Synthesis, molecular modelling, and antiproliferative and cytotoxic effects of carbocyclic derivatives of distamycin with chlorambucil moiety

Bartulewicz, Danuta; Bielawski, Krzysztof; Bielawska, Anna; Różański, Andrzej

doi:10.1016/s0223-5234(01)01232-6

Cited by 22 publications

(11 citation statements)

References 13 publications

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“…191 The carbocyclic analog of MEN-10710, in which the pyrroles were substituted with phenyl rings, showed very low antiproliferative activity (90-100 mM) against MCF-7 mammal tumor cells, with an increased affinity toward GC sequences. 192 In a study on chemical and biological activities of alkylating agents, Bardos 193 has shown that in aromatic mustards, the reactivity is largely controlled by the leaving group ability of the halogen and that the replacement of chlorine with bromine greatly increased the antitumor activity in vivo (Walker carcinosarcoma 256) with an ED90 for the p[N,N-bis (2-bromoethyl) amino] benzoic acid approximately eightfold higher than that of the corresponding chloro derivative.…”

Section: B Benzoic Acid Mustard Distamycin Derivativesmentioning

confidence: 99%

DNA minor groove binders as potential antitumor and antimicrobial agents

Baraldi

Bovero

Fruttarolo

et al. 2004

Medicinal Research Reviews

364

222

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DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1-c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames.

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Section: B Benzoic Acid Mustard Distamycin Derivativesmentioning

confidence: 99%

DNA minor groove binders as potential antitumor and antimicrobial agents

Baraldi

Bovero

Fruttarolo

et al. 2004

Medicinal Research Reviews

364

222

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“…The therapeutic utility of the alkylating agents would be greatly enhanced if they could be more precisely targeted to defined genomic sites.Recent work on the targeting of nitrogen mustard alkylating agents to DNA by the use of DNA minor groove-binding ligands has shown that this strategy can greatly enhance both, the in vitro cytotoxicity and the in vivo antitumor activity of the mustard moiety, when compared with untargeted mustards of similar reactivity [3][4][5][6]. Such targeting can also significantly alter the pattern of DNA alkylation by the mustard [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Structure‐Activity Studies of Novel Amidine Analogues of Chlorambucil: Correlation of Cytotoxic Activity with DNA‐Binding Affinity and Topoisomerase II Inhibition

Bielawska

Bielawski

Wołczyński

et al. 2003

Archiv der Pharmazie

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A series of amidine analogues of chlorambucil (9-12), where 5-[4-(N-alkylamidino)phenyl]-2-furancarboxamide and the chlorambucil moiety are linked by a NH(CH(2))(2)NH chain, was synthesized and their cytotoxicity has been tested against the growth of human breast cancer MCF-7 cells. Evaluation of the cytotoxicity of compounds 9-12 employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA demonstrated that these conjugates were more active than chlorambucil. Data from the ethidium displacement assay indicated that these compounds bind in the minor groove of DNA and show moderate specificity for AT base pairs. Compounds 9-12 were potent topoisomerase II inhibitors, with 50% inhibitory concentrations (IC(50))ranging from 10 to 40 microM. The cytotoxicity of the compounds 9-12 correlates with their DNA-binding affinities and their relative potency as topoisomerase II inhibitors. Altogether, these data suggest (i) that the cytotoxic activity of compounds 9-12 may be due to the combined effects of alkylation, DNA-minor groove binding, and (ii) that N-(2-aminoethyl)-5-(4-N-alkylamidinophenyl)-2-furancarboxamides (5-8) ligands are suitable linkers that favors DNA targeting by chlorambucil derivatives.

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“…Recent work on the targeting of antitumor agents to DNA by the use of DNA minor groove-binding ligands has shown that this strategy can greatly enhance both the in vitro cytotoxicity and the in vivo antitumor activity of the alkylating moiety, when compared with untargeted compounds of similar reactivity [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Novel dinuclear platinum(II) complexes targets NFkappaB signaling pathway to induce apoptosis and inhibit metabolism of MCF-7 breast cancer cells.

Popławska

Bielawska²,

Surażyński³

et al. 2010

Folia Histochem Cytobiol.

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Four novel dinuclear platinum(II) complexes of formula [Pt 2 L 4 (berenil) 2 ]Cl 4 (Pt1-Pt4) where L is piperazine (Pt1), 4-picoline (Pt2), 3-picoline (Pt3) or isopropylamine (Pt4) were compared to cisplatin in respect to collagen biosynthesis, β 1 -integrin receptor, IGF-I receptor, phosphorylated MAP-kinases (ERK 1 /ERK 2 and p38), phosphorylated Akt kinase expression and appearance of apoptosis in MCF-7 breast cancer cells. It was found that Pt1-Pt4 were more active inhibitor of collagen biosynthesis than cisplatin. The expression of IGF-I and β 1 integrin receptor, as well as phosphorylated MAPK, (ERK 1 and ERK 2 and p38) was significantly increased in cells incubated for 24 h with 20 μM Pt1-Pt4 compared to the control, not treated cells. The phenomenon was related to the increase expresion of NFκB by Pt1-Pt4 as shown by Western immunoblot analysis. Experiments made with annexin V-FITC and detection of apoptosis by a fluorescent microscopy assay revealed that novel dinuclear platinum(II) complexes (Pt1-Pt4) inhibited the proliferation of MCF-7 breast cancer cells by increasing the number of apoptotic and necrotic cells.

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Synthesis, molecular modelling, and antiproliferative and cytotoxic effects of carbocyclic derivatives of distamycin with chlorambucil moiety

Cited by 22 publications

References 13 publications

DNA minor groove binders as potential antitumor and antimicrobial agents

DNA minor groove binders as potential antitumor and antimicrobial agents

Structure‐Activity Studies of Novel Amidine Analogues of Chlorambucil: Correlation of Cytotoxic Activity with DNA‐Binding Affinity and Topoisomerase II Inhibition

Novel dinuclear platinum(II) complexes targets NFkappaB signaling pathway to induce apoptosis and inhibit metabolism of MCF-7 breast cancer cells.

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