Publications by authors named "Nilgün Karali"

14 Publications

  • Page 1 of 1

Selective Cytotoxic Effects of 5-Trifluoromethoxy-1H-indole-2,3-dione 3-Thiosemicarbazone Derivatives on Lymphoid-originated Cells.

Anticancer Agents Med Chem 2021 Mar 1. Epub 2021 Mar 1.

Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazıt, Istanbul. Turkey.

Aim: The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3-thiosemicarbazone derivatives. These compounds could be promissing anticancer agents in leukemia treatment.

Background: Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to non-specificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life.

Method: In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt's lymphoma P3HR1, acute promyelocytic leukemia HL60 cells and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and resulting apoptotic activities were demonstrated.

Result: All compounds tested have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC50= 0.89-1.80 µM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistant. The most effective and selective compound is 4-bromophenyl substituted compound I (IC50=0.96 and 0.89 µM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC50=2.38 µM), while the allyl substituted compound C is effective on all cell lines (IC50=1.13-2.21 µM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC50=1.00-2.41 µM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC50= 1.13 µM). Additionally, all compounds exhibited cytotoxic effects on lymphoid-derived cells at 1µM concentration. These results are in accordance with the results obtained in lymphoma cells.

Conclusion: All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold promise for the future treatment of leukemia cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1871520621666210302084230DOI Listing
March 2021

Synthesis, molecular modeling and antiviral activity of novel 5-fluoro-1H-indole-2,3-dione 3-thiosemicarbazones.

Bioorg Chem 2020 11 26;104:104202. Epub 2020 Aug 26.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey.

In this work, novel 5-fluoro-1-methyl/ethyl-1H-indole-2,3-dione 3-[4-(substituted phenyl)-thiosemicarbazones] 6a-n and 7a-n were synthesized. The antiviral effects of the compounds were tested against HSV-1 (KOS), HSV-2 (G) HSV-1 TK KOS ACV and VV in HEL cell cultures using acyclovir and ganciclovir as standards, and Coxsackie B4 virus in Vero cell cultures using ribavirin and mycophenolic acid as standards. R ethyl substituted 7 derivatives were found effective against viruses tested. R 4-CF substituted 7d, R 4-OCH substituted 7 g and R 3-Cl substituted 7 l showed activity against HSV-1 (KOS), HSV-2 (G) HSV-1 TK KOS ACV and VV. Whereas only R 4-Br substituted 7n has selective activity against coxsackie B4 virus. Molecular modelingstudies of 7d and 7l were performed to determine binding side on HSV-1 glycoprotein B and D, HSV-2 glycoprotein B structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.104202DOI Listing
November 2020

Novel 2-indolinones containing a sulfonamide moiety as selective inhibitors of candida β-carbonic anhydrase enzyme.

J Enzyme Inhib Med Chem 2019 Dec;34(1):528-531

b Sezione di Scienza Farmaceutiche, Neurofarba Department , Universita degli Studi di Firenze , Florence , Italy.

Inhibition of the β-carbonic anhydrase (CA, EC 4.2.1.1) from pathogenic Candida glabrata (CgNce103) by 1H-indole-2,3-dione 3-[N-(4-sulfamoylphenyl)thiosemicarbazones] 4a-m was investigated. All the compounds were found to be potent inhibitors of CgNce103, with inhibition constants in the range of 6.4-63.9 nM. The 5,7-dichloro substituted derivative 4l showed the most effective inhibition (K of 6.4 nM) as well as the highest selectivity for inhibiting CgNce103 over the cytosolic human (h) isoforms hCA I and II. A possible binding interaction of compound 4l within the active site of CgNce103 has been proposed based on docking studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2018.1564045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366411PMC
December 2019

Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases.

Bioorg Med Chem 2017 07 15;25(14):3714-3718. Epub 2017 May 15.

Department of NEUROFARBA, Sezione di Scienze Farmaceutiche Universita degli Studi di Firenze, Sesto Fiorentino (Florence) 50019, Italy. Electronic address:

Human carbonic anhydrases IX and XII are upregulated in many tumors and form a novel target for new generation anticancer drugs. Here we report the synthesis of novel 2-indolinone derivatives with the sulfonamide group as a zinc binding moiety. Enzyme inhibition assays confirmed that the compounds showed selectivity against hCA IX and XII over the widely distributed off-targets hCA I and II. Molecular modelling studies were performed to suggest modes of binding for these compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2017.05.029DOI Listing
July 2017

Isatin analogs as novel inhibitors of Candida spp. β-carbonic anhydrase enzymes.

