Publications by authors named "Danuta Drozdowska"

19 Publications

  • Page 1 of 1

Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents.

Int J Mol Sci 2021 Apr 1;22(7). Epub 2021 Apr 1.

Department of Organic Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland.

Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds () were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (DHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Data from the ethidium displacement test confirmed their DNA-binding capacity. Compounds (49.89% and 43.85%) and (41.68% and 42.99%) showed a higher binding affinity to pBR322 plasmid than NT. The possibility of binding in a minor groove as well as determination of association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT), and poly (dG-dC). With the exception of compounds (IC50 = 56.05 µM) and (IC50 = 55.32 µM), all of the compounds showed better inhibitory properties against DHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards DHFR. Derivatives , , , , and were found to be the most potent DHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30.
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http://dx.doi.org/10.3390/ijms22073685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037161PMC
April 2021

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs.

Molecules 2019 Dec 27;25(1). Epub 2019 Dec 27.

Department of Organic Chemistry, Medical University of Bialystok, 15222 Bialystok, Poland.

A new series of trimethoprim (TMP) analogs containing amide bonds (-) have been synthesized. Molecular docking, as well as dihydrofolate reductase (DHFR) inhibition assay were used to confirm their affinity to bind dihydrofolate reductase enzyme. Data from the ethidium displacement test showed their DNA-binding capacity. Tests confirming the possibility of DNA binding in a minor groove as well as determination of the association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT) and poly (dG-dC). Additionally, the mechanism of action of the new compounds was studied. In conclusion, some of our new analogs inhibited DHFR activity more strongly than TMP did, which confirms, that the addition of amide bonds into the analogs of TMP increases their affinity towards DHFR.
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http://dx.doi.org/10.3390/molecules25010116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983048PMC
December 2019

Recent Design and Structure-Activity Relationship Studies on the Modifications of DHFR Inhibitors as Anticancer Agents.

Curr Med Chem 2021 ;28(5):910-939

Department of Organic Chemistry, Faculty of Pharmacy, Medical University, Białystok, Poland.

Background: Dihydrofolate reductase (DHFR) has been known for decades as a molecular target for antibacterial, antifungal and anti-malarial treatments. This enzyme is becoming increasingly important in the design of new anticancer drugs, which is confirmed by numerous studies including modelling, synthesis and in vitro biological research. This review aims to present and discuss some remarkable recent advances in the research of new DHFR inhibitors with potential anticancer activity.

Methods: The scientific literature of the last decade on the different types of DHFR inhibitors has been searched. The studies on design, synthesis and investigation structure-activity relationships were summarized and divided into several subsections depending on the leading molecule and its structural modification. Various methods of synthesis, potential anticancer activity and possible practical applications as DHFR inhibitors of new chemical compounds were described and discussed.

Results: This review presents the current state of knowledge on the modification of known DHFR inhibitors and the structures and searches for about eighty new molecules, designed as potential anticancer drugs. In addition, DHFR inhibitors acting on thymidylate synthase (TS), carbon anhydrase (CA) and even DNA-binding are presented in this paper.

Conclusion: Thorough physicochemical characterization and biological investigations highlight the structure-activity relationship of DHFR inhibitors. This will enable even better design and synthesis of active compounds, which would have the expected mechanism of action and the desired activity.
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http://dx.doi.org/10.2174/0929867326666191016151018DOI Listing
April 2021

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors.

J Antibiot (Tokyo) 2020 01 2;73(1):5-27. Epub 2019 Oct 2.

Department of Organic Chemistry, Medical University of Białystok, Mickiewicza Street 2a, 15-222, Białystok, Poland.

