/j.ejmech.2017.07.019DOI Listing
June 2018

HLA Genotypes in Turkish Hematopoietic Cell Recipients and Likelihood of Finding a Matched Donor Through Family Searches.

Exp Clin Transplant 2019 12 28;17(6):813-818. Epub 2017 Mar 28.

Department of Pediatric Hematology, Gazi University Medical School, Ankara, Turkey.

Objectives: Allogeneic hematopoietic stem cell transplant is a life-saving treatment, but donor numbers in Turkey do not meet the increasing demand for this procedure. Here, our objectives were (1) to assess the frequency of HLA-matched related donors in the Turkish population and (2) to identify the HLA antigens and haplotypes that are most frequent in Turkey.

Materials And Methods: The HLA genotypes of 841 consecutive recipients and 3071 family members were retrospectively reviewed.

Results: Matched related donors were identified for 368/841 recipients (44%). Extended family donor searches were performed for 111/181 pediatric recipients (61%), with nonsibling matched related donors found for 23 patients (21%). Matched related donors were found for a significantly higher proportion of pediatric patients (52%) than adult patients (41%) (odds ratio of 2.5; 95% confidence interval, 1.9-4.1; P = .02). The percentage of pediatric versus adult patients with 3 or more siblings was 13% versus 46% (odds ratio of 5.6; 95% confidence interval, 3.6-8.5; P = .001). The most frequent HLA class I antigens at each locus were HLA-A*02 (20.2%), HLA-B*35 (19.5%), and HLA-C*07 (19.8%). The most frequent HLA class II antigens at each locus were HLA-DRB1*11 (21.6%) and HLA-DQB1*03 (40.2%). The most common 3-locus haplotypes were HLA-A*24 B*35 DRB1*11 (F:0.020) and HLA-A*01 B*08 DRB1*03 (F:0.015). When adult and pediatric groups were combined, the most common locus haplotypes were found in 43/345 sibling donors (12%) and in 7/23 nonsibling pediatric donors (30%) (odds ratio of 2.7; 95% confidence interval, 1.2-6.4; P = .02).

Conclusions: The results indicate that, in Turkey, it can be beneficial to revise donor search algorithms to include an extended family donor search before an unrelated donor search. This type of search can be effective because of the HLA haplotype diversity in Turkey, the frequency of consanguinity, and the country's limited donor pool.
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http://dx.doi.org/10.6002/ect.2016.0135DOI Listing
December 2019

BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly.

Biochem Pharmacol 2016 Nov 31;119:17-26. Epub 2016 Aug 31.

Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany. Electronic address:

The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC=7-10nM), and upon activation by ionophore A23187 (IC=10-60nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E synthase-1 (IC=0.2μM), another MAPEG member. In vivo, BRP-187 (10mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation.
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http://dx.doi.org/10.1016/j.bcp.2016.08.023DOI Listing
November 2016

Synthesis and biological evaluation of C(5)-substituted derivatives of leukotriene biosynthesis inhibitor BRP-7.

Eur J Med Chem 2016 Oct 5;122:510-519. Epub 2016 Jul 5.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey. Electronic address:

Pharmacological intervention with 5-lipoxygenase (5-LO) pathway leading to suppression of leukotriene (LT) biosynthesis is a clinically validated strategy for treatment of respiratory and cardiovascular diseases such as asthma and atherosclerosis. Here we describe the synthesis of a series of C(5)-substituted analogues of the previously described 5-LO-activating protein (FLAP) inhibitor BRP-7 (IC50 = 0.31 μM) to explore the effects of substitution at the C(5)-benzimidazole (BI) ring as a strategy to increase the potency against FLAP-mediated 5-LO product formation. Incorporation of polar substituents on the C(5) position of the BI core, exemplified by compound 11 with a C(5)-nitrile substituent, significantly enhances the potency for suppression of 5-LO product synthesis in human neutrophils (IC50 = 0.07 μM) and monocytes (IC50 = 0.026 μM).
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http://dx.doi.org/10.1016/j.ejmech.2016.07.004DOI Listing
October 2016

4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).

Eur J Med Chem 2016 May 15;113:1-10. Epub 2016 Feb 15.

Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743, Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany.

In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.027DOI Listing
May 2016

Synthesis and preliminary mechanistic evaluation of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid amides with potent antiproliferative activity on human cancer cell lines.

Eur J Med Chem 2014 Nov 20;87:140-9. Epub 2014 Sep 20.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey. Electronic address:

We synthesized a series of novel amide derivatives of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid and assessed their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines) with the sulforhodamine B assay. Compound 4j with 2-chloro-4-pyridinyl group in the amide part exhibited promising cytotoxic activity against all cell lines with IC50 values of 1.6 μM, 3.3 μM and 1.1 μM for Huh7, MCF7 and HCT116 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G1 phase as an indicator of apoptotic cell death induction. On the basis of their high potency in cellular environment, these straightforward pyrazole-3-carboxamide derivatives may possess potential in the design of more potent compounds for intervention with cancer cell proliferation.
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http://dx.doi.org/10.1016/j.ejmech.2014.09.056DOI Listing
November 2014

Chromatographic separation and biological evaluation of benzimidazole derivative enantiomers as inhibitors of leukotriene biosynthesis.

J Pharm Biomed Anal 2014 Feb 7;89:88-92. Epub 2013 Nov 7.

Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. Electronic address:

For an explicit analysis of the chirality on the effectiveness of a recently identified racemic benzimidazole derivative (BRP7) as inhibitor of leukotriene biosynthesis, we optimized a HPLC-based chiral chromatographic method enabling the quantitative isolation of its enantiomers in sufficient amount to carry out biological investigations. The use of a Lux Amylose-2 column revealed especially profitable to fulfil our task. Indeed, the employment of the amylose-based chiral stationary phase (CSP) in combination with a n-hexane/EtOH/DEA - 99/1/02 (v/v/v) mobile phase allowed getting the enantiomeric peaks fully resolved (α=1.80, RS=2.39). Four consecutive injections repeated at 1-min intervals produced overloaded peaks with a very limited level of isomeric contamination. This procedure allowed the isolation of ca. 20mg of each enantiomer, with enantiomeric excess higher than 99% and 95% for the (S)- and the (R)-isomer, respectively. The enantiomeric elution order was established using synthetic reference compounds of lower enantiomeric excess values. The biological evaluation of the purified individual enantiomers revealed no significant difference in terms of their IC50 values with respect to the previously investigated racemic BRP7: 0.18μM for the (R)-enantiomer (R(2)=0.999) and 0.26μM for the (S)-enantiomer (R(2)=0.986).
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http://dx.doi.org/10.1016/j.jpba.2013.10.039DOI Listing
February 2014

Pyrazole derivatives as inhibitors of arachidonic acid-induced platelet aggregation.

Eur J Med Chem 2013 Jun 6;64:42-53. Epub 2013 Apr 6.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3, Etiler, Yenimahalle, Ankara 06330, Turkey.

Antiplatelet drugs are promising therapeutics to intervene with platelet aggregation in arterial thrombosis, most prominently in myocardial infarction and ischemic stroke. Here, we describe the synthesis and structure-activity relationships of potent inhibitors of platelet aggregation based on the 1,5-diarylpyrazol-3-carboxamide scaffold. Analogs from this series demonstrated potent anti-aggregatory activities against arachidonic acid-induced platelet aggregation, as measured by turbidimetric method of Born. 1,5-Diarylpyrazole-3-carboxamides obtained with small-basic amines (7, 8, 50, 51, 61, 62) displayed the strongest activity with IC50 values in low nanomolar range (5.7-83 nM). On the basis of their high potency in cellular environment, these straightforward pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases.
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http://dx.doi.org/10.1016/j.ejmech.2013.03.048DOI Listing
June 2013

Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors.

Expert Opin Drug Discov 2013 Jan 25;8(1):49-63. Epub 2012 Oct 25.

Gazi University, Department of Pharmaceutical Chemistry, Taç Sok. No:3 Yenimahalle, Ankara, Turkey.

Introduction: LTA(4)H is a bifunctional enzyme with hydrolase and aminopeptidase activities. The hydrolase function of this enzyme specifically catalyzes the rate-limiting step in the conversion of LTA(4) to LTB(4), one of the most potent chemoattractant and activator of neutrophils. The wealth of in vitro and in vivo data favors in support of LTA(4)H as an appealing target for the discovery and development of anti-inflammatory drugs.

Areas Covered: The authors provide an overview of the recent advances on LTA(4)H inhibitors since 2000. The review details the medicinal chemistry efforts leading to the generation of novel inhibitor chemotypes with desirable drug-like properties as well as the advantages and disadvantages of LTA(4)H as a desirable therapeutic target.

Expert Opinion: Most of the LTA(4)H inhibitors block pro-inflammatory LTB(4) biosynthesis by concomitant inhibition of both the hydrolase and aminopeptidase activities of LTA(4)H. However, the degradation of another endogenous chemoattractant substrate (PGP) by aminopeptidase function of LTA(4)H was shown, introducing a new anti-inflammatory mission for this pro-inflammatory enzyme. LTA(4)H inhibitors were also shown to maintain anti-inflammatory lipoxin formation. Hence, the data on new LTA(4)H inhibitors should be cautiously interpreted with regard to potential repercussions of preventing PGP degradation as well as for the clinical benefits of concomitant lipoxin formation.
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http://dx.doi.org/10.1517/17460441.2013.735228DOI Listing
January 2013

Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP).

Bioorg Med Chem 2012 Jun 1;20(12):3728-41. Epub 2012 May 1.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Yenimahalle, Ankara, Turkey.

Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.
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http://dx.doi.org/10.1016/j.bmc.2012.04.048DOI Listing
June 2012

Pyrazol-3-propanoic acid derivatives as novel inhibitors of leukotriene biosynthesis in human neutrophils.

Eur J Med Chem 2011 Oct 11;46(10):5021-33. Epub 2011 Aug 11.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Etiler, Ankara, Turkey.

We recently presented that compounds 4a-b moderately inhibited leukotriene (LT) formation in human neutrophils. For structural derivatization of 4a-b, novel thirty-six title compounds were synthesized and led to more potent inhibition of LT biosynthesis in activated human neutrophils exemplified by compounds 15, 27-30, 32-37, 41, 42 with IC(50) values in the range of 1.6-3.5 μM. Moreover, compounds 32, 35, 42, 43 and 44 showed a substantial inhibition of platelet COX-1 activity with IC(50) of 2.5, 0.041, 0.3, 0.9 and 0.014 μM, respectively, leading up to dual acting inhibitors. On the basis of their high potency in cellular environment, these straightforward pyrazole-3-propanoic acid derivatives may possess potential in the design of more potent compounds for intervention with inflammatory and allergic diseases.
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http://dx.doi.org/10.1016/j.ejmech.2011.08.009DOI Listing
October 2011