Bioorg Med Chem 2016 Apr 27;24(8):1648-52. Epub 2016 Feb 27.

Universita degli Studi di Firenze, NEUROFARBA Department, Sezione di Scienza Farmaceutiche, Via Ugo Schiff 6, 5001 Sesto Fiorentino (Florence), Italy. Electronic address:

Enzyme inhibition data of structurally novel isatin-containing sulfonamides were determined for two carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic Candida species (CaNce103 from C. albicans and CgNce103 from C. glabrata). The compounds show KI values in the low nanomolar range for the fungal CAs, while they have significantly higher KI values for the human CAs. Homology models were constructed for the CaNce103 and CgNce103 and subsequently the ligands were docked into these models to rationalize their enzyme inhibitory properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2016.02.036DOI Listing
April 2016

Discovery of novel isatin-based sulfonamides with potent and selective inhibition of the tumor-associated carbonic anhydrase isoforms IX and XII.

Org Biomol Chem 2015 Jun 13;13(23):6493-9. Epub 2015 May 13.

Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazıt, Istanbul, Turkey.

A series of 2/3/4-[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)amino]benzenesulfonamides, obtained from substituted isatins and 2-, 3- or 4-aminobenzenesulfonamide, showed low nanomolar inhibitory activity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII - recently validated antitumor drug targets, being much less effective as inhibitors of the off-target cytosolic isoforms CA I and II.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5ob00688kDOI Listing
June 2015

New spiroindolinones bearing 5-chlorobenzothiazole moiety.

J Enzyme Inhib Med Chem 2014 Aug 5;29(4):457-68. Epub 2013 Jun 5.

Department of Pharmaceutical Chemistry and.

In this study, 5-chloro-3H-spiro-[1,3-benzothiazole-2,3'-indole]-2'(1'H)-one derivatives 3a-l were synthesized by the reaction of 1H-indole-2,3-diones 1a-l with 2-amino-4-chlorothiophenol 2 in ethanol. 3a-l were tested for their abilities to inhibit lipid peroxidation (LP), scavenge DPPH(•) and ABTS(•+) radicals, and to reduce Fe(3+) to Fe(2+). Most of the tested compounds exhibited potent scavenging activities against ABTS(•+) radical, reducing powers and strong inhibitory capacity on LP. 3 a, 3 d, 3 e, 3h, 3 j and 3 k chosen as prototypes were evaluated in the National Cancer Institute's in vitro primary anticancer assay. The greatest growth inhibitions were observed against a non-small cell lung cancer cell line HOP-92 for R1-fluoro substituted 3 d and a renal cancer cell line RXF-393 for R-chloro substituted 3 e in the primary screen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/14756366.2013.800058DOI Listing
August 2014

Synthesis of new spiroindolinones incorporating a benzothiazole moiety as antioxidant agents.

Eur J Med Chem 2010 Mar 21;45(3):1068-77. Epub 2009 Dec 21.

Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Istanbul University, 34116 Beyazit, Istanbul, Turkey.

3H-Spiro[1,3-benzothiazole-2,3'-indol]-2'(1'H)-ones 3a-c and 4a-e were synthesized from treating the 5-substituted 1H-indole-2,3-diones with 2-aminothiophenol in ethanol. The structures were confirmed by elemental analyses, spectrometry (IR, (1)H NMR, (13)C NMR, HSQC-2D and LCMS-APCI) and single crystal X-ray analysis. The new compounds were screened for their antioxidant activities such as the Fe(3+)/ascorbate system induced inhibition of lipid peroxidation (LP) in liposomes, trolox equivalent antioxidant capacity (TEAC), scavenging effect on diphenylpicryl hydrazine (DPPH*), and reducing power. These compounds showed potent scavenging activities against DPPH* and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS*(+)) radicals, reducing powers, and strong inhibitory capacity on lipid peroxidation. Compound 4a incorporating methyl both at R(1) and R(2) was found to be the most potent antioxidant described in this study. Compounds 3b and 4b were selected as representative compounds by the National Cancer Institute for screening against anticancer activity and these compounds were found to be cytotoxic against CNS cancer cell line SNB-75 in the primary screen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2009.12.001DOI Listing
March 2010

5-Chloro-benzothia-zole-2-spiro-3'-indolin-2'-one.

