Optimization of the photodynamic inactivation of prions by a phthalocyanine photosensitizer: The crucial involvement of singlet oxygen.

Prion disorders are fatal neurodegenerative diseases caused by the autocatalytic conversion of a natively occurring prion protein (PrPC ) into its misfolded infectious form (PrPTSE ). The proven resistance of PrPTSE to common disinfection procedures increases the risk of prion transmission in medical settings. Herein, we present the effective photodynamic inactivation (PDI) of prions by disulfonated hydroxyaluminum phthalocyanine (AlPcOH(SO3 )2 ) utilizing two custom-built red light sources. The treatment eliminates PrPTSE signal in infectious mouse brain homogenate with efficiency that depends on light intensity but has a low effect on the overall protein content. Importantly, singlet oxygen (O2 (1 Δg )) is the only species significantly photogenerated by AlPcOH(SO3 )2 , and it is responsible for the PDI of prions. More intensive light conditions show not only higher O2 (1 Δg ) production but also decreases in AlPcOH(SO3 )2 photostability. Our findings suggest that PDI by AlPcOH(SO3 )2 -generated O2 (1 Δg ) represents a promising approach for prion inactivation that may be useful in future decontamination strategies for delicate medical tools.

Synthesis and biological activity of 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin.

The trisubstituted purine myoseverin has been recently identified as a novel inhibitor of microtubule assembly. To analyze the effects of modifying its heterocyclic skeleton, we prepared 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin and compared their biological activities. Rearrangement of nitrogen atoms in the heterocycle changes the affinity of the compounds to purified tubulin, as demonstrated by the results of polymerization assays, and affects the proliferation of cancer cell lines. Surprisingly, compound E2GG, a pyrazolo[4,3-d]pyrimidine analogue of myoseverin, displayed inhibitory activity towards both tubulin polymerization and the activity of cyclin-dependent kinases 1, 2 and 7. Such a dual specificity-inhibitor offers a starting point for developing a novel class of antiproliferative agents.

Pyrazolo[4,3-d]pyrimidines as new generation of cyclin-dependent kinase inhibitors.

A search among analogues of anti-CDK purines led to the identification of substituted pyrazolo[4,3-d]pyrimidines as novel inhibitors of CDK1/cyclin B. Some of these derivatives also show antiproliferative activity on cancer cell line K-562, thus may find an application as anticancer agents.

2,6,8,9-tetrasubstituted purines as new CDK1 inhibitors.

Purine inhibitors of cyclin-dependent kinases attract attention as potential anticancer drugs because their first representative roscovitine recently entered clinical trials. Although well described in terms of structure-activity relationships, we still present here a novel modification of the purine scaffold influencing their inhibitory properties. The introduced C-8 substituents, however, lowered the CDK inhibitory activity of roscovitine, whereas the antiproliferative potential of several derivatives remained high.