Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. D 9 -Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagymediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas.

Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.

Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecule as weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria.

Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)maleimides and bis(indol-1-yl)maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-1-yl)maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.

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Intramolecular cyclization reactions of 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2, and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids were studied in order to estimate the parameters of the interaction between protonated and unprotonated indole moieties. Geometric parameters, charge distributions, energy characteris tics, and information concerning the frontier orbitals of bisindolylmaleimides 1-3 were ob tained from density functional B3LYP/6 31G(d) quantum chemical calculations. Alternative pathways of protonation of bisindolylmaleimides with differently bonded indole and maleimide moieties were studied and pathways of cyclization of corresponding conjugated acids leading to polyannelated compounds were analyzed. All the key intermediates of the cyclization reactions correspond to stationary points on the potential energy surfaces (minima and transition states). Analysis of the potential energy surfaces revealed almost linear dependences of the activation energies of the cyclization reactions under study on the distances between the reaction centers, on the angle of approach of intramolecular electrophile, and on the energy gap (energy differ ence between frontier orbitals). The key role in the cyclization reactions is played by structural similarity between the starting indoleninium cations and the activated complexes of the reac tions under study.Research on the chemical properties and reactivity of 3,4 bisindolylmaleimides is of interest in connection with the fact that some compounds of this series and related indolo[2,3]carbazoles possess valuable biological proper ties. 1,2 Earlier, 3,4 it was shown that intramolecular cy clizations of 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2, and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids proceed differently and result in different types of compounds. 3,4 Bis(indol 3 yl)maleimides 1 under acid catalysis con ditions and after dehydrogenation form indolo[2,3]carb azole derivatives 4 (Scheme 1). In the absence of oxidant (DDQ) intermediate 5 undergoes isomerization into aminophenylcarbazole 6 (see Scheme 1). Possible mecha nisms of the cyclization and isomerization of system 1 are shown in Scheme 2.Unlike 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2 and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids undergo 2-4´ or 2-7´ cyclization to give 8b,9 dihydroin dolo [4´,3´:3,4,5]pyrrolo[3´,4´:6,7][1,4]azepino[1,2 a]in dol 1,3(2H,5H ) diones 7 or 9b,10 dihydroindo lo[1´,7´:4,5,6]pyrrolo[3´,4´:2,3][1,4]diazepino[1,7 a]in dol 1,3 diones 8, respectively (Scheme 3). Compounds 7 and 8 under the action of DDQ in toluene were converted to indolo[4´,3´:3,4,5]pyrrolo[3´,4´:6,7]azepino[1,2 a]in dol 1,3(2H,5H ) diones 9 and 1H indolo[1´,7´:4,5,6]pyr rolo[3´,4´:2,3][1,4]diazepino[1,7 a]indol 1,3(2H ) diones 10, respectively. Possible cyclization mecha nisms 3,4 are shown in Scheme 3.Since the cyclization reactions of differently fused bisind...

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