Unforeseen Possibilities To Investigate the Regulation of Polyamine Metabolism Revealed by Novel C-Methylated Spermine Derivatives.

The biogenic polyamines, spermine (Spm) and spermidine, are organic polycations present in millimolar concentrations in all eukaryotic cells participating in the regulation of vital cellular functions including proliferation and differentiation. The design and biochemical evaluation of polyamine analogues are cornerstones of polyamine research. Here we synthesized and studied novel C-methylated Spm analogues: 2,11-dimethylspermine (2,11-Me2Spm), 3,10-dimethylspermine (3,10-Me2Spm), 2-methylspermine, and 2,2-dimethylspermine. The tested analogues overcame growth arrest induced by a 72 h treatment with α-difluoromethylornithine, an ornithine decarboxylase (ODC) inhibitor, and entered into DU145 cells via the polyamine transporter. 3,10-Me2Spm was a poor substrate of spermine oxidase and spermidine/spermine-N1-acetyltransferase (SSAT) when compared with 2,11-Me2Spm, thus resembling 1,12-dimethylspermine, which lacks the substrate properties required for the SSAT reaction. The antizyme (OAZ1)-mediated downregulation of ODC and inhibition of polyamine transport are crucial in the maintenance of polyamine homeostasis. Interestingly, 3,10-Me2Spm was found to be the first Spm analogue that did not induce OAZ1 and, consequently, was a weak downregulator of ODC activity in DU145 cells.

Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A.

Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC50 values vary from 0.077 µM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC50 50-100 µM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy.

Effect of Photodynamic Antibacterial Chemotherapy Combined with Antibiotics on Gram-Positive and Gram-Negative Bacteria.

The well-known and rapidly growing phenomenon of bacterial resistance to antibiotics is caused by uncontrolled, excessive and inappropriate use of antibiotics. One of alternatives to antibiotics is Photodynamic Antibacterial Chemotherapy (PACT). In the present study, the effect of PACT using a photosensitizer Rose Bengal alone and in combination with antibiotics including methicillin and derivatives of sulfanilamide synthesized by us was tested against antibiotic-sensitive and antibiotic-resistant clinical isolates of Gram-positive S. aureus and Gram-negative P. aeruginosa. Antibiotic-sensitive and resistant strains of P. aeruginosa were eradicated by Rose Bengal under illumination and by sulfanilamide but were not inhibited by new sulfanilamide derivatives. No increase in sensitivity of P. aeruginosa cells to sulfanilamide was observed upon a combination of Rose Bengal and sulfanilamide under illumination. All tested S. aureus strains (MSSA and MRSA) were effectively inhibited by PACT. When treated with sub-MIC concentrations of Rose Bengal under illumination, the minimum inhibitory concentrations (MIC) of methicillin decreased significantly for MSSA and MRSA strains. In some cases, antibiotic sensitivity of resistant strains can be restored by combining antibiotics with PACT.

UR-144 in products sold via the Internet: identification of related compounds and characterization of pyrolysis products.

The synthetic cannabinoid, UR-144 ((1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone), was identified in commercial 'legal high' products (herbal, resin, and powder). Along with this, six related compounds were detected. The most abundant one (2.1) was identified as 4-hydroxy-3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pentan-1-one, a product of the electrophilic addition of water to the cyclopropane moiety in UR-144. Compound 2.1 was found to be undergo cyclisation which leads to the formation of two additional interconvertable compounds (2.3, tentatively identified as 1-pentyl-3-(4,4,5,5-tetramethyl-4,5-dihydrofuran-2-yl)-1H-indole which is stable only in absence of water and also observed as GC artifact) and 2.2, a protonated derivative of 2.3 which is formed in acidic solutions. The remaining compounds were identified as possible degradation products of the group 2 compounds (4,4,5,5-tetramethyldihydrofuran-2(3H)-one and 1-pentylindoline-2,3-dione) and intermediates or by-products from the synthesis of UR-144 ((1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone, 1-pentyl-1H-indole and 1-(1-pentyl-1H-indol-3-yl)hexan-1-one). Pyrolysis of herbal products containing the group 2 compounds or UR-144 resulted in the formation of 3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pent-4-en-1-one (3). This was confirmed by separate pyrolysis of 2.1 and UR-144. Also, the two additional minor compounds, 1-(1-pentyl-1H-indol-3-yl)ethanone and 1-(1-pentyl-1H-indol-3-yl)propan-1-one, were detected. Pathways for these transformations are presented.