The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer diseases have been a serious clinical problem around the world for over 50 years. Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important. Dihydrofolate reductase (DHFR) has attracted a lot of attention as a molecular target for bacterial resistance over several decades, resulting in a number of useful agents. Trimethoprim (TMP), (2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine) is the well-known dihydrofolate reductase inhibitor and one of the standard antibiotics used in urinary tract infections (UTIs). This review highlights advances in design, synthesis, and biological evaluations in structural modifications of TMP as DHFR inhibitors. In addition, this report presents the differences in the active site of human and pathogen DHFR. Moreover, an excellent review of DHFR inhibition and their relevance to antimicrobial and parasitic chemotherapy was presented.
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http://dx.doi.org/10.1038/s41429-019-0240-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102388PMC
January 2020

Synthesis and cellular effects of novel 1,3,5-triazine derivatives in DLD and Ht-29 human colon cancer cell lines.

Invest New Drugs 2020 08 13;38(4):990-1002. Epub 2019 Sep 13.

Department of Organic Chemistry, Medical University of Bialystok, Białystok, Poland.

This study provides new information on the cellular effects of 1,3,5-triazine nitrogen mustards with different peptide groups in DLD and Ht-29 human colon cancer cell lines. A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing 2-chloroethyl and oligopeptide moieties was designed and synthesized. The most cytotoxic derivative was triazine with an Ala-Ala-OMe substituent on the ring (compound 7b). This compound induced time- and dose-dependent cytotoxicity in the DLD-1 and HT-29 colon cancer cell lines. The triazine derivative furthermore induced apoptosis through intracellular signaling pathway attenuation. Compound 7b may be a candidate for further evaluation as a chemotherapeutic agent against colorectal cancer.
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http://dx.doi.org/10.1007/s10637-019-00838-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340680PMC
August 2020

The cellular effects of novel triazine nitrogen mustards in glioblastoma LBC3, LN-18 and LN-229 cell lines.

Invest New Drugs 2019 10 15;37(5):984-993. Epub 2019 Jan 15.

Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Bialystok, Poland.

1,3,5-triazine is an important heterocyclic skeleton for mono, two or three 2-chloroethylamine groups. The study presented here provides novel information on cellular effects of 1,3,5-triazine with mono, two or three 2-chloroethylamine groups in glioblastoma LBC3, LN-18 and LN-229 cell lines. In our study, the most cytotoxic effect was observed in 1,3,5-triazine with three 2-chloroethylamine groups (12f compound). It has been demonstrated that 12f induce time- and dose-dependent cytotoxicity in all investigated glioma cell lines. Apart from that in glioblastoma cells, treated with 12f compound, we noticed strong induction of apoptosis. In conclusion, this research provides novel information concerning cellular effects of apoptosis in LBC3, LN-18 and LN-229 cell lines. Moreover, we suggest that 12f compound may be a candidate for further evaluation as an effective chemotherapeutic agent for human glioblastoma cells.
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http://dx.doi.org/10.1007/s10637-018-0712-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736897PMC
October 2019

Carbocyclic Analogues of Distamycin and Netropsin.

Mini Rev Med Chem 2019 ;19(2):98-113

Department of Organic Chemistry, Medical University, Bialystok 15-222, Mickiewicza Street 2c, Poland.

The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from their selective interaction with DNA in the minor groove and from their ability to interfere with biological processes such as enzyme catalysis, replication and transcription. The discovery of the details of minor groove binding drugs, such as netropsin and distamycin A, oligoamides built of 4-amino-1-methylpyrrole-2-carboxylic acid residues, allowed to develop various DNA sequence-reading molecules, named lexitropsins, capable of interacting with DNA precisely, strongly and with a high specificity, and at the same time exhibiting significant cytotoxic potential. Among such compounds, lexitropsins built of carbocyclic sixmembered aromatic rings occupy a quite prominent place in drug research. This work is an attempt to present current findings in the study of carbocyclic lexitropins, their structures, syntheses and biological investigations such as DNA-binding and antiproliferative activity.
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http://dx.doi.org/10.2174/1389557518666181009143203DOI Listing
January 2019

ANTIPROLIFERATIVE EFFECTS ON BREAST CANCER CELLS AND SOME INTERACTIONS OF NEW DISTAMYCIN ANALOGUES WITH DNA, ENDONUCLEASES AND DNA TOPOISOMERASES.

