Showing papers by "Zygmunt Kazimierczuk published in 2008"

The selectivity of inhibitors of protein kinase CK2: an update.

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.

Substituted benzimidazoles: antiviral activity and synthesis of nucleosides

Abstract: The antiviral activity of a series of benzimidazole derivatives and substituted benzimidazole β-Land β-D-2’-deoxyribonucleosides against selected RNA and DNA viruses including HIV-1, BVDV, YFV, DENV-2, WNV, HBV, HCV and human RSV was evaluated. In addition, the synthesis of several benzimidazole β-L-2’-deoxyribonucleosides (1-4) and 2’-deoxy-2’-fluoro-βD-arabinofuranosyl nucleoside 5 is described. The stereoselective glycosylation of the anions of the functionalized benzimidazoles 6a, 12a and 28 with 3,5-di-O-(4-methylbenzoyl)-2-deoxy-αL-erythro-pentofuranosyl chloride (29) furnished β-L-2’-deoxyribonucleosides 1-4 while the glycosylation of the anion of 2-bromobenzimidazole (12a) with 3,5-di-O-benzoyl-2-deoxy-2fluoro-α-D-arabinofuranosyl bromide 34 gave the 2’-deoxy-2-fluoro-β-D-arabinofuranosyl nucleoside 5. Moreover, the crystal structure of the benzoylated 2-bromobenzimidazole 2’deoxy-2’-fluoro-β-D-arabinofuranosyl nucleoside 35 is reported.

Synthesis and antimycobacterial activity of selected nitrobenzyloxylated benzotriazoles.

Abstract: A series of 1-nitrobenzyloxybenzotriazoles was prepared by the benzylation of the respective halogenosubstituted 1-hydroxybenzotriazoles. The newly obtained compounds were tested against four Mycobacterium strains. Particularly high antimycobacterial activity, comparable with that of isoniazide, was found for 5,6-dichloro- 1-(3,5-dinitrobenzyloxy)- 1H-benzotriazole.

Hoogsteen vs. Watson—Crick Base Pairing: Incorporation of 2-Substituted Adenine- and 7-Deazaadenine 2′-Deoxy-β-D-ribonucleosides into Oligonucleotides.

Abstract: Various 2-substituted 2'-deoxyadenosines and 7-deazaadenosines have been synthesized. The phosphonate building block 9 of 2-chloro-7-deaza-2'-deoxyadenosine (7-deazacladribine; 2) was prepared by 4,4'-dimethoxytritylation of the parent nucleoside (-->7), followed by protection of the amino function with a formamidine residue (-->8). The latter was reacted with PCl3/N-methylmorpholine/1,2,4-triazole to give compound 9. Moreover, 2-methoxy-2'-deoxyadenosine (2'-deoxyspongosine; 1b) was converted into the fully protected derivative 12, which was then transformed into the 2-cyanoethyl phosphoramidite 14. Also the 2-(trifluoromethyl)-substituted 2'-deoxyadenosines 19-21 were prepared by glycosylation of the chromophore 16 with the halogenose 17, followed by one-pot deprotection and nucleophilic displacement of the 6-Cl substituent. The new DNA building blocks 9 and 14 were used--together with formerly prepared cladribine derivative 4--for solid-phase synthesis of a series of oligodeoxyribonucleotides. These were studied with respect to their thermal stability as well as of the base pairing mode (Watson-Crick vs. Hoogsteen) of modified bases.

UVC induced oxidation of chloropurines: excited singlet and triplet pathways for the photoreaction

Abstract: The phototransformation of 2-chloro, 6-chloro and 2,6-dichloropurines under UVC excitation (254 nm) has been studied and the major photoproducts have been identified using absorption spectroscopy, HPLC and mass spectrometry. It was shown that hydroxypurines were formed as the main products for all three investigated compounds both in the presence and absence of oxygen. In the case of 6-chloro- and 2,6-dichloropurine, a photodimer is also formed as a minor photoproduct in the absence of oxygen but is efficiently quenched in the presence of oxygen. Nanosecond photolysis experiments also revealed significant intersystem crossing to the triplet state of the chloropurines which has been characterized (transient absorption spectra, triplet formation quantum yields and rate constants of quenching by oxygen, Mn2+ ions and ground state). Experimental evidence allows to conclude that the triplet state is involved in photodimer formation whereas the hydroxypurine is formed from the reaction of the excited singlet state of chloropurines with the solvent (water addition) through heterolytic C–Cl bond rupture. Mass spectrometry and 1H NMR results allowed to propose a chemical pathway for dimer formation in the case of 2,6-dichloropurine in a two-step process: first a homolytic rupture of C–Cl bond in the triplet state of the molecule with the formation of purinyl radicals, which subsequently react with an excess of ground state molecules and/or hydroxypurine primarily formed.