ATP site-directed inhibitors of protein kinase CK2: an update.

CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of "non oncogene addiction". A wide spectrum of cell permeable, fairly specific ATP site-directed CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their "normal" counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelman's disease and multiple myeloma. The solution of a wide range of 3D structures of inhibitors bound to the catalytic subunits of CK2 reveals that their efficacy substantially relies on hydrophobic interactions within a cavity which is smaller than in other protein kinases. Accordingly the potency of tetra-halogenated benzimidazoles increases upon replacement of chlorine by bromine and, even more, by iodine, and decreases if two unique bulky side chains on CK2 (Val66 and Ile174) are mutated to alanines. Many CK2 inhibitors have been tested on a panel of more than 60 kinases providing Promiscuity Scores useful to evaluate their selectivity, the lowest value (9.47), denoting highest selectivity, being displayed by quinalizarin. The observation that CK2 inhibitors with medium/high promiscuity scores share the ability to inhibit a group of protein kinases as effectively as CK2 discloses the possibility of using their scaffolds for the rational development of selective inhibitors of these kinases, with special reference to PIMs, DYRKs, HIPK2, PKD and ERK8.

Structural study of selected polyhalogenated benzimidazoles (protein kinase CK2 inhibitors) by nuclear quadrupole double resonance, X-ray, and density functional theory.

Protein kinase CK2 inhibitors, polyhalogenated benzimidazoles, have been studied experimentally in solid state by NMR-NQR double resonance and X-ray and theoretically by the density functional theory (DFT). Six resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in each polyhalogenated benzimidazole molecule. The effects of prototropic annular tautomerism and polymorphism related to stable cluster formation due to intermolecular hydrogen bonding interactions on the (14)N NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism. The studies suggest that all polyhalogenobenzimidazoles are isostructural and can exhibit polymorphism and that (14)N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. NQDR and DFT results suggest the presence of the prototropic annular tautomerism 50:50, which is in a good agreement with the X-ray and (1)H NMR data.

Synthesis and anticancer activity of 5'-phthaloylnucleosides.

A series of novel 5'-phthaloylnucleosides were synthesized via Mitsunobu reaction starting from AZT or 2'-deoxyadenosine and numerous phthalimides and their sulphur analogues-thioimides. Some of them showed significant anticancer activity.

Synthesis and antimicrobial activity of new adamantane derivatives I.

A series of fourteen derivatives of adamantane was synthesised. The new compound 4-(adamant-1-ylmethoxycarbonyl)phthalanhydride obtained from 1-adamantane-methanol and trimellitic anhydride chloride appeared very useful for preparation of a number of N-substituted phthalimides. Antimicrobial activity of the newly obtained derivatives such as, for example, 4-(adamant-1-ylmethoxycarbonyl)-N-(5-carboxypentamethylene)p hthalimide or 4-(adamant-1-ylmethoxycarbonyl)-N-(L-alanyl)phthalimide was tested against Staphylococcus aureus, Bacillus sp., Micrococcus flavus and Enterococcus faecium. The minimal inhibitory concentration (MIC) for these compounds against S. aureus were 0.022 and 0.05 microg/ml, respectively.

Synthesis and antimicrobial activity of new adamantane derivatives II.

A series of new derivatives of adamantane was synthesised. The new compound 4-(adamant-1-ylethylenoxycarbonyl)phthalanhydride obtained from 1-adamantaneethanol and trimellitic anhydride chloride, as well as 4-(adamant-1-ylmethylenoxycarbonyl)phthalanhydride, appeared very useful for preparation of a number of N-substituted phthalimides. Antimicrobial activity of newly obtained derivatives such as, for example, 4-(adamant-1-ylethylenoxycarbonyl)-N-(L-phenylalanyl)phthalimide or 4-(adamant-1-ylmethylenoxycarbonyl)-N-(L-leucyl)-phthalimide was tested against Staphylococcus aureus, Bacillus sp., Micrococcus flavus and Enterococcus faecium. The minimal inhibitory concentrations for these compounds against Bacillus cereus were 15 and 8 microg/ml, respectively.

Antimicrobial activity of organic thiosulfates (Bunte salts).

A number of organic thiosulfates (Bunte salts) were prepared from appropriate primary bromides or iodides. In the case of substrates with long aliphatic chains, an addition of benzyltrimethylammonium chloride as phase transfer catalyst was very successful. The Bunte salts obtained were tested for antibacterial and fungicidal activity by means of the agar disc-diffusion method and by assignation of the minimum inhibitory concentrations (MIC). It was found that the microorganisms Proteus vulgaris, Candida albicans and Staphylococcus aureus showed the highest sensitivity. Biological activity of the compounds studied was dependent on the length of the aliphatic chain. Among the investigated compounds, aliphatic thiosulfates with 10-13 carbon atom chain were the most potent.