Acta Pol Pharm 2016 Jan-Feb;73(1):47-53

The evaluation of a new group of distamycin analogues 1-6 as potential minor groove binders for the treatment of cancer were investigated. The activity of the new compounds against several restriction enzymes was examined. The studied compounds did not block GC-rich sequences regions of DNA but inhibited catalytic action of endonucleases in AA, AT, TT and AG restriction sites. Determination of association constants using calf thymus DNA, T4 coliphage DNA, poly(dA-dT)₂ and poly(dG-dC)₂ have confirmed that the tested compounds bind within minor groove of B-DNA. All of the compounds demonstrated activity against DNA topoisomerases II at the concentration 10 µM, but they did not inhibit activity of topoisomerase I. The studied derivatives were evaluated in human MCF-7 breast cancer cells and showed antiproliferative and cytotoxic effects in the range of 81.70 µM and 200.00 µM.
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April 2016

Synthesis of Arylamino-1,3,5-triazines Functionalized with Alkylatin 2-chloroethylamine Fragments and Studies of their Cytotoxicity on the Breast Cancer MCF-7 Cell Line.

Anticancer Agents Med Chem 2016 ;16(11):1435-1444

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

Dual action alkyl(aryl)amino-1,3,5-triazines functionalized with nitrogen mustards were obtained by treating 2-alkyl(aryl) amino-4-chloro-6-methoxy-1,3,5-triazines with amines or amino acid methyl esters, followed by reactions with 1,4-diazabicyclo[2.2.2]octane (DABCO) and rearrangement with an opening diazabicyclic fragment, leading to the formation of 2-chloroethylamino moiety. In vitro antitumor activity was tested in the standard human breast cancer MCF-7 and MDA-MB-231cell lines using flow cytometry, based on the detection of apoptosis through qualitative analysis of morphological changes, DNA fragmentation, DNA loss and membrane changes. For all the compounds studied, induced apoptosis was substantially stronger than necrosis at concentrations of both 5 μM and 50 μM, and in some cases there was no increase in necrotic cell death for the estrogen dependent MCF-7 cell line. The most active compounds were derivatives of triazine substituted with phenylamine (IC50 = 12.30 μM) and/or p-tolylamine fragments (IC50 = 7.40 μM).
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http://dx.doi.org/10.2174/1871520616666160204111430DOI Listing
June 2017

Semi-automatic synthesis, antiproliferative activity and DNA-binding properties of new netropsin and bis-netropsin analogues.

Molecules 2014 Jul 31;19(8):11300-15. Epub 2014 Jul 31.

Department of Organic Chemistry, Medical University, Mickiewicza 2A Str., 15-222 Białystok, Poland.

A general route for the semi-automatic synthesis of some new potential minor groove binders was established. Six four-numbered sub-libraries of new netropsin and bis-netropsin analogues have been synthesized using a Syncore Reactor. The structures of the all new substances prepared in this investigation were fully characterized by NMR ((1)H, (13)C), HPLC and LC-MS. The antiproliferative activity of the obtained compounds was tested on MCF-7 breast cancer cells. The ethidium displacement assay using pBR322 confirmed the DNA-binding properties of the new analogues of netropsin and bis-netropsin.
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http://dx.doi.org/10.3390/molecules190811300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271738PMC
July 2014

Effect of short peptides containing lysine and epsilon-aminocaproic acid on fibrinolytic activity of plasmin and topoisomerase II action on supercoiled DNA.

Acta Pol Pharm 2013 May-Jun;70(3):431-4

Department of Organic Chemistry, Medical University of Białystok, Kiliński St. 1, 15-089 Białystok, Poland.