Acta Crystallogr Sect E Struct Rep Online 2010 Jan 20;66(Pt 2):o399-400. Epub 2010 Jan 20.

The title compound, C(14)H(9)ClN(2)OS, crystallizes with two unique mol-ecules, A and B, in the asymmetric unit. The five-membered rings of the benzothia-zole groups in both mol-ecules adopt an envelope conformation [puckering parameters: q(2) = 0.242 (1) Å and ϕ(2) = 217.5 (4)° for A, and q(2) = 0.234 (1) Å and ϕ(2) = 37.7 (4)° for B]. The five-membered rings of the indolinone groups in both mol-ecules are also not planar, with a twisted conformation [puckering parameters are q(2) = 0.112 (2) Å and ϕ(2) = 126.3 (8)° for A, and q(2) = 0.108 (2) Å and ϕ(2) = 306.4 (9)° for B]. In the crystal structure, there are inter-molecular N-H⋯O, N-H⋯S and C-H⋯O hydrogen-bonding inter-actions, forming the layers propagating normal to c.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1107/S1600536810001285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2979878PMC
January 2010

Synthesis and antituberculosis activity of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives.

Bioorg Med Chem 2008 Oct 27;16(19):8976-87. Epub 2008 Aug 27.

Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey.

New series of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones 3a-t, 1-methyl-5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones 4a-y and 5-trifluoromethoxy-1-morpholinomethyl-1H-indole-2,3-dione 3-thiosemicarbazones 5a-m were synthesized. The structures of the synthesized compounds were confirmed by spectral data and elemental analysis. The new 5-methyl/trifluoromethoxy-1H-indole-2,3-dione derivatives, along with previously synthesized 5-methyl-1H-indole-2,3-dione 3-thiosemicarbazones 6a-l, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. 5-Methyl-1H-indole-2,3-dione 3-thiosemicarbazones (3b, 3d, 3f, 6c, 6d, and 6f), 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones (3q-s) and 5-trifluoromethoxy-1-morpholinomethyl-1H-indole-2,3-dione 3-thiosemicarbazones (5e and 5j-l) were found to be the most potent inhibitors of M. tuberculosis growth described in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2008.08.050DOI Listing
October 2008

Synthesis and structure-antituberculosis activity relationship of 1H-indole-2,3-dione derivatives.

Bioorg Med Chem 2007 Sep 2;15(17):5888-904. Epub 2007 Jun 2.

Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Beyazit, Istanbul, Turkey.

New series of 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones 2a-k and 5-fluoro-1-morpholino/piperidinomethyl-1H-indole-2,3-dione-3-thiosemicarbazones 3a-r were synthesized. The structures of the synthesized compounds were confirmed by spectral data, elemental and single crystal X-ray diffraction analysis. The new 5-fluoro-1H-indole-2,3-dione derivatives, along with previously reported 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 2l-v, 1-morpholino/piperidinomethyl-5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 4a-l, and 5-nitro-1H-indole-2,3-dione-3-[(4-oxo-1,3-thiazolidin-2-ylidene)hydrazones] 5a-s, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones (2p, 2r, and 2s) and its 1-morpholinomethyl derivatives (4a, 4e, 4g, and 4i) exhibited significant inhibitory activity in the primary screen. The antituberculosis activity of molecules with diverse skeletons was investigated by means of the Electronic-Topological Method (ETM). Ten pharmacophores and ten anti-pharmacophores that have been found by this form the basis of the system capable of predicting the structures of potentially active compounds. The forecasting ability of the system has been tested on structures that differ from those synthesized. The probability of correct identification for active compounds was found as equal to 93% in average. To obtain the algorithmic base for the activity prediction, Artificial Neural Networks were used after the ETM (the so-called combined ETM-ANN method). As the result, only 9 pharmacophores and anti-pharmacophores were chosen as the most important ones for the activity. By this, ANNs classified correctly 94.4%, or 67 compounds from 71.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2007.05.063DOI Listing
September 2007

Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones.

Eur J Med Chem 2003 Jun;38(6):633-43

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, 34452 Istanbul, Turkey.

