Eco-friendly synthesis of new olanzapine derivatives and evaluation of their anticancer potential.

New derivatives of the known antipsychotic drug olanzapine have been obtained as potential compounds with anticancer activity in two metabolically different breast cancer cell lines: MCF-7 and triple negative MDA-MB-231. The compounds were obtained under phase transfer catalysis (PTC) in the presence of microwave irradiation (MW) or ultrasound (")))"), evaluating the effect of solvents such as dimethylformamide, water, or choline chloride/urea (natural deep eutectic solvent, NaDES). In the best option, the compounds were obtained within 2 minutes with a yield of 57-86% in MW. Two of the obtained compounds which have a naphthalimide moiety and a pentyl (7) or hexyl chain (8) show pronounced cytotoxicity. Interestingly, neither olanzapine nor desmethylolanzapine (DOLA), which was one of the substrates for the synthesis reaction, showed any significant activity in the study.

Synthesis of Novel 2-(Cyclopentylamino)thiazol-4(5H)-one Derivatives with Potential Anticancer, Antioxidant, and 11ß-HSD Inhibitory Activities.

In this study, a series of nine new 2-(cyclopentylamino)thiazol-4(5H)-one derivatives were synthesized, and their anticancer, antioxidant, and 11ß-hydroxysteroid dehydrogenase (11ß-HSD) inhibitory activities were tested. Anticancer activity has been assessed using the MTS (MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay against human colon carcinoma (Caco-2), human pancreatic carcinoma (PANC-1), glioma (U-118 MG), human breast carcinoma (MDA-MB-231), and skin melanoma (SK-MEL-30) cancer cell lines. Cell viability reductions, especially in the case of Caco-2, MDA-MB-231, and SK-MEL-30 lines, were observed for most compounds. In addition, the redox status was investigated and oxidative, but nitrosative stress was not noted at a concentration of 500 µM compounds tested. At the same time, a low level of reduced glutathione was observed in all cell lines when treated with compound 3g (5-(4-bromophenyl)-2-(cyclopentylamino)thiazol-4(5H)-one) that most inhibited tumor cell proliferation. However, the most interesting results were obtained in the study of inhibitory activity towards two 11ß-HSD isoforms. Many compounds at a concentration of 10 µM showed significant inhibitory activity against 11ß-HSD1 (11ß-hydroxysteroid dehydrogenase type 1). The compound 3h (2-(cyclopentylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one) showed the strongest 11ß-HSD1 inhibitory effect (IC50 = 0.07 µM) and was more selective than carbenoxolone. Therefore, it was selected as a candidate for further research.

The Val34Met, Thr164Ile and Ser220Cys Polymorphisms of the ß2-Adrenergic Receptor and Their Consequences on the Receptor Conformational Features: A Molecular Dynamics Simulation Study.

The gene encoding the ß2-adrenergic receptor (ß2-AR) is polymorphic, which results in possible differences in a primary structure of this protein. It has been shown that certain types of polymorphisms are correlated with some clinical features of asthma, including airways reactivity, whereas the influence of other is not yet understood. Among polymorphisms affecting amino acids at positions 16, 27, 34, 164 and 220, the latter three are present in the crystal structure of ß2-AR, which facilitates studying them by means of molecular dynamics simulations. The current study was focused on investigating to what extent the three polymorphisms of ß2-AR (i.e., Val34Met, Thr164Ile and Ser220Cys) affect the interaction of ß2-AR with its natural molecular environment which includes: lipid bilayer (in the case of all three polymorphs) and Gs protein (which participates in ß2-AR-mediated signaling; in the case of Ser220Cys). We have designed and carried out a series of molecular dynamics simulations at different level of resolution (i.e., either coarse-grained or atomistic simulations), accompanied by thermodynamic integration protocol, in order to identify potential polymorphism-induced alterations in structural, conformational or energetic features of ß2-AR. The results indicate the lack of significant differences in the case of energies involved in the ß2-AR-lipid bilayer interactions. Some differences have been observed when considering the polymorphism-induced alterations in ß2-AR-Gs protein binding, but their magnitude is also negligible in relation to the absolute free energy difference correlated with the ß2-AR-Gs affinity. The Val34Met and Thr164Ile polymorphisms are weakly correlated with alteration of the conformational features of the receptor around polymorphic sites. On the contrary, it has been concluded that the Ser220Cys polymorphism is correlated with several structural alterations located in the intracellular region of ß2-AR, which can induce G-protein binding and, subsequently, the polymorphism-correlated therapeutic responses. More precisely, these alterations involve vicinity of intracellular loops and, in part, are the direct consequence of disturbed interactions of Ser/Cys220 sidechain within 5th transmembrane domain. Structurally, the dynamic structure exhibited by the ß2-ARSer220 polymorph is closer to the Gs-compatible structure of ß2-AR.

The Antipsychotic D2AAK1 as a Memory Enhancer for Treatment of Mental and Neurodegenerative Diseases.

The treatment of memory impairments associated with the central nervous system diseases remains an unmet medical need with social and economic implications. Here we show, that a multi-target ligand of aminergic G protein-coupled receptors with antipsychotic activity in vivo (D2AAK1) stimulates neuron growth and survival and promotes neuron integrity. We focused on the multilevel evaluation of the D2AAK1-related effects on neurons in terms of behavioral, cellular, molecular, and biochemical features in vivo and in vitro, such as memory-related responses, locomotor activity, tissue sections analysis, metabolic activity, proliferation level, neurons morphology, and proteins level involved in intracellular signaling pathways. In silico studies indicate that activation of calcium/calmodulin-dependent protein kinase I (CaMKI) may underline some of the observed activities of the compound. Furthermore, the compound increases hippocampal neuron proliferation via the activation of neurotrophic factors and cooperating signals responsible for cell growth and proliferation. D2AAK1 improves memory and learning processes in mice after both acute and chronic administration. D2AAK1 also causes an increase in the number of hippocampal pyramidal neurons after chronic administration. Because of its neuroprotective properties and pro-cognitive activity in behavioral studies D2AAK1 has the potential for the treatment of memory disturbances in neurodegenerative and mental diseases.