Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed.

Pincer complexes featuring readily tunable tridentate ligand frameworks comprise one of the most actively studied classes of organometallic and metalorganic compounds and find extensive use in catalysis, organic synthesis, materials science, and other fields of chemistry and allied disciplines. Currently growing attention is devoted to non-classical ligand scaffolds, such as functionalized carboxamides, which offer multiple options for directed structural modifications. In this study, the reactions of (methylsulfanyl)acetyl and propanoyl chlorides with 2-(aminomethyl)pyridine, 2-(2-aminoethyl)pyridine, 8aminoquinoline and 2-(diphenylthiophosphoryl)aniline afford a series of new pincer-type ligands based on functionalized carboxamides. The ligands obtained readily undergo direct cyclopalladation under the action of PdCl 2 (NCPh) 2 in dichloromethane at room temperature, resulting in Pd(II) pincer complexes with N,N,S-and S,N,S-donor sets. Importantly, some of the cyclopalladated derivatives can also be produced efficiently under solvent-free conditions according to the approach recently developed by our group. The complexes obtained have been tested for cytotoxicity against several human cancer cell lines and catalytic activity in the model Suzuki reaction. The results have been compared to those for the related Pd(II) pincer complexes to define the main structure-activity relationships and to outline the most promising structures for further investigations. Yield: 87 mg (95%). M.p. > 225°C (dec.). 1 H NMR (400.13 MHz, CDCl 3 , δ, ppm): 2.73 (ddd, 1H, CH 2 , 2 J HH = 1.9 Hz, 3 J HH = 16.8 Hz, 3 J HH = 7.3 Hz), 3.15 (ddd, 1H, CH 2 S(O), 2 J HH = 2.2 Hz, 3 J HH = 16.8 Hz, 3 J HH = 11.4 Hz), 3.36 (ddd, 1H, CH 2 , 2 J HH = 1.9 Hz, 3 J HH = 13.0 Hz, 3 J HH = 11.4 Hz), 3.47 (ddd, 1H, CH 2 S(O), 2 J HH = 2.2 Hz, 3 J HH = 13.0 Hz, 3 J HH = 7.3 Hz), 3.51 (s, 3H, Me), 5.03 and 5.22 (ABq, 2H, CH 2 Py, J AB = 20.3 Hz), 7.35-7.39 (m, 1H, H(C4)), 7.48 (d, 1H, H(C2), 3 J HH = 7.9 Hz), 7.91 (dt, 1H, H(C3), 3 J HH = 7.9 Hz, 4 J HH = 1.6 Hz), 9.05 (d, 1H, H(C5), 3 J HH = 5.4 Hz).13

Protoporphyrin IX (PpIX) is widely used in photodynamic diagnosis. To date, the details of molecular mechanisms underlying PpIX accumulation in malignant cells after 5-ALA administration remain unclear. The fluorescence of PpIX was studied in human glioma cells. Several cell cultures were established from glioma tumor tissue to study the differences between fluorescence-positive and fluorescence-negative human glioma tumors. The cell cultures demonstrated fluorescence profiles similar to those of source tumor tissues, which allows us to use these cultures in experimental research. Dynamics of the rates of synthesis and degradation of fluorescent protoporphyrin IX was studied in the cultures obtained. In addition, the expression of CPOX, an enzyme involved in PpIX synthesis, was evaluated. mRNA levels of heme biosynthesis enzymes were analyzed, and PpIX fluorescence proved to correlate with the CPOX protein level, whereas no such correlation was observed at the mRNA level. Fluorescence intensity decreased at low levels of the enzyme, which indicates its critical role in PpIX fluorescence. Finally, the fluorescence intensity proved to correlate with the proliferative activity.

The reactions of picolinyl and 4-chloropicolinyl chlorides with methyl esters of S-methyl-l-cysteine, l- and d-methionine, and l-histidine afforded a series of functionalized carboxamides, which readily formed pincer-type complexes upon interaction with PdCl(NCPh) in solution under mild conditions. The direct cyclopalladation of the ligands derived was also accomplished in the solid phase, in particular, mechanochemically, although it was complicated by the partial deactivation of the starting amides. The resulting complexes with 5,5- and 5,6-membered fused metallocycles were fully characterized by IR and NMR spectroscopy, including variable-temperature and 2D-NMR studies. In the case of some cysteine- and methionine-based derivatives, the realization of κ-N,N,S-coordination was supported by X-ray diffraction. The cytotoxic effects of these complexes were examined on HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 as a representative of normal cells. The comparative studies allowed us to determine that the presence of the sulfide ancillary donor group is crucial for cytotoxic activity of this type of Pd(II) complexes. The main structure-activity relationships and the most promising palladocycles were outlined. The additional studies by gel electrophoresis revealed that 4-chloropicolinyl derivatives, despite the nature of an amino acid, can bind with DNA and inhibit topoisomerase I activity.