Effects of eight short peptides containing lysine and epsilon-aminocaproic acid (EACA) on prolongation of the clot lysis time, as well as hemolytic and antibacterial activities were investigated. Interaction with plasmids pBR322 and pUC19 with the use of ethidium bromide assay and determination of influence on the activity of topoisomerase I and II were also tested. Examined compounds inhibited fibrinolytic activity of plasmin and five of them were more active than EACA. Amides of dipeptides were most active antifibrinolytics (IC50 < 0.2 mM). According to the obtained data, the significant inhibition of fibrinolytic activity of plasmin was not associated with hemolytic effects. Examined compounds did not show antibacterial activity (MIC > 512 mg/L). DNA binding effects determined with the use of ethidium bromide were weak for all peptides and similar to those observed with EACA. Six compounds inhibited topoisomerase II action on supercoiled DNA.
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August 2013

Amino and chlorambucil analogues of pentamidine--synthesis and biological examinations.

Acta Pol Pharm 2012 Jan-Feb;69(1):63-73

Department of Organic Chemistry, Medical University, Mickiewicza 2A, 15-222 Białystok, Poland.

The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic effect on MCF-7 human breast cancer cell line (IC50 = 22 - 95 +/- 2 pM), mainly by the induction of apoptosis. The topoisomerase I/II inhibition assay and the ethidium displacement assay with the use of pBR322 plasmid DNA were used to the study of mechanism by which the obtained compounds could act. All the compounds are able to bind with DNA and interfere in vitro with the activity of topoisomerase (I and II). The determination of association constants with the use of calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 showed that the tested compounds bind within minor groove of B-DNA, but not selectively. The alkylating activity of chlorambucil derivatives determined in vitro using a Preussmann test was similar to the activity of chlorambucil. The influence of all the compounds on the amidolytic activity of plasmin and trypsin was also examined. The plasmin activity was inhibited by pentamidine, chlorambucil and aromatic bis-amines (IC50 = 0.1 - 8 mM), whereas the trypsin activity was influenced only by pentamidine.
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May 2012

Synthesis and cytotoxicity studies of bifunctional hybrids of nitrogen mustards with potential enzymes inhibitors based on melamine framework.

J Enzyme Inhib Med Chem 2012 Oct 8;27(5):619-27. Epub 2011 Sep 8.

Institute of Organic Chemistry, Technical University of Lodz, Poland.

The new class of hybrid anticancer drugs were obtained by selective functionalization of the triazine scaffold. These were prepared by rearrangement of mono-, bis- and/or tris-(1,3,5-triazin-2-yl)-1,4-diazabicyclo[2.2.2]octanium chlorides leading to formation of 2-chloroethylamino fragments attached to 1,3,5-triazine via one, two or three piperazine rings respectively. Their inhibitory effect was found strongly dependent on the structure of substituents in triazine ring. The anti-proliferative activity of the hybrids evaluated in vitro by using mammalian tumour cells estimated as IC(50) was in the range 0.62-139,78 µM. Both cytotoxicity and alkylating activity depended on the substituents of triazine ring, however, also the mono-functional analogues of nitrogen mustards, which are unable to form liaisons between two DNA strands, induced apoptosis and necrosis in the tested cells.
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http://dx.doi.org/10.3109/14756366.2011.604482DOI Listing
October 2012

New solid phase synthesis of distamycin analogues.

Molecules 2011 Apr 11;16(4):3066-76. Epub 2011 Apr 11.

Department of Organic Chemistry, Medical University, Mickiewicza 2A Str., 15-222 Białystok, Poland.

A novel and straightforward solid phase synthesis of distamycin analogues containing benzene units has been developed.
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http://dx.doi.org/10.3390/molecules16043066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260608PMC
April 2011

Carbocyclic potential DNA minor groove binders and their biological evaluation.