New esters (2b and 2c) and hydrazides (3b and 3c) were synthesized from 6-methyl/fluoro-3-phenyl-4(1H, 3H)-quinazolinone-2-thiones (1b and 1c). Subsequent treatment of 3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetic acid hydrazides (3a-e) with 1H-indole-2,3-diones (4a-e) furnished the corresponding 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones (5a-u). The structures of new compounds were determined by analytical and spectral (IR, 1H-NMR, (13)C-NMR, EIMS) methods. Previously reported 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-bromo-1H-2-indolinone 5v and compounds 5b, 5d and 5o chosen as prototypes were evaluated against the full panel of 60 human tumour cell lines at a minimum of five concentrations at tenfold dilutions in the National Cancer Institute in vitro primary cytotoxicity assay. Sulforhodamine B protein assay was used to estimate cell stability or growth. 3-[[(6-Chloro-3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-fluoro-1H-2-indolinone 5o showed the most favourable cytotoxicity against a renal cancer cell line UO-31 (log(10)GI(50) value -6.68). Compound 5v was also tested against human immunodeficiency virus 1 (HIV-1). Compound 5v was confirmed moderately active against HIV-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0223-5234(03)00085-0DOI Listing
June 2003

Synthesis and primary cytotoxicity evaluation of new 5-nitroindole-2,3-dione derivatives.

Authors:
Nilgün Karali

Eur J Med Chem 2002 Nov;37(11):909-18

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.

A new series of 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones (3a-k) obtained by condensation of 5-nitro-1H-indole-2,3-dione (1) with N-substituted-thiosemicarbazides (2a-k) were treated with morpholine or piperidine and formaldehyde to yield 1-morpholino/piperidinomethyl-5-nitroindole-2,3-dione-3-thiosemicarbazones (4a-m). The structures of all the compounds were determined by analytical and spectral (IR, 1H-NMR, EIMS) methods. Compounds 3b, 3c, 3f, 3k, 4a, 4c, 4f and 4l chosen as prototypes were evaluated in the National Cancer Institute's 3-cell line, one dose in vitro primary cytotoxicity assay. All the compounds that passed the criteria for activity in this assay were scheduled automatically for evaluation against the full panel of 60 human tumour cell lines at a minimum of five concentrations at 10-fold dilutions. Sulphorhodamine B (SRB) protein assay was used to estimate cell stability or growth. The most active compound was found to be 1-morpholinomethyl-5-nitroindole-2,3-dione-3-N-(chlorophenyl)thiosemicarbazone (4l). This compound demonstrated the most marked effects in the National Cancer Institute's 60 human tumour cell line in vitro screen on a non-small cell lung cancer cell line (HOP-62, log(10)GI(50) value <-8.00) and on leukaemia cell lines (HL-60(TB), log(10)GI(50) value -6.30; MOLT-4, log(10)GI(50) value -6.18).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0223-5234(02)01416-2DOI Listing
November 2002

Synthesis and primary cytotoxicity evaluation of new 5-bromo-3-substituted-hydrazono-1H-2-indolinones.

Arch Pharm (Weinheim) 2002 Aug;335(8):374-80

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Istanbul, Istanbul, Turkey.

In this study a new series of 5-bromo-3-[(3-substituted-5-methyl-4-thiazolidinone-2-ylidene)-hydrazono]-1H-2-indolinones (3a-i) and 5-bromo-3-[(2-thioxo-3-substituted-4, 5-imidazolidinedione-1-yl)imino]-1H-2-indolinones (4a-f) was synthesized by the cyclization of 5-bromo-3-(N-substituted-thiosemicarbazono)-1H-2-indolinones (2a-i)with ethyl 2-bromopropionate in anhydrous ethanolic medium and oxalyl cloride in anhydrous diethyl ether, respectively. Six compounds chosen as prototypes were evaluated in the 3-cell line, one dose in vitro primary cytotoxicity assay. Four of them were evaluated against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. Among the compounds tested, the 4-fluoro-phenylthiosemicarbazone derivative 2f showed the most favorable cytotoxicity. This compound demonstrated the most marked effects on a breast cancer cell line (BT-549, log(10)GI(50) value -6.40), a non small cell lung cancer cell line (NCI-H23, log(10)GI(50) value -6.10), and an ovarian cancer cell line (IGROV1, log(10)GI(50) value -6.02).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1521-4184(200211)335:8<374::AID-ARDP374>3.0.CO;2-KDOI Listing
August 2002