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Zygmunt Kazimierczuk

Bio: Zygmunt Kazimierczuk is an academic researcher from Warsaw University of Life Sciences. The author has contributed to research in topics: Glycosylation & Benzimidazole. The author has an hindex of 27, co-authored 130 publications receiving 3114 citations. Previous affiliations of Zygmunt Kazimierczuk include Polish Academy of Sciences & University of Osnabrück.


Papers
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Journal ArticleDOI
TL;DR: DMAT and its parent compound TBI are potent inhibitors of several other kinases, with special reference to PIM (provirus integration site for Moloney murine leukaemia virus), and TBB is significantly more selective toward CK2, although it also inhibits PIM1 and PIM3.
Abstract: CK2 (casein kinase 2) is a very pleiotropic serine/threonine protein kinase whose abnormally high constitutive activity has often been correlated to pathological conditions with special reference to neoplasia. The two most widely used cell permeable CK2 inhibitors, TBB (4,5,6,7-tetrabromo-1H-benzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole), are marketed as quite specific CK2 blockers. In the present study we show, by using a panel of approx. 80 protein kinases, that DMAT and its parent compound TBI (or TBBz; 4,5,6,7-tetrabromo-1H-benzimidazole) are potent inhibitors of several other kinases, with special reference to PIM (provirus integration site for Moloney murine leukaemia virus)1, PIM2, PIM3, PKD1 (protein kinase D1), HIPK2 (homeodomain-interacting protein kinase 2) and DYRK1a (dual-specificity tyrosine-phosphorylated and -regulated kinase 1a). In contrast, TBB is significantly more selective toward CK2, although it also inhibits PIM1 and PIM3. In an attempt to improve selectivity towards CK2 a library of 68 TBB/TBI-related compounds have been tested for their ability to discriminate between CK2, PIM1, HIPK2 and DYRK1a, ending up with seven compounds whose efficacy toward CK2 is markedly higher than that toward the second most inhibited kinase. Two of these, K64 (3,4,5,6,7-pentabromo-1H-indazole) and K66 (1-carboxymethyl-2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole), display an overall selectivity much higher than TBB and DMAT when tested on a panel of 80 kinases and display similar efficacy as inducers of apoptosis.

235 citations

Journal ArticleDOI
TL;DR: A novel compound, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), is described, which is superior to the commonly used specific CK2 inhibitor 4, 5, 6, 7-t Petrabromobenzotriazoles (TBB) in several respects and is the first choice CK2 inhibitors for in vivo studies available to date.

189 citations

Journal ArticleDOI
TL;DR: It is proposed to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies, because 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine.
Abstract: Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signaling pathways affected by this kinase, in perspective, may give rise to pharmacological tools. One of the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we show that its inhibitory properties can be markedly improved by generating adducts in which N(2) is replaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8), isopropylamino (2e), and amino (2a) congeners. All these compounds display K(i) values <100 nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB (DC(50) value 2.7 vs 17 microM) and, unlike TBB, it does not display any side effect on mitochondria polarization up to 10 microM concentration. Molecular modeling of the CK2-2c complex, based on the crystal structure of the CK2-TBB complex suggests that a number of additional apolar contacts between its two methyl groups and hydrophobic residues nearby could account for its superior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies.

188 citations

Journal ArticleDOI
TL;DR: In this paper, the 1D 1 H NOE difference spectra of 50 base and/or sugar-modified nucleosides were measured in (CD 3 ) 2 SO with irradiation of various protons.
Abstract: The 1D 1 H NOE difference spectra of 50 base- and/or sugar-modified nucleosides were measured in (CD 3 ) 2 SO with irradiation of various protons. The resulting NOE data were used for a conformational analysis with respect to their syn-anti conformer equilibrium. Measurement of the NOE spectra of sterically hindered nucleosides implied that both the chemical properties as well as the van der Waals radius of nucleobase substituent are of decisive importance for the conformation around the N-glycosylic bond

146 citations


Cited by
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Journal ArticleDOI
TL;DR: The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.
Abstract: The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.

2,582 citations

01 Dec 2007

1,121 citations

Patent
24 Nov 1992
TL;DR: In this article, novel oligomers are disclosed which have enhanced ability with respect to forming duplexes or triplexes compared with oligomers containing only conventional bases, which can be incorporated into pharmaceutically acceptable carriers and can be constructed to have any desired sequence.
Abstract: Novel oligomers are disclosed which have enhanced ability with respect to forming duplexes or triplexes compared with oligomers containing only conventional bases. The oligomers contain the bases 5-(1-propynyl)uracil, 5-(1-propynyl)cytosine or related analogs. The oligomers of the invention are capable of (i) forming triplexes with various target sequences such as virus or oncogene sequences by coupling into the major groove of a target DNA duplex at physiological pH or (ii) forming duplexes by binding to single-stranded DNA or to RNA encoded by target genes. The oligomers of the invention can be incorporated into pharmaceutically acceptable carriers and can be constructed to have any desired sequence, provided the sequence normally includes one or more bases that is replaced with the analogs of the invention. Compositions of the invention can be used as pharmaceutical agents to treat various diseases such as those caused by viruses and can be used for diagnostic purposes in order to detect viruses or disease conditions.

753 citations

Patent
12 Aug 1991
TL;DR: In this paper, the authors proposed a method for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins, such as HIV, herpes virus, papillomavirus and other infections.
Abstract: Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of HIV, herpes virus, papillomavirus and other infections is provided.

708 citations

Journal Article
TL;DR: It’s time to get used to the idea that there is no such thing as a safe place to die.
Abstract: 它是美国国立医学图书馆(NLM)生产的国际性生物医学文献联机书目数据库,是美国国立医学图书馆MEDLARS系统30多个数据库中最大的一个数据库,是世界上最著名的生物医学数据库之一。其内容相当于3种印刷本检索刊物:《医学索引》(index medicus,IM)、《牙科文献索引》、《国际护理学索引》,收录了1966年以来的70多个国家4300多种期刊的题录和文摘共1100万条记录,

678 citations