J Enzyme Inhib Med Chem 2010 Oct;25(5):629-34

Department of Organic Chemistry, Medical University, Białystok, Poland.

The biological evaluation of carbocyclic minor groove binders 1-6 is described. The cytotoxicity of the obtained compounds was tested on MDA-MB-231 breast cancer cells. The mechanism of action of compounds 1-6 was studied employing the topoisomerase I/II inhibition assay and ethidium displacement assay using pBR322. Determination of association constants was done using calf thymus DNA, T4 coliphage DNA, poly(dA-dT)(2), and poly(dG-dC)(2). The effect of compounds 1-6 on the amidolytic activity of plasmin, trypsin, thrombin, and urokinase was also examined.
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http://dx.doi.org/10.3109/14756360903389872DOI Listing
October 2010

Analogues of distamycin--synthesis and biological evaluation of new aromatic oligopeptides, potential anticancer agents.

Acta Pol Pharm 2009 Nov-Dec;66(6):633-8

Department of Organic Chemistry, Medical University, 2A Mickiewicza, 15-222 Białystok, Poland.

Six new aromatic oligopeptides were synthesized and evaluated for their activity in the standard cell line of the mammalian tumor MCF-7 as well as in a cell-free system employing the topoisomerase I/II inhibition assay.
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January 2010

Synthesis and biological evaluation of distamycin analogues - new potential anticancer agents.

Arch Pharm (Weinheim) 2009 Feb;342(2):87-93

Department of Haematological Diagnostics, Medical University, Białystok, Poland.

Eight of analogues of distamycin, potential minor-groove binders, were synthesized and tested for in-vitro cytotoxicity towards human breast cancer cells MCF-7 and MDA-MB-231. The method of synthesis is simple and convenient. All of the compounds 1-8 showed antiproliferative and cytotoxic effects against both cell lines in the range 3.47 to 12.53 microM for MDA-MB-231 and 4.35 to 12.66 microM for MCF-7. All compounds demonstrated activity against DNA topoisomerases I and II at a concentration of 50 microM. The ethidium bromide assay showed that these compounds bind to plasmid pBR322, yet weaker than distamycin. Further investigations concerning the mechanism of cytotoxicity are now in progress, but the IC(50) values suggest that synthetic distamycin analogues with a free amino group, 3-4 and 7-8, can serve as potential carriers of strong acting elements, e. g. alkylating groups.
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http://dx.doi.org/10.1002/ardp.200800122DOI Listing
February 2009

The new analogues of nitrogen mustard with one, two or three 2-chloroethylamino fragments. Reactions with nucleophiles.

Acta Pol Pharm 2008 Nov-Dec;65(6):709-14

Institute of Organic Chemistry, Technical University of Łódź, 116 Zeromskiego St., 90-924 Łódź, Poland.

1,3,5-Triazines substituted with mono-, di, and tri-[4-(2-chloroethyl)piperazin-l-yl] groups gave products of substitution of chlorine atom when treated with ethanol, phenol, butylamine, toluidine,or thiophenol under mild reaction conditions.
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March 2009

Carbocyclic analogues of lexitropsin--DNA affinity and endonuclease inhibition.

Acta Pol Pharm 2007 Mar-Apr;64(2):115-9

Department of Organic Chemistry, Medical University of Białystok, A. Mickiewicza 2a Str. 15-222 Białystok, Poland.

A DNA-binding affinity and the effect on restriction enzymes activity of seven carbocyclic mono- and bis-lexitropsins and two analogues of pentamidine with unsubstituted N-terminal amine group were investigated. DNA association constants (Kapp) show that DNA affinity of mono-compounds is much weaker than netropsin and distamycin. Bis-analogues of netropsin bind DNA more strongly than mono-ligands, but without sequence-selectivity. Only pentamidine derivatives reveal preference to AT-rich sequence. The studied compounds can inhibit catalytical action of endonucleases recognizing sequence of four AT base pairs following one another.
